Greenfields Surgery Scientific Principles 6th Edition

ERRNVPHGLFRVRUJ Greenfield’s
SURGERY Scientific Principles & Practice
SIXTH EDITION
EDITORS
Michael W. Mulholland, MD, PhD

Frederick A. Coller Distinguished Professor of Surgery
Chair, Department of Surgery
University of Michigan
Ann Arbor, Michigan
Keith D. Lillemoe, MD
Surgeon-in-Chief
Chief, Department of Surgery
Massachusetts General Hospital
The W. Gerald Austen Professor
Harvard Medical School
Boston, Massachusetts
Gerard M. Doherty, MD
Surgeon-in-Chief
Brigham and Women’s Health Care & Dana-Farber Cancer Institute
Moseley Professor of Surgery
Gilbert R. Upchurch, Jr., MD

Chief of Vascular and Endovascular Surgery
William H. Muller, Jr. Professor of Surgery
Professor of Molecular Physiology and Biological Physics
University of Virginia
Charlottesville, Virginia
Hasan B. Alam, MD
Norman W. Thompson Professor of Surgery
Head of General Surgery
Department of Surgery
Ann Arbor, Michigan
Timothy M. Pawlik, MD, MPH, PhD

Professor of Surgery and Oncology
2
The Urban Meyer III and Shelley Meyer Chair for Cancer Research
The Ohio State University Wexner Medical Center
Columbus, Ohio
Illustrations by Holly R. Fischer, MFA
3
Acquisitions Editor: Keith Donnellan
Product Development Editor: Brendan Huffman
Production Project Manager: Bridgett Dougherty
Design Coordinator: Elaine Kasmer
Senior Manufacturing Coordinator: Beth Welsh
Marketing Manager: Dan Dressler
Prepress Vendor: Aptara, Inc.
Sixth Edition
Copyright © 2017 Wolters Kluwer
Fifth Edition © 2011 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business
Fourth Edition © 2006 by LIPPINCOTT WILLIAMS & WILKINS
Third Edition © 2001 by LIPPINCOTT WILLIAMS & WILKINS
All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by
any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval
system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews.
Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not
covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001
Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via our website at lww.com (products and services).
987654321
Printed in China
Library of Congress Cataloging-in-Publication Data
Names: Mulholland, Michael W., editor.

Title: Greenfield’s surgery : scientific principles and practice / editors,
Michael W. Mulholland, Keith D. Lillemoe, Gerard Doherty, Gilbert R.
Upchurch, Jr., Hasan B. Alam, Timothy M. Pawlik ; illustrations by Holly
R. Fischer.
Other titles: Surgery : scientific principles and practice
Description: Sixth edition. | Philadelphia : Wolters Kluwer, [2017] |
Includes bibliographical references and index.
Identifiers: LCCN 2016038680 | ISBN 9781469890012
Subjects: | MESH: General Surgery | Surgical Procedures, Operative
Classification: LCC RD31 | NLM WO 100 | DDC 617—dc23
LC record available at https://lccn.loc.gov/2016038680
This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as
to accuracy, comprehensiveness, or currency of the content of this work.
This work is no substitute for individual patient assessment based upon healthcare professionals’ examination of each patient and
consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data
and other factors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a
reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical
judgments and for any resulting diagnosis and treatments.
Given continuous, rapid advances in medical science and health information, independent professional verification of medical
diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare
professionals should consult a variety of sources. When prescribing medication, healthcare professionals are advised to consult the
product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of
use, warnings and side effects and identify any changes in dosage schedule or contraindications, particularly if the medication to be
administered is new, infrequently used or has a narrow therapeutic range. To the maximum extent permitted under applicable
law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products
liability, negligence law or otherwise, or from any reference to or use by any person of this work.
4
LWW.com
5
Contributors
David B. Adams, MD
Professor of Surgery
The Department of Surgery
Medical University of South Carolina
Charleston, South Carolina
N. Scott Adzick, MD
Surgeon-in-Chief
Children’s Hospital of Philadelphia
C. Everett Koop Professor of Pediatric Surgery
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, Pennsylvania
Gorav Ailawadi, MD
Chief, Section of Adult Cardiac Surgery
Associate Professor, Cardiothoracic Surgery and Biomedical Engineering
Director, Minimally Invasive Cardiac Surgery
Surgical Director, Advanced Cardiac Valve Center
Chair, VCSQI Research and Writing Committee
Hasan B. Alam, MD
Norman W. Thompson Professor of Surgery
Head of General Surgery
Ann Arbor, Michigan
Shehab Ahmad Redha AlAnsari, MD

Resident physician
Department of Internal Medicine
Cleveland Clinic Foundation
Cleveland, Ohio
Husain T. AlQattan, MD
Miller School of Medicine
University of Miami – Jackson Health System
Miami, Florida
Marjorie J. Arca, MD
Professor of Surgery–Pediatric Surgery and Pediatrics
Surgical Director of Pediatric Critical Care
Milwaukee, Wisconsin
Ali Azizzadeh, MD
Department of Cardiothoracic and Vascular Surgery
University of Texas Medical School at Houston
Memorial Hermann Heart & Vascular Institute
Houston, Texas
Chad G. Ball, MD
Associate Professor of Surgery and Oncology
6
University of Calgary
Foothills Medical Center
Calgary, Canada
Thanh U. Barbie, MD
Instructor of Surgery
Attending Surgeon
Brigham and Women’s Hospital/Faulkner Hospital/Dana Farber Cancer Institute
Bradley D. Beasley, DPM, CWS

Private Practice
Restoration Foot & Ankle, PLLC
Broken Arrow, Oklahoma
Adam W. Beck, MD
Assistant Professor of Surgery
Division of Vascular Surgery and Endovascular Therapy
University of Florida College of Medicine
Gainesville, Florida
Elizabeth R. Benjamin, MD, PhD

Assistant Professor of Surgery and Emergency Medicine
Division of Trauma and Surgical Critical Care
University of Southern California
Los Angeles, California
Christopher K. Bichakjian, MD
Professor of Dermatology
Department of Dermatology
Ann Arbor, Michigan
Timothy R. Billiar, MD
George Vance Foster Endowed Professor
Distinguished Professor of Surgery
University of Pittsburgh
Pittsburgh, Pennsylvania
John D. Birkmeyer, MD
Executive Vice President, Integrated Delivery Systems
Chief Academic Officer
Dartmouth-Hitchcock Health
One Medical Center Drive
Lebanon, New Hampshire
C. Richard Boland, MD
Chief, Division of Gastroenterology
Baylor Scott and White
Baylor University Medical Center
Dallas, Texas
Edward L. Bove, MD
Helen and Marvin Kirsh Professor of Cardiac Surgery
Chair, Cardiac Surgery Department
Cardiovascular Center
7
Ann Arbor, Michigan
Darren Bowe, MD
Attending Surgeon
Wyoming Medical Center
Casper, Wyoming
Robert S. Bresalier, MD
Professor of Medicine
Birdie J. and Lydia J. Resoft Distinguished Professor in Gastrointestinal Oncology
Department of Gastroenterology, Hepatology, and Nutrition
The University of Texas MD Anderson Cancer Center
Houston, Texas
Jonathan R. Brody, PhD

Director of Surgical Research, Professor
Thomas Jefferson University
Carlos V.R. Brown, MD

Associate Professor
Dell Medical School
University of Texas at Austin
Trauma Medical Director
University Medical Center Brackenridge
Austin, Texas
David L. Brown, MD
Associate Professor of Surgery
Section of Plastic Surgery
Ann Arbor, Michigan
Brandon R. Bruns, MD
Associate Professor
University of Maryland School of Medicine
R Adams Cowley Shock Trauma Center
Baltimore, Maryland
Steven R. Buchman, MD
M. Haskell Newman Professor in Plastic Surgery
Professor of Neurosurgery
Program Director, Craniofacial Surgery Fellowship
University of Michigan Medical School
Chief, Pediatric Plastic Surgery
CS Mott Children’s Hospital
Director, Craniofacial Anomalies Program
University of Michigan Medical Center
Ann Arbor, Michigan
J. Kenneth Byrd, MD
Assistant Professor
Department of Otolaryngology – Head and Neck Surgery
Medical College of Georgia
Augusta, Georgia
Andrew M. Cameron, MD, PhD
8
Director of Liver Transplantation
The Johns Hopkins University School of Medicine
Baltimore, Maryland
E. Ramsay Camp, MD
Division of Oncologic and Endocrine Surgery
Darrell A. Campbell, Jr., MD

Ann Arbor, Michigan
Robert M. Cannon, MD
Instructor/Fellow
Division of Transplantation
University of Alabama at Birmingham
Birmingham, Alabama
Kenneth Cardona, MD
Division of Surgical Oncology
Emory University Hospital Midtown
Emory Winship Cancer Institute
Atlanta, Georgia
Darrell L. Cass, MD
Associate Professor
Departments of Surgery, Pediatrics, and Obstetrics and Gynecology
Baylor College of Medicine
Co-Director, Texas Children’s Fetal Center
Texas Children’s Hospital
Houston, Texas
Paul S. Cederna, MD
Chief, Section of Plastic Surgery
Robert Oneal Professor of Plastic Surgery
Professor, Department of Biomedical Engineering
Ann Arbor, Michigan
Rajiv Chandawarkar, MD
Director, Plastic Surgery, OSU East Hospital
Associate Professor of Plastic Surgery
Adjunct Associate Professor of Orthopedics
Columbus, Ohio
Andrew C. Chang, MD
John Alexander Distinguished Professor
Head, Section of Thoracic Surgery
Ann Arbor, Michigan
9
Kristofer M. Charlton-Ouw, MD
Houston, Texas
Randall M. Chesnut, MD
Professor
Neurological Surgery, Orthopaedics and Sports Medicine
University of Washington
Seattle, Washington
Jayer Chung, MD, MSc

Assistant Professor
Michael E. DeBakey Department of Surgery
Baylor College of Medicine
Houston, Texas
Kevin C. Chung, MD, MS

Chief of Hand Surgery
Charles B. G. de Nancrede Professor of Surgery
Professor of Orthopaedic Surgery
Assistant Dean for Faculty Affairs
Ann Arbor, Michigan
Robert E. Cilley, MD
Professor of Surgery and Pediatrics
Penn State College of Medicine
Penn State Children’s Hospital
State College, Pennsylvania
Damon Clark, MD
Acute Care Surgery
Dawn M. Coleman, MD
Assistant Professor – Vascular Surgery
Cardiovascular Center
Ann Arbor, Michigan
Dorin T. Colibaseanu, MD
Section of Colon and Rectal Surgery
Mayo Clinic
Jacksonville, Florida
Zara Cooper, MD
10
Division of Trauma, Burns, and Surgical Critical Care
Brigham and Women’s Hospital
Bryan A. Cotton, MD, MPH

University of Texas Health Science Center
Houston, Texas
Joseph Cuschieri, MD
Director of Surgical Critical Care, Harborview Medical Center
Associate Program Director, Surgical Critical Care Fellowship
Seattle, Washington
Michael C. Dalsing, MD
Chief
Division of Vascular Surgery
Indiana University School of Medicine
Indianapolis, Indiana
Kimberly A. Davis, MD, MBA

Vice Chairman of Clinical Affairs
Chief of the Section of General Surgery, Trauma, and Surgical Critical Care
Yale School of Medicine
Trauma Medical Director
Surgical Director, Quality and Performance Improvement
New Haven, Connecticut
Jonathan D’Cunha, MD, PhD

Vice Chairman, Academic Affairs
Surgical Director, Lung Transplantation
Surgical Director, ECMO
Associate Program Director, Thoracic Surgery Program Director, Advanced Lung/Heart Failure Fellowship
Department of Cardiothoracic Surgery at UPMC
M. George DeBusk, MD, MSc, FACS, FCCP

Assistant Professor
Division of Trauma, Surgical Critical Care and Acute Care Surgery
UMass Memorial Medical Center
Worcester, MA
Steven R. DeMeester, MD
Thoracic, Foregut and Minimally Invasive Surgery
The Oregon Clinic
Portland, Oregon
Demetrios Demetriades, MD, PhD

Director of Trauma, Emergency Surgery, Surgical Critical Care
11
Justin B. Dimick, MD, MPH
George D. Zuidema Professor of Surgery
Director, Center for Healthcare Outcomes & Policy
Chief, Division of Minimally Invasive Surgery
Ann Arbor, Michigan
Gerard M. Doherty, MD
Surgeon-in-Chief
Brigham and Women’s Health Care & Dana-Farber Cancer Institute
Moseley Professor of Surgery
Christine Durand, MD
Assistant Professor of Medicine and Oncology Division of Infectious Diseases
The Johns Hopkins University School of Medicine
Baltimore, Maryland
Jean C. Emond, MD
Thomas S. Zimmer Professor of Surgery
Director of Transplantation
Columbia University and The New York Presbyterian Hospital
New York, New York
Michael J. Englesbe, MD
Division of Transplantation
Ann Arbor, Michigan
Anthony L. Estrera, MD
Houston, Texas
Sandy H. Fang, MD
Assistant Professor
Ravitch Division, Colon and Rectal Surgery
Johns Hopkins Hospital
Baltimore, Maryland
Robert L. Ferris, MD, PhD

Professor
Vice-Chair for Clinical Operations
Chief, Division of Head and Neck Surgery
Associate Director for Translational Research
Co-Leader, Cancer Immunology Program
University of Pittsburgh Cancer Institute
Robert J. Fitzgibbons, Jr., MD

Harry E. Stuckenhoff Professor and Chairman
Creighton University School of Medicine
Medical Director of Surgical Services and Anesthesia
12
Alegent Creighton Clinic
Co-editor-in-Chief, Hernia
Omaha, Nebraska
James W. Fleshman, MD
Helen Buchanan and Stanley Joseph Seeger Professor and Chairman
Baylor University Medical Center
Texas A&M Health Science Center
Dallas, Texas
Yuman Fong, MD
Professor and Chairman
City of Hope Medical Center
Duarte, California
Douglas L. Fraker, MD
Jonathan E. Rhoads Associate Professor of Surgery
Chief, Division of Surgical Oncology
University of Pennsylvania
Heidi Frankel, MD
Chris E. Freise, MD
Transplant Division
University of California
San Francisco, California
Samir K. Gadepalli, MD
Clinical Lecturer
Co-Director of Pediatric Surgical Critical Care
Ann Arbor, Michigan
Julio Garcia-Aguilar, MD, PhD

Chief, Colorectal Service
Benno C. Schmidt Chair in Surgical Oncology
Memorial Sloan Kettering Cancer Center
New York, New York
Paul G. Gauger, MD
William J. Fry Professor of Surgery
Professor of Learning Health Sciences
Program Director – General Surgery
Division Head – Endocrine Surgery
Ann Arbor, Michigan
Ravi K. Ghanta, MD
Division of Cardiothoracic Surgery
13
Kristina A. Giles, MD
William E. Gillanders, MD
Washington University School of Medicine
Attending Surgeon
Barnes-Jewish Hospital
St. Louis, Missouri
A. Marc Gillinov, MD
Staff Surgeon
The Judith Dion Pyle Chair in Heart Valve Research
Department of Thoracic and Cardiovascular Surgery
Cleveland Clinic
Cleveland, Ohio
Jason S. Gold, MD
Chief of Surgical Oncology
Surgical Service
VA Boston Healthcare System
West Roxbury, Massachusetts
Batya R. Goldwaser, DMD, MD

Oral and Maxillofacial Surgeon
Former Fellow and Resident
Department of Oral and Maxillofacial Surgery
Niraj J. Gusani, MD, MS

Associate Professor of Surgery, Medicine, & Public Health Sciences
Section of Surgical Oncology
Director, Program for Liver, Pancreas, & Foregut Tumors
Co-Medical Director, Outpatient Services
Penn State Cancer Institute
Hershey, Pennsylvania
Jonathan W. Haft, MD
Associate Professor, Cardiac Surgery
Ann Arbor, Michigan
Mark R. Hemmila, MD
Division of Acute Care Surgery
Ann Arbor, Michigan
14
Peter K. Henke, MD
Leland Ira Doan Professor of Surgery
Chief, Vascular Surgery AAVA
Ann Arbor, Michigan
Jennifer C. Hirsch-Romano, MD
Assistant Professor of Cardiac Surgery & Pediatrics
Associate Director, Pediatric Cardiothoracic Intensive Care Unit
C.S. Mott Children’s Hospital
Ann Arbor, Michigan
John B. Holcomb, MD
Houston, Texas
Michael G. House, MD
Thomas S. Huber, MD, PhD

Chief, Division of Vascular Surgery and Endovascular Therapy
David T. Hughes, MD
Division of Endocrine Surgery
Ann Arbor, Michigan
Kenji Inaba, MD
Associate Professor of Surgery, Emergency Medicine, and Anesthesia
Division of Trauma and Surgical Critical Care
Craig M. Jarrett, MD, MBA

Fellow in Cardiothoracic Surgery
Division of Cardiac Surgery
Eric K. Johnson, MD
MultiCare Colon and Rectal Surgery
Tacoma, Washington
Uniformed Services University of the Health Sciences
Bethesda, Maryland
Timothy M. Johnson, MD
Lewis and Lillian Becker Professor
Department of Dermatology
Ann Arbor, Michigan
15
Bellal Joseph, MD,
University of Arizona
Tucson, Arizona
Gregory J. Jurkovich, MD
Professor and Vice-Chairman
UC Davis Health System
Sacramento, California
Leonard B. Kaban, MD, DMD

Chief, Oral and Maxillofacial Surgery
Loay S. Kabbani, MD
Senior Staff Surgeon
Department of Vascular Surgery
Henry Ford Hospital
Detroit, Michigan
Jussuf T. Kaifi, MD, PhD

Chief, Thoracic Surgery
University of Missouri
Columbia, Missouri
Giorgos C. Karakousis, MD
Division of Endocrine and Oncologic Surgery
George Kasotakis, MD, MPH

Boston University Medical School
Division of Trauma, Acute Care Surgery & Surgical Critical Care
Boston Medical Center
Kaitlyn J. Kelly, MD
Moores Cancer Center
University of California, San Diego
La Jolla, California
Sachin Kheterpal, MD
Associate Professor of Anesthesiology
Ann Arbor, Michigan
Eric T. Kimchi, MD, MBA

Chief, Surgical Oncology
Medical Director, Ellis Fischel Cancer Center
16
Columbia, Missouri
Martyn Knowles, MD
Assistant Professor
Division of Vascular and Endovascular Surgery
University of Texas Southwestern
Dallas, Texas
David A. Kooby, MD
Director of Surgical Oncology
Emory/Saint Joseph’s Hospital
Director of Minimally Invasive GI Surgical Oncology
Emory University School of Medicine
Winship Cancer Institute
Atlanta, Georgia
Marijan Koprivanac, MD, MS

Resident
Department of General Surgery Research Fellow
Department of Cardiothoracic Surgery
Cleveland Clinic
Clinical Instructor
Case Western University
Cleveland, Ohio
Lauren A. Kosinski, MD
Welkin Group, Inc.
Chestertown, Maryland
Jeffrey H. Kozlow, MD, MS

Clinical Assistant Professor
Section of plastic Surgery
Ann Arbor, Michigan
Devi Mukkai Krishnamurty, MD

Clinical Fellow
Colon and Rectal Surgery
Washington University School of Medicine-Barnes Jewish Hospital
St. Louis, Missouri
William M. Kuzon, Jr., MD, PhD

Reed O. Dingman Professor of Surgery
Chief of Surgery
Ann Arbor VA Healthcare
Ann Arbor, Michigan
David W. Larson, MD, MBA

Professor of Surgery and Chair
Division of Colon and Rectal Surgery
Mayo Clinic
Rochester, Minnesota
Adriana Laser, MD
University of Maryland Medical Center
17
Baltimore, Maryland
Harish Lavu, MD
Section Chief HPB Surgery
Associate Professor
Steven G. Leeds, MD
Assistant Clinical Professor of Surgery
Texas A&M College of Medicine
Medical Director of MIS Research and Surgical Simulation
Division of Minimally Invasive Surgery
Baylor University Medical Center at Dallas
Dallas, Texas
Benjamin Levi, MD
Director, Burn/Wound and Regenerative Medicine Laboratory
Director, Burn Reconstruction and Scar Rehabilitation Program
Assistant Professor in Surgery
Divisions of Plastic and Reconstructive Surgery and Burn Surgery
Ann Arbor, Michigan
Edward A. Levine, MD
Chief, Surgical Oncology
Wake Forest University
Winston-Salem, North Carolina
Keith D. Lillemoe, MD
W. Gerald Austen Professor of Surgery, Harvard Medical School
Chief of Surgery and Surgeon-in-Chief
The Massachusetts General Hospital
Jules Lin, MD
Surgical Director, Lung Transplant
Associate Professor
Section of Thoracic Surgery
Ann Arbor, Michigan
Kirk Ludwig, MD
The Vernon O. Underwood Professor
Chief, Division of Colorectal Surgery
Medical College of Wisconsin
Felix Y. Lui, MD
Section of General Surgery, Trauma, and Surgical Critical Care
Yale School of Medicine
New Haven, Connecticut
James D. Luketich, MD
Chairman, Department of Cardiothoracic Surgery
18
University of Pittsburgh Medical Center
Henry T. Bahson Professor of Cardiothoracic Surgery
Chairman, Department of Cardiothoracic Surgery
University of Pittsburgh School of Medicine
Geoffrey T. Manley, MD, PhD

Professor and Vice Chairman of Neurological Surgery
University of California, San Francisco
Chief of Neurosurgery, San Francisco General Hospital
Co-Director, Brain and Spinal Injury Center
John C. Mansour, MD
Surgical Oncologist
Associate Professor Surgery
University of Texas Southwestern Medical Center
Dallas, Texas
David J. Maron, MD, MBA

Vice Chair
Department of Colorectal Surgery
Cleveland Clinic Florida
Weston, Florida
Juan L. Martinez-Poyer, MD
Clinical Assistant Professor of Obstetrics and Gynecology
Perelman School of Medicine
Attending Physician, The Center for Fetal Diagnosis and Treatment
The Children’s Hospital of Philadelphia
Michael R. Marvin, MD
Chief, Division of Transplantation
Director of Liver Transplantation
University of Louisville
Jewish Hospital
Louisville, Kentucky
Peter T. Masiakos, MS, MD

Associate Professor of Surgery, Harvard Medical School
Associate Visiting Pediatric Surgeon
Director, Pediatric Trauma Service
Michael R. Mathis, MD
Clinical Lecturer, Anesthesiology
Ann Arbor, Michigan
Amit K. Mathur, MD, MS

Mayo Medical School
19
Senior Associate Consultant
Transplant Surgery
Mayo Clinic Arizona
Phoenix, Arizona
Tomislav Mihaljevic, MD
Cleveland Clinic Lerner College of Medicine
Chief Executive Officer, Cleveland Clinic Abu Dhabi
Abu Dhabi, UAE
Dianna Milewicz, MD, PhD

Houston, Texas
Michael J. Miller, MD
Chairman
Department of Plastic Surgery
Columbus, Ohio
Charles C. Miller III, PhD

Houston, Texas
Rebecca M. Minter, MD
Alvin Baldwin, Jr. Chair in Surgery
Dallas, Texas
Jason S. Mizell, MD
Division of Colon and Rectal Surgery
Director of Surgery Clerkship
University of Arkansas for Medical Sciences
Little Rock, Arkansas
J. Gregory Modrall, MD
Dallas, Texas
Adeyiza O. Momoh, MD
Ann Arbor, Michigan
Gregory L. Moneta, MD
Professor of Surgery, Chief of Vascular Surgery
Knight Cardiovascular Institute
Oregon Health & Science University
20
Portland, Oregon
Katherine A. Morgan, MD
Division of Gastrointestinal and Laparoscopic Surgery
Nathan Mowery, MD
Wake Forest University
Winston-Salem, North Carolina
Marc de Moya, MD
Acute Care Surgery Program Director
Division of Trauma, Acute Care Surgery

Frederick A. Coller Distinguished Professor of Surgery
Ann Arbor, Michigan
George B. Mychaliska, MD
Robert Bartlett, M.D. Collegiate Professor of Pediatric Surgery
Associate Professor of Surgery and Obstetrics and Gynecology
Director, Fetal Diagnosis and Treatment Center
Associate Chair for Faculty Development
Co-Director, ECMO Program
Section of Pediatric Surgery
Ann Arbor, Michigan
Satish N. Nadig, MD, PhD

Assistant Professor Surgery, Microbiology, & Immunology
Transplant Surgery
Jeffry Nahmias, MD
Assistant Professor, Surgery
Tufts University School of Medicine
Director of Trauma Summer Undergraduate Research Program (T-SURP)
Baystate Medical Center
Springfield, Massachusetts
Attila Nakeeb, MD
Lena M. Napolitano, MD
21
Division Chief, Acute Care Surgery
Director, Trauma and Surgical Critical Care
Ann Arbor, Michigan
Hari Nathan, MD, PhD

Assistant Professor
Ann Arbor, Michigan
Laura L. Neff, MD
Attending Otolaryngologist
Pediatric Otolaryngology
The Children’s Mercy Hospital
Kansas City, Missouri
Erika Adams Newman, MD

Assistant Professor in Pediatric Surgery
Associate Program Director, General Surgery
Surgical Director, Mott Solid Tumor Oncology Program (MSTOP)
Translational Oncology Program
CS Mott Children’s Hospital
The University of Michigan
Ann Arbor, Michigan
Trevor L. Nydam, MD
Assistant Professor and Transplant Surgeon
University of Colorado Hospital (UCH)
Aurora, Colorado
Robert W. O’Rourke, MD
Associate Professor
University of Michigan and Ann Arbor Veteran’s Administration Hospital
Ann Arbor, Michigan
Daniel S. Oh, MD
Division of Thoracic Surgery
Keck School of Medicine
Richard G. Ohye, MD
Professor of Cardiac Surgery
Head, Section of Pediatric Cardiovascular Surgery
Surgical Director, Pediatric Cardiovascular Transplant Program
Program Director, Congenital Cardiac Surgery Residency
Co-Director, Michigan Congenital Heart Center
Ann Arbor, Michigan
John A. Olson, Jr., MD, PhD

Campbell and Jeanette Plugge Professor of Surgery
Vice Chair, Department of Surgery
Chief, Division of General and Oncologic Surgery
The University of Maryland School of Medicine
Baltimore, Maryland
22
Mary F. Otterson, MD, MS
Professor of Surgery and Physiology
Medical College of Wisconsin
Zablocki Veteran Affairs Medical Center
Francis D. Pagani, MD, PhD

Otto Gago, MD Professor in Cardiac Surgery
Department of Cardiac Surgery
Ann Arbor, Michigan
John M. Park, MD
Cheng-Yang Chang Professor of Pediatric Urology
Department of Urology
Ann Arbor, Michigan
Pauline Park, MD
Ann Arbor, Michigan
Richard N. Pierson III, MD

Cardiac Surgery
College Park, Maryland
Thomas H. Quinn, MS, PhD

Professor of Anatomy and Surgery
Assistant Dean for Medical Admissions
Past President, American Association of Clinical Anatomists
Creighton University School of Medicine
Omaha, Nebraska
Reza Rahbar, DMD, MD

Associate Otolaryngologist-in-Chief
McGill Chair in Pediatric Otolaryngology
Department of Otolaryngology
Boston Children’s Hospital/Harvard Medical School
Steven E. Raper, MD, JD

Perelman School of Medicine, University of Pennsylvania
Todd E. Rasmussen, MD
Harris B Shumacker Professor of Surgery
The Uniformed Services University of the Health Sciences
Bethesda, Maryland
John E. Rectenwald, MD, MS

Associate Professor of Surgery & Radiology
Program Director, Vascular Surgery
Section of Vascular Surgery
23
Ann Arbor, Michigan
Rishindra M. Reddy, MD
Assistant Professor of Thoracic Surgery
Ann Arbor, Michigan
Amy B. Reed, MD
Chief and Program Director, Vascular Surgery
Heart and Vascular Institute
Penn State Hershey Medical Center
Peter Rhee, MD, MPH

Senior Vice President
Chief of Acute Care Surgery and Trauma Medical Director
Grady Memorial Hospital
Atlanta, Georgia
Taylor S. Riall, MD, PhD

Professor, Chief of General Surgery and Surgical Oncology
Banner-University Medical Center
University of Arizona
Tucson, Arizona
Haris Riaz, MD
Resident physician
Department of Internal Medicine
Cleveland Clinic Foundation
Cleveland, Ohio
William P. Robinson III, MD

Associate Professor
Heron E. Rodriguez, MD
Associate Professor of Vascular Surgery
Northwestern University Feinberg School of Medicine
Chicago, Illinois
Matthew R. Rosengart, MD, MPH

Associate Professor of Surgery, Critical Care Medicine
Director, University of Pittsburgh Surgical Critical Care Fellowship Program
Co-Director, University of Pittsburgh Department of Surgery, Surgical Outcomes Research Center
Michael S. Sabel, MD
University of Michigan Health System
Ann Arbor, Michigan
Hazim J. Safi, MD
24
Houston, Texas
Ali Salim, MD
Professor
Division Chief, Trauma, Burns, and Surgical Critical Care
Gordan Samoukovic, MD
Department of Cardiothoracic Surgery
McGill University
Montreal, Quebec
Canada
Gurjit Sandhu, PhD

Assistant Professor
Departments of Surgery and Learning Health Sciences
Ann Arbor, Michigan
Ariel P. Santos, MD, MPH

Assistant Professor
Associate Program Director of Emergency General Surgery
Division of Trauma, Acute Care and Critical Care Surgery
Penn State Milton S. Hershey Medical Center
Mary C. Santos, MD
Associate Professor of Surgery and Pediatrics
Penn State Children’s Hospital
State College, Pennsylvania
Thomas T. Sato, MD
Division of Pediatric Surgery
CEO, Children’s Specialty Group
Senior Associate Dean of Clinical Affairs
Children’s Hospital of Wisconsin and The Medical College of Wisconsin
Thomas M. Scalea, MD
Physician-in-Chief, Shock Trauma Center
System Chief for Critical Care Services
University of Maryland Medical System
The Honorable Francis X. Kelly Distinguished Professor in Trauma
Director, Program in Trauma
Baltimore, Maryland
Richard D. Schulick, MD, MBA

The Aragón/Gonzalez-Gíustí Chair
Professor and Chair
University of Colorado Anschutz Medical Campus
Aurora, Colorado
25
Alexander D. Shepard, MD
Head, Division of Vascular Surgery
Szilagyi Chair in Vascular Surgery
Henry Ford Hospital
Wayne State University School of Medicine
Detroit, Michigan
Junichi Shindoh, MD, PhD

Assistant Professor
Hepatobiliary-pancreatic Surgery Division
Graduate School of Medicine
The University of Tokyo
Tokyo, Japan
Matthew J. Sideman, MD
Associate Professor
Vascular Surgery Division
University of Texas Health Science Center at San Antonio
San Antonio, Texas
Raymond Malcolm Smith, MB CHB, MD

Chief, Orthopaedic Trauma Service
Associate Professor of Orthopaedics
Elizabeth S. Soukup, MD, MMSc

Pediatric Surgeon, Elliot Health System
Geisel School of Medicine
Dartmouth Hitchcock Medical Center
Hanover, New Hampshire
David I. Soybel, MD
David L. Nahrwold Professor of Surgery
Division Chief, General Surgery Specialties & Surgical Oncology
Penn State Hershey Medical Center
Kevin F. Staveley-O’Carroll, MD, PhD

Hugh E. Stephenson, Jr., MD, Chair of Surgery
Director, Ellis Fischel Cancer Center
Columbia, Missouri
Scott R. Steele, MD
Vice Chairman for Clinical Affairs, Department of Surgery
Chief, Division of Colorectal Surgery
University Hospitals Case Medical Center
Case Western Reserve University
Cleveland, Ohio
Peter G. Stock, MD, PhD
26
University of California, San Francisco
Randall S. Sung, MD
Surgical Director, Kidney and Pancreas Transplantation
Ann Arbor, Michigan
Brooke Swearingen, MD
Professor of Neurosurgery
Neurosurgical Service, Massachusetts General Hospital
Phiroz E. Tarapore, MD
Assistant Professor of Clinical Neurosurgery
Department of Neurological Surgery
University of California San Francisco
Kevin E. Taubman, MD
Assistant Professor of Surgery and Program Director Vascular Surgery Fellowship
Section of Vascular and Endovascular Surgery
University of Oklahoma College of Medicine, Tulsa
Tulsa, Oklahoma
John R. Taylor III, MD

Clinical Instructor in Surgery
Houston, Texas
Carlos H. Timaran, MD
Chief, Endovascular Surgery
G. Patrick Clagett Professorship in Surgery
Associate Professor, Division of Vascular and Endovascular Surgery
University of Texas Southwestern
Dallas, Texas
Shahab Toursavadkohi, MD
University of Maryland Medical Center
Baltimore, Maryland
Nicholas A. Tritos, MD, DSc

Neuroendocrine Unit
Department of Medicine
Assistant Professor of Medicine
Maria J. Troulis, DDS, MSc

Chief, Oral Maxillofacial Surgery
Walter Guralnick Professor and Chair, Oral Maxillofacial Surgery
27
Harvard Dental School
Richard H. Turnage, MD
Professor and Chairman
University of Arkansas for Medical Sciences
Little Rock, Arkansas
Douglas J. Turner, MD
Chief of Surgery
Baltimore VA Medical Center
Baltimore, Maryland
Gilbert R. Upchurch, Jr., MD

Chief of Vascular and Endovascular Surgery
William H. Muller, Jr. Professor of Surgery
Professor of Molecular Physiology and Biological Physics
Jean-Nicolas Vauthey, MD
Professor
Department of Surgical Oncology
The University of Texas MD Anderson Cancer Center
Houston, Texas
George Velmahos, MD, PhD, MSEd

John F. Burke Professor of Surgery
Chief, Division of Trauma, Emergency Surgery, and Surgical Critical Care
Christian J. Vercler, MD, MA

Assistant Professor
Ann Arbor, Michigan
Richard B. Wait, MD, PhD

Professor Emeritus of Surgery
Tufts University School of Medicine
Chairman of Surgery (retired)
Baystate Medical Center
Springfield, Massachusetts
Thomas W. Wakefield, MD
Stanley Professor of Vascular Surgery
Section Head, Section of Vascular Surgery, Department of Surgery
Director, Samuel and Jean Frankel Cardiovascular Center
Ann Arbor, Michigan
J. Patrick Walker, MD
28
Chief of Surgery
Houston County Medical Center
Crockett, Texas
Vice-Chair of Education
University of Texas Medical Branch
Galveston, Texas
Julian Wan, MD
Reed Nesbit Professor of Urology
Ann Arbor, Michigan
Stewart C. Wang, MD, PhD

First Endowed Professor of Burn Surgery
Director, Burn Center
Director, State of Michigan Burn Coordinating Center
Director, Morphomic Analysis Group
Director, International Center for Automotive Medicine
Ann Arbor, Michigan
Mitchell R. Weaver, MD
Assistant Clinical Professor
Henry Ford Hospital
Wayne State University School of Medicine
Detroit, Michigan
Sharon Weber, MD
Tim and MaryAnn McKenzie Chair of Surgery
Director for Surgical Oncology, UW Carbone Cancer Center
Vice Chair of Academic Affairs, General Surgery
Professor of Surgery, Department of Surgery
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin
Theodore H. Welling, MD
Co-Director, Multidisciplinary Liver Tumor Program
Section of Transplantation
Ann Arbor, Michigan
Hunter Wessells, MD
Professor and Nelson Chair
Seattle, Washington
Steven D. Wexner, MD, PHD (Hon)

Director, Digestive Disease Center
Chair, Department of Colorectal Surgery
Cleveland Clinic Florida
Affiliate Professor, Florida Atlantic University College of Medicine
Clinical Professor, Florida International University College of Medicine
Miami, Florida
29
Edward E. Whang, MD
Elizabeth C. Wick, MD
University of California San Francisco
Edwin G. Wilkins, MD, MS

Ann Arbor, Michigan
Joshua H. Winer, MD
Emory University/Saint Joseph’s Hospital
Winship Cancer Institute
Atlanta VA Medical Center
Atlanta, Georgia
Sandra L. Wong, MD, MS

Professor and Chair
Dartmouth-Hitchcock Medical Center
Geisel School of Medicine at Dartmouth
Hanover, New Hampshire
Charles J. Yeo, MD
Samuel D. Gross Professor and Chairman
Jefferson Medical College
Adam C. Yopp, MD
Dallas, Texas
30
Preface
The editors are pleased to present the sixth edition of Greenfield’s Surgery: Scientific Principles & Practice.
The field of surgery has changed fundamentally in the years since the first edition of this text. Growth
in the knowledge base of clinical surgery continues exponentially. Surgical practice has been
transformed through advancements in physiologic and cellular investigation, integration of new
techniques derived from imaging and robotics, from the concept of patient-centered care, and from the
emerging field of biocomputation. The accelerating pace of scientific progress demands rapid adoption
of new ideas into surgical therapy and a commitment to lifelong learning. Accordingly, the new edition
of Greenfield’s Surgery seeks to integrate new scientific knowledge with evolving changes in surgical
care.
The sixth edition has been enhanced in every way, with changes to the book’s editorial board,
authorship, content, organization, and visual presentation. It reflects the founding principles and
guidance of Lazar J. Greenfield, MD, whose perceptive wisdom helped to create a truly unique book
that balances scientific advance with clinical practice. With this new edition, we welcome new editors—
Hasan Alam, MD and Timothy Pawlik, MD. Their expertise, energy, and vision have invigorated this
edition.
We have solicited contributions from well over 200 authors, all chosen because of their scientific and
clinical sophistication. Each contributor is currently an active practitioner in the field of surgery.
Moreover, many have presented seminal articles and developed the new concepts in their disciplines
that are featured in the text. Advances ranging from patient safety to fetal surgery mark the book as
truly unique.
Organizationally, the book begins with topics of broad relevance to the practice of surgery, followed
with chapters arranged by organ system. Trauma and transplantation are presented in the form of
separate sections rather than subdivided chapters. The content within each has been presented as
individual chapters in appreciation of the significance of each topic.
The book has been designed to create a text that not only looks better but also works better. The text
is produced in a full range of colors, creating both visual impact and more opportunity to convey
information quickly and with greater meaning. We continue our commitment to superb medical art in
the form of line drawings. These illustrations have been enhanced to ensure a presentation that
maximizes teaching effectiveness and clinical utility. Each chapter begins with a series of highlighted
key teaching points, which are referenced within the text that follows. Individually numbered decision-
making algorithms are featured throughout the book to provide diagnostic and management
information in a simplified format. Tables carry classification bars, such as diagnosis or results, useful
both when scanning the text for information and when accessing the book’s contents digitally. The most
important articles and chapters on the topic are highlighted in the reference list.
The sixth edition continues to be highly integrated with electronic elements to provide supplemental
educational material, including Morbidity and Mortality Case Discussions and an interactive question
bank.
Today, Greenfield’s Surgery: Scientific Principles & Practice has become the gold standard text in the field
of surgery. The editors continue their commitment to the education of contemporary surgeons, and to
improved care of the patients that they serve. We believe that with the many improvements
implemented in this sixth edition, it will continue be the text by which all other surgery texts are
judged.
31
Contents
Contributors
Preface
Part One Scientific Principles

1 Lifelong Learning
Gurjit Sandhu and Rebecca M. Minter
2 Principles of Intermediary Metabolism
Steven E. Raper
3 Surgical Nutrition and Metabolism
George Kasotakis
4 Obesity and Metabolic Disease
Robert W. O’Rourke and Michael W. Mulholland
5 Wound Healing
Rajiv Chandawarkar and Michael J. Miller
6 Hemostasis
Peter K. Henke and Thomas W. Wakefield
7 Inflammation
Matthew R. Rosengart and Timothy R. Billiar
8 Surgical Infections
Lena M. Napolitano
9 Shock
Joseph Cuschieri and Darren Bowe
10 Critical Care
Damon Clark and Heidi Frankel
11 Fluids, Electrolytes, and Acid–Base Balance
Richard B. Wait, M. George DeBusk, and Jeffry Nahmias
12 Burns
Benjamin Levi, Mark R. Hemmila, and Stewart C. Wang
13 Anesthesiology and Pain Management
Sachin Kheterpal and Michael R. Mathis
14 Oncology
Adam C. Yopp and John C. Mansour
15 Preoperative Risk Assessment
Pauline Park
16 Measuring the Quality of Surgical Care
Justin B. Dimick and John D. Birkmeyer
17 Policy Approaches to Improving Surgical Quality
John D. Birkmeyer and Justin B. Dimick
18 Patient Safety
Darrell A. Campbell, Jr.
Part Two Surgical Practice

SECTION A: TRAUMA
19 Trauma and Trauma Care: General Considerations
32
Hasan B. Alam
20 Prehospital and New Advances in Resuscitation
John R. Taylor III, John B. Holcomb, and Bryan A. Cotton
21 Head Trauma
Phiroz E. Tarapore, Geoffrey T. Manley, and Randall M. Chesnut
22 Maxillofacial Injuries
Batya R. Goldwaser, Leonard B. Kaban, and Maria J. Troulis
23 Neck Injuries
Brandon R. Bruns and Thomas M. Scalea
24 Thoracic Trauma
Marc de Moya and George Velmahos
25 Abdominal Trauma
Kenji Inaba, Elizabeth R. Benjamin, and Demetrios Demetriades
26 Genitourinary Trauma
Hunter Wessells
27 Vascular Trauma
Adriana Laser, Shahab Toursavadkohi, and Todd E. Rasmussen
28 The Principles of Orthopedic Surgery for Trauma
Raymond Malcolm Smith
29 Pediatric Trauma
Elizabeth S. Soukup and Peter T. Masiakos
30 Geriatric Trauma
Carlos V.R. Brown, Zara Cooper, and Ali Salim
31 Trauma in Pregnancy
Felix Y. Lui and Kimberly A. Davis
32 Postinjury Management
Bellal Joseph and Peter Rhee
33 Environmental Injuries
J. Patrick Walker and Gregory J. Jurkovich
SECTION B: TRANSPLANTATION
34 Clinical Transplant Immunology
Amit K. Mathur and Satish N. Nadig
35 Organ Procurement and Preservation
Michael J. Englesbe
36 Renal Transplantation
Chris E. Freise and Peter G. Stock
37 Hepatic Transplantation
Theodore H. Welling
38 Cardiac Transplantation
Richard N. Pierson III
39 Pulmonary Transplantation
Jules Lin and Andrew C. Chang
40 Pancreas and Islet Transplantation
Randall S. Sung
SECTION C: HEAD AND NECK

41 Head and Neck
J. Kenneth Byrd and Robert L. Ferris
SECTION D: ESOPHAGUS
33
42 Esophageal Anatomy and Physiology and Gastroesophageal Reflux Disease
Daniel S. Oh and Steven R. DeMeester
43 Esophageal Tumors and Injury
Jonathan D’Cunha and James D. Luketich
SECTION E: STOMACH AND DUODENUM

44 Gastric Anatomy and Physiology
Michael W. Mulholland
45 Gastroduodenal Ulceration
46 Management of Obesity
Robert W. O’Rourke
47 Gastric Neoplasms
Hari Nathan and Rebecca M. Minter
SECTION F: SMALL INTESTINE

48 Anatomy and Physiology of the Small Intestine
E. Ramsay Camp, Kevin F. Staveley-O’Carroll, Niraj J. Gusani, Jussuf T. Kaifi, and Eric T. Kimchi
49 Ileus and Bowel Obstruction
David I. Soybel and Ariel P. Santos
50 Crohn Disease
Scott R. Steele and Eric K. Johnson
51 Small Bowel Tumors
Steven G. Leeds and James W. Fleshman
SECTION G: PANCREAS
52 Pancreas Anatomy and Physiology
Taylor S. Riall
53 Acute Pancreatitis
Jason S. Gold and Edward E. Whang
54 Chronic Pancreatitis
Katherine A. Morgan and David B. Adams
55 Neoplasms of Exocrine Pancreas
Attila Nakeeb, Michael G. House, and Keith D. Lillemoe
56 Neoplasms of the Endocrine Pancreas
Harish Lavu, Jonathan R. Brody, and Charles J. Yeo
SECTION H: HEPATOBILIARY AND PORTAL VENOUS SYSTEM

57 Hepatobiliary Anatomy
Trevor L. Nydam and Richard D. Schulick
58 Hepatic Infection and Acute Liver Failure
Andrew M. Cameron and Christine Durand
59 Cirrhosis and Portal Hypertension
Michael R. Marvin, Robert M. Cannon, and Jean C. Emond
60 Hepatic Neoplasms
Junichi Shindoh and Jean-Nicolas Vauthey
61 Calculous Biliary Disease
David A. Kooby, Joshua H. Winer, and Kenneth Cardona
62 Biliary Injuries and Strictures and Sclerosing Cholangitis
Chad G. Ball and Keith D. Lillemoe
63 Biliary Neoplasms
Kaitlyn J. Kelly, Yuman Fong, and Sharon Weber
34
SECTION I: COLON AND RECTUM
64 Colon and Rectal Anatomy and Physiology
Sandy H. Fang and Elizabeth C. Wick
65 Acute Gastrointestinal Hemorrhage
Jason S. Mizell and Richard H. Turnage
66 Ulcerative Colitis
Dorin T. Colibaseanu and David W. Larson
67 Colonic Polyps and Polyposis Syndromes
Robert S. Bresalier and C. Richard Boland
68 Colorectal Cancer
Julio Garcia-Aguilar
69 Diverticular Disease
Lauren A. Kosinski, Kirk Ludwig, and Mary F. Otterson
70 Anorectal Disorders
David J. Maron and Steven D. Wexner
71 Diseases of Appendix
Edward A. Levine and Nathan Mowery
SECTION J: HERNIA AND SPLEEN

72 Abdominal Wall Hernias
Robert J. Fitzgibbons, Jr., Thomas H. Quinn, and Devi Mukkai Krishnamurty
73 The Spleen
Giorgos C. Karakousis and Douglas L. Fraker
SECTION K: SURGICAL ENDOCRINOLOGY

74 Breast Disease
Thanh U. Barbie and William E. Gillanders
75 Thyroid Gland
David T. Hughes and Paul G. Gauger
76 Parathyroid Glands
Gerard M. Doherty
77 Adrenal Gland
John A. Olson, Jr. and Douglas J. Turner
78 Pituitary Surgery
Brooke Swearingen and Nicholas A. Tritos
SECTION L: LUNG
79 Lung Neoplasms
Andrew C. Chang and Jules Lin
80 Non-Neoplastic Thoracic Disease
Rishindra M. Reddy
SECTION M: VASCULAR DISEASE

81 Congenital Heart Disease
Jennifer C. Hirsch-Romano, Richard G. Ohye, and Edward L. Bove
82 Valvular Heart Disease and Cardiac Tumors
Tomislav Mihaljevic, Craig M. Jarrett, Husain T. AlQattan, Shehab Ahmad Redha AlAnsari, Haris Riaz, Marijan Koprivanac, and
A. Marc Gillinov
83 Ischemic Heart Disease
Jonathan W. Haft
84 Mechanical Circulatory Support for Cardiac Failure
35
Gordan Samoukovic and Francis D. Pagani
85 Thoracic Aortic Aneurysms and Aortic Dissection
Ravi K. Ghanta and Gorav Ailawadi
86 Pericardium
Jules Lin
87 Vascular Diagnostics: The Noninvasive Vascular Laboratory
Gregory L. Moneta
88 Vascular Infection
Jayer Chung and J. Gregory Modrall
89 Cerebrovascular Disease
Martyn Knowles and Carlos H. Timaran
90 Upper Extremity Arterial Disease
Heron E. Rodriguez
91 Renal and Splanchnic Vascular Disease
Dawn M. Coleman, John E. Rectenwald, and Gilbert R. Upchurch, Jr.
92 Aortoiliac Disease
Loay S. Kabbani, Mitchell R. Weaver, and Alexander D. Shepard
93 Peripheral Arterial Disease
William P. Robinson III
94 Lower Extremity Amputation
Matthew J. Sideman, Kevin E. Taubman, and Bradley D. Beasley
95 Thoracoabdominal Aortic Aneurysms
Hazim J. Safi, Anthony L. Estrera, Charles C. Miller III, Kristofer M. Charlton-Ouw, Dianna Milewicz, and Ali Azizzadeh
96 Abdominal Aortic Aneurysms
Adam W. Beck, Kristina A. Giles, and Thomas S. Huber
97 Lower Extremity Aneurysms
Amy B. Reed
98 Venous Disease
Thomas W. Wakefield and Michael C. Dalsing
SECTION N: PEDIATRIC SURGERY

99 Fetal, Neonatal, and Pediatric Physiology
Samir K. Gadepalli and George B. Mychaliska
100 Fetal Intervention
George B. Mychaliska and Darrell L. Cass
101 Pediatric Head and Neck
Laura L. Neff and Reza Rahbar
102 The Pediatric Chest
Mary C. Santos and Robert E. Cilley
103 Pediatric Abdomen
Thomas T. Sato and Marjorie J. Arca
104 Pediatric Genitourinary System
John M. Park and Julian Wan
105 Childhood Tumors
Erika Adams Newman
106 The Pregnant Patient
Juan L. Martinez-Poyer and N. Scott Adzick
SECTION O: SKIN AND SOFT TISSUE

107 Cutaneous Neoplasms
Michael S. Sabel, Timothy M. Johnson, and Christopher K. Bichakjian
36
108 Sarcomas of Soft Tissue and Bone
Sandra L. Wong
109 Plastic and Reconstructive Surgery
Christian J. Vercler, David L. Brown, Steven R. Buchman, Paul S. Cederna, Kevin C. Chung, Jeffrey H. Kozlow, William M.
Kuzon, Jr., Adeyiza O. Momoh, and Edwin G. Wilkins
Index
37
List of Algorithms
Algorithm 8-1. Empiric antimicrobial treatment of extrabiliary cIAIs, community acquired
versus healthcare associated
Algorithm 8-2. Biliary infections and algorithm for diagnosis and management
Algorithm 8-3. Step-up approach to management of necrotizing infected pancreatitis
Algorithm 9-1. Neurohormonal response to hypovolemia
Algorithm 9-2. Shock resuscitation algorithm
Algorithm 11-1. Hyponatremia
Algorithm 11-2. Acute hyperkalemia
Algorithm 11-3. Guidelines for the treatment of diabetic ketoacidosis
Algorithm 12-1. Protocol for frostbite injury
Algorithm 13-1. Decision aid for preoperative cardiac evaluation prior to noncardiac surgery.
This decision tree for preoperative evaluation takes into account not only the
patient’s physical status but also the severity of the surgical procedure
Algorithm 13-2a-b. Algorithm for managing a patient on chronic buprenorphine therapy
Algorithm 15-1. Stepwise Approach to Perioperative Cardiac Assessment for CAD
Algorithm 15-2. Proposed algorithm for antiplatelet management in patients with PCI and
noncardiac surgery
Algorithm 15-3. Preoperative evaluation of patients with lung cancer for resection
Algorithm 15-4. Proposed algorithm for preoperative evaluation of patients with liver disease
Algorithm 19-1. 2011 Guidelines for the Field Triage of the Injured Patients
Algorithm 21-1. Glasgow Coma Scale (GCS) triage guide for initial evaluation of head injury.
For the motor scale, the best response for any limb is recorded
Algorithm 21-2. Prehospital evaluation and treatment of a patient with severe traumatic brain
injury. “Signs of increased ICP” is the decision point for determining the
necessity of intracranial pressure (ICP)-lowering therapy. These signs include
pupillary abnormalities, motor posturing, or neurologic deterioration not
related to medications. The order of steps is determined by the risk–benefit
ratio for individual treatment maneuvers. This algorithm should be viewed as
“expert opinion” and used as a framework, which may be useful in guiding an
approach to field management of such patients
Algorithm 21-3. Evaluation and treatment of the patient with severe traumatic brain injury on
arrival at the trauma center. The order of steps is determined by the risk–
benefit ratio for individual treatment maneuvers. This algorithm should be
viewed as “expert opinion” and used as a framework, which may be useful in
guiding an approach to initial hospital management of such patients prior to
the initiation of ICP monitoring
Algorithm 26-1. Algorithm for the evaluation and management of renal injury
Algorithm 26-2. Algorithm for the evaluation and management of ureteral injury
Algorithm 26-3. Algorithm for the evaluation and management of urethral injury
Algorithm 28-1. The Denver Protocol for management of major pelvic fractures
Algorithm 29-1. PECARN rules to identify children at very low risk of clinically important TBI.
CT algorithm for children younger than 2 years (A) and for those aged 2 years
and older (B) with GCS scores of 14–15 after head trauma
Algorithm 29-2a-b. Algorithm generated by the Brain Trauma Foundation Committee for the first
edition of the Guidelines for the Medical Management of Severe Traumatic Brain
Injury in Infants, Children, and Adolescents for first-tier therapies (A) and
second-tier therapies (B)
Algorithm 29-3. New ATOMAC guidelines for management of pediatric solid organ injury
Algorithm 36-1. Stepwise approach to the management of decreased low urine output
posttransplant
38
Algorithm 39-1. The donor management algorithm used at the University of Michigan in
coordination with the organ procurement organization, Gift of Life. Optimal
PEEP is determined by increasing PEEP 2 cm of H2O every 3 to 5 minutes
until compliance decreases. Recruitment maneuvers include CPAP at 30 cm of
H2O for 30 seconds every 20 minutes × 3
Algorithm 41-1. Workup of a Neck Mass in an Adult Patient
Algorithm 42-1. 24-Hour Esophageal pH Monitoring
Algorithm 43-1. Evaluation and treatment of esophageal perforation
Algorithm 43-2. Proposed algorithm for evaluation and management of acute caustic ingestion
Algorithm 43-3. Evaluation and treatment of esophageal leiomyoma
Algorithm 45-1. Treatment of bleeding duodenal ulceration
Algorithm 46-1. Algorithm for management of abdominal pain months or years after Roux-en-
Y reconstruction
Algorithm 47-1. Treatment of gastric adenocarcinoma
Algorithm 49-1. Algorithm for the management of adhesive small bowel obstruction
Algorithm 49-2. Approach to the management of malignant bowel obstruction
Algorithm 50-1. Crohn disease with anal complaints
Algorithm 50-2. Anal skin tags in Crohn disease
Algorithm 50-3. Hemorrhoids in Crohn disease
Algorithm 50-4. Anal abscess/fistula in Crohn disease
Algorithm 50-5. Anal fissure in Crohn disease
Algorithm 50-6. Anal stenosis/stricture and Crohn disease
Algorithm 51-1. Management algorithm for patients with advanced neuroendocrine tumors
(NETs) of the gastrointestinal tract
Algorithm 51-2. Algorithm showing the management of patients with small bowel
adenocarcinomas. The treatment strategy depends on disease stage and
involves en bloc resection for locoregional disease and systemic chemotherapy
for metastatic disease. All current recommendations are based on case series,
retrospective reviews or nonrandomized prospective trials because of an
absence of any randomized data
Algorithm 51-3. Treatment algorithms for patients with (A) advanced/metastatic GIST and (B)
resectable GIST. GIST indicates gastrointestinal stromal tumor
Algorithm 53-1. Algorithm for the management of acute pancreatitis
Algorithm 54-1. Algorithm for operative decision-making in chronic pancreatitis
Algorithm 55-1. International consensus guidelines for the management of IPMNs
Algorithm 55-2. Management strategy based on CT criteria for resectability of pancreatic
cancer
Algorithm 56-1. Diagnosis and management of pancreatic endocrine neoplasms
Algorithm 59-1. Suggested treatment options, in order of preference, for patients who fail
medical management for variceal bleeding
Algorithm 60-1. BCLC algorithm for treatment selection in patients with HCC
Algorithm 60-2. Treatment algorithm of patients with hepatocellular carcinoma (HCC) based
on serum bilirubin level and indocyanine green retention rate at 15 minutes
Algorithm 60-3. Multidisciplinary treatment approach for colorectal liver metastasis
Algorithm 61-1. Algorithm for the management of common bile duct stones
Algorithm 61-2. Management of acute cholangitis
Algorithm 62-1. Algorithm for diagnosis and management of bile duct injury associated with
laparoscopic cholecystectomy
Algorithm 65-1. Diagnostic steps in the evaluation of gastrointestinal hemorrhage
Algorithm 68-1. Approach to rectal cancer according to clinical staging
Algorithm 68-2. Approach to locally advanced rectal cancer based on a three-tier risk
stratification system (“the good, the bad, and the ugly”)
Algorithm 68-3. Stage IV rectal cancer treatment algorithm
Algorithm 69-1. Diverticulitis Treatment based on Modified Hinchey Score (0–IV)
39
Algorithm 72-1. Management of initial inguinal hernia
Algorithm 72-2. Management of recurrent inguinal hernia
Algorithm 72-3. Management of groin pain after herniorraphy
Algorithm 72-4. Management of incisional hernia
Algorithm 74-1. Diagnosis and management of the patient with a clinically benign breast mass.
The use of imaging studies varies according to age because breast carcinoma is
infrequent in women younger than 35 years old
Algorithm 74-2. Diagnosis and management of the patient with a clinically indeterminate or
suspicious solid breast mass. In this circumstance, imaging studies are
insufficient to exclude malignancy, and tissue sampling is required
Algorithm 74-3. Diagnosis and management of the patient with a cystic lesion. Bloody fluid on
aspiration, failure of the mass to resolve completely, and prompt refilling of
the same cyst are indications for surgical biopsy
Algorithm 74-4. Management of the patient with an abnormal screening mammogram. When
pathology is benign, concordance or discordance with imaging findings
dictates whether surgical excisional biopsy is indicated
Algorithm 75-1. Management algorithm for thyroid mass
Algorithm 77-1. Diagnosis of hypercortisolism
Algorithm 77-2. Diagnosis and management of hyperaldosteronism
Algorithm 77-3. Diagnosis and management of the incidental adrenal mass
Algorithm 78-1. Treatment algorithm for acromegaly
Algorithm 78-2. Treatment algorithm for Cushing disease
Algorithm 79-1. Management of the incidental solitary pulmonary nodule
Algorithm 79-2. Evaluation of the patient who presents with a pulmonary mass
Algorithm 79-3. This algorithm illustrates the preoperative functional evaluation prior to lung
cancer resection
Algorithm 80-1. Algorithm for management of lung abscess
Algorithm 80-2. Hemoptysis management
Algorithm 80-3. LVRS candidate workup
Algorithm 80-4. Algorithm to treat pneumothorax.
Algorithm 80-5. Algorithm for management of tracheal masses
Algorithm 84-1. Current algorithm for assessing patients with advanced heart failure for heart
transplantation and mechanical circulatory support. Transplant status is
initially assessed to determine appropriate indication for MCS use; BTT vs. DT
Algorithm 86-1. This algorithm outlines the initial approach to a patient with a large
pericardial effusion
Algorithm 92-1. Patient with symptomatic aortoiliac occlusive disease
Algorithm 97-1. Management of femoral pseudoaneurysm
Algorithm 98-1. Treatment of chronic venous insufficiency
40
Part One Scientific Principles
41
Chapter 1
Lifelong Learning
Gurjit Sandhu and Rebecca M. Minter
Key Points
1 Self-regulated learning is a skill that can be taught to trainees.

2 The Dreyfus model of skill development is helpful for understanding the growth and depth of self-
regulated learning from novice to expert level.
3 As self-regulated learning solidifies and becomes habitual for the trainee, it enhances transitions into
effective lifelong learning.
4 Lifelong learning is an essential component of safe patient care with up-to-date knowledge and skills.
5 Surgeons who are lifelong learners are better prepared to deal with the complexities of future
practice.
LIFELONG LEARNING FOR PERSONAL, PROFESSIONAL, AND

SOCIAL RESPONSIBILITY
The Accreditation Council for Graduate Medical Education (ACGME) Task Force on Quality Care and
Professionalism has drawn a clear and explicit connection among professionalism, safe patient care, and
lifelong learning.1 This is a direct reference to ensuring that graduate medical education programs are
graduating fully trained physicians who are prepared to practice independently.1,2 In order to achieve
this goal, exposure to the curriculum is insufficient. Surgeons in training must demonstrate that they are
able to perform the activities of a specialist in that field. This becomes a complex feat of curriculum
development and learner assessment when one considers that even as learners are graduating from their
training programs, their specialties are evolving. With a patient population that is older, has higher
acuity, greater number of chronic diseases and comorbidities, accompanied with unprecedented growth
in medical knowledge, it is naive to assume that trainees will graduate with mastery of every facet of
their discipline.3,4 Hence, graduating physicians who are primed for lifelong learning becomes a salient
professional and social responsibility of graduate medical education programs.
Ultimately, lifelong learning is about bringing together individual responsibility with safe patient
care. The commitment to ongoing reflective learning lends itself to a practice where research,
education, and experience come together to best serve the needs of the patient. ACGME emphasis on
lifelong learning is evidenced in two concrete ways: (1) by the continuum with which milestones are
developed – beginning with the pretrained novice and extending throughout the physician’s career –
reinforcing learning and growth beyond graduation; and (2) an explicit ACGME Common Program
Requirement stating “residents must demonstrate the ability to investigate and evaluate their care of
patients, to appraise and assimilate scientific evidence, and to continuously improve patient care based
on constant self-evaluation and lifelong learning.”5,6 Several surgical specialties have gone on to include
lifelong learning as a milestone within the practice-based learning and improvement competency.7–10
If lifelong learning is an outcome that is sought among high performing, safe, up-to-date surgeons, it
is imperative that surgeons in training develop appropriate knowledge, skills, and attitudes during
training that will foster this habitual behavior for when they are in professional practice. Just as
management of complex problems or knowledge about postoperative complications of most essential
operations are milestones that are met in a progressive manner, the same is true about lifelong learning
as a milestone that is met in a progressive manner. As a trainee works toward honing and
demonstrating expertise for lifelong learning, progressive development toward this goal while still in a
residency program would be called self-regulated learning. In other words, the goal over time is for a
resident/fellow to fully and intuitively adopt self-regulated learning and graduate from training
entrusted to embrace lifelong learning. Before considering the development of self-regulated learning in
42
a graduated manner across the continuum of graduate medical education, it is important to define and
establish the relationship between self-regulated and lifelong learning.
SELF-REGULATED LEARNING
1 Self-regulated learning has been used to describe students who are “metacognitively, motivationally,
and behaviorally active participants in their own learning process.”11 This includes the ability to plan
and organize self-instruction, monitor and assess self, and seek out optimal learning opportunities.
White et al.12 argue that these are not merely innate attributes, but skills that can be taught during
medical training. Self-regulated learning is framed as a cycle of four phases12:
1. Planning
2. Learning
3. Assessment
4. Adjustment
Planning is about setting personal goals, establishing desired outcomes, and having the belief in one’s
ability to achieve those goals. In this phase, intrinsic motivation and extrinsic motivation are important
considerations in the setting and reaching of learning goals. While extrinsic motivation is embedded in
graduate medical education (e.g., passing certifying oral examinations), it is intrinsic motivation that is
“key to the development of autonomy” and “autonomy is key to lifelong learning.”12 Therefore, during
the planning phase, learners develop a sense of urgency for their own learning and an ability to plan
and act on goals.
During the Learning phase, learners need clarity about how they learn most effectively. This includes
developing awareness about one’s personal beliefs toward acquiring knowledge, preferred ways of
learning (e.g., visual, auditory), learning strategies (e.g., where and when studying happens), and
finally aligning learning expectations with those of the educator.
Assessment requires timely, specific, and regular formative feedback (e.g., from supervisors,
colleagues, medical students) as well as internal monitoring that compares one’s progress against the
goal that was set. Together these sources of feedback guide the learner’s next steps toward reaching the
goal.
Finally, Adjustment is where the learner synthesizes what has been gained through the planning,
learning, and assessment phases and makes adjustments either in the nature of the goal or in the
strategies needed to reach the goal. How learners integrate information about successes or failures
could be seen as a matter of attribution – how performance is accounted for ranging from ability to
effort. Examining the performance feedback that has been gathered to date, considering the validity of
the information, and then determining how to make sense of it in relation to what they already know is
a complex process of reflection.13
Through explicit teaching and practice at each phase, learners are guided toward sustaining strategies
for ongoing, more effective self-regulated learning. Sustainable strategies form the basis for lifelong
learning. White et al.12 underscore sustainable strategies as a key to continuing medical education
(CME) for the practicing surgeon and point to the link between CME and quality health care.
LIFELONG LEARNING
If the phases of self-regulated learning solidify for the trainee, they become habitual characteristics of
effective lifelong learning. In the broadest sense, lifelong learning is about ongoing learning from cradle
to grave. However, in the context of entering the workplace after graduate medical education, we look
at physicians and lifelong learning more closely as the “ability to guide their own learning throughout
their lives and in the wide variety of situations they will encounter after leaving formal education.”14
This ongoing reflexive process of lifelong learning includes five characteristics14:
1. set goals
2. apply appropriate knowledge and skills
3. engage in self-direction and self-evaluation
4. locate required information
5. adapt their learning strategies to different conditions
43
These characteristics are meant to extend the physician’s concept of ongoing learning from “lifelong
schooling” to “life-wide learning” so that personal inquiry can happen, for example, at the bedside or in
the community and is not constrained to formal educational opportunities.14
As a trainee transitions through different levels in residency, the nature of self-regulated learning will
also change depending on the learner’s needs. As learners meet increasingly more complex patient care
milestones, the practice of self-regulated learning transforms accordingly. Solidifying the phases of self-
regulated learning during graduate medical education feeds into establishing effective characteristics for
lifelong learning that become a critical part of a physician’s everyday practice (Table 1-1). As such,
medical education programs have a social and professional obligation to further develop and deepen
characteristics of self-regulated learning among learners so that graduating surgeons pursue professional
learning throughout their careers.5 It is critically important that a robust curriculum be established
within graduate medical education for teaching, engaging with, and assessing practices for lifelong
learning.
Table 1-1 Relationship Between Self-Regulated Learning and Lifelong Learning
Self-regulated learning evolving and deepening into lifelong learning is best understood using the
Dreyfus model for skill development.15 This is in keeping with the foundational framework from which
the milestone frameworks have been structured to assess residents/fellows in surgical disciplines.1
DREYFUS MODEL FOR SKILL DEVELOPMENT

The Dreyfus model for skill development identifies five levels of skill development15–17:
1. Novice
2. Advanced Beginner
3. Competent
4. Proficient
5. Expert
On this continuum, learners pass from one level to the next as skills are acquired. At each level, there
are “recognizable, qualitatively different ways of acting and performing in the process of learning a
given skill. Individuals at a given level do better than individuals at the previous level.”18 Table 1-2
presents the five levels of the Dreyfus model with the addition of delineating each level along four
characteristics of skill development: knowledge; decision-making; perception of context; and
autonomy.19–23 Increasing understanding, confidence, and independence associated with these
characteristics is in keeping with higher levels of competency with the skill being measured. This
delineated view demonstrates in a granular way how a learner progresses and performs differently at
each level. Based on criteria, it is clear why not every learner reaches the highest level. The criterion-
based foundation of the Dreyfus model makes it a widely adapted process for assessment.23,24
2 At the novice level, learners largely have textbook familiarity with a skill. After having advanced to
the expert level, learners have extensive experiential knowledge with a skill and are seen to be highly
intuitive. We understand self-regulated learning to be a skill that can be learned, will progressively
grow and deepen over time, is carried out differently at each successive level, and ought to be carried
out in the workplace. As the skill is honed and becomes habitual, self-regulated learning transitions into
lifelong learning. This progression in skill development makes the Dreyfus model highly appropriate for
understanding, teaching, and assessing self-regulated learning.
Table 1-2 Dreyfus Model of Skill Development: Novice to Expert Levels for Self-
44
Regulated Learning
DREYFUS MODEL OF SKILL DEVELOPMENT APPLIED TO SELF-

REGULATED LEARNING IN SURGERY
The attributes and practice of self-regulated learning change as learners transition from one level to the
next. In other words, as learners attain greater levels of responsibility, the goals they set for
themselves, insights adopted about learning, feedback they require, and adjustments they make based
on successes and failures will be different from one level to the next. This is in line with gradually more
mature forms of reflection and insightful learning plans learners develop for themselves. Self-regulated
learning will be described at each level in terms of the learner’s skills, but also includes suggestions for
educators on how to teach at the level of the learner and establish scaffolds to support the learner
advancing to the next level.23,24
Novice
The novice learner is focused on figuring out how textbook knowledge applies to the current
experience. The goals learners set for themselves are about making sense of uncertain or unfamiliar
content by connecting it to existing familiar sets of knowledge. At this point, the learner adheres to
step-by-step rules, regardless of context. Working through a methodical line of reasoning without
situational awareness or discretion makes it difficult for the trainee to deal with exceptions and
45
complexity.24 The learner searches for absolute answers. Tendencies toward binary sets of knowledge
reveal that learners at this level often do not know what they do not know (unconscious incompetence),
suggesting they have an incomplete development of self-assessment.25 After routine-guided observations
of procedures being performed, novice learners are incrementally moved to close supervision with
explicit instruction in order to complete tasks. Reflecting on their behavior during experiential
opportunities along with the feedback received from faculty or more senior residents and fellows causes
learners to revisit the knowledge they believed to be universally true and adjust their goals and views
on learning.
Educators must be deliberate and specific in the feedback that is provided, even being explicit about
the phases of effective self-regulated learning that should be developed. Educators become a resource as
trainees learn to develop appropriate goals and establish a plan forward. Determining the existing level
of the learner and learning preferences of the trainee is essential for educators so that they can guide
the learner toward suitable challenges that will scaffold him/her to the next level.
Advanced Beginner
For the advanced beginner, emphasis is on gaining practical experiences and knowledge. The balance
tilts from taking textbook knowledge and applying it to the context, to better understanding the
context, patient indicators, and beginning to discern and apply rules. Although perception is improving,
judgments are still quite limited. The advanced beginner continues to be rational and analytic, but now
sees actions as related rather than a series of independent steps.24 Developing an understanding of
connectedness helps learners realize the complexity of situations and with that comes an appreciation
for how much they do not know (conscious incompetence).25
Faculty provide trainees with structured opportunities and directly observe their skills. Under this
closely guided practical experience, trainees assist with performing a procedure and receive some
opportunities to try simpler tasks on their own. There is a high likelihood these trainees will be able to
accomplish these simpler tasks successfully. With the learner starting to see steps as related, this is an
opportunity for the educator to give feedback that will push the learner to be aware of more complex
connections. Learners still require supervision for the procedure largely because they continue to have
difficulty with troubleshooting. Educators should provide challenges just at the edge of the learners
comfort level. The trainee’s performance will help the educator identify where emphasis needs to be
placed in the next educational encounter. It is important to debrief this experience with the learner so
s/he can reflect back on emotions, thinking, and skills and establish subsequent goals. Educators
simultaneously assess how much scaffolding learners require to extend them to the next level while also
removing scaffolds as the learner demonstrates task competence.
Competent
At the competent level, the learner has well-developed conceptual models and fund of knowledge in a
specialty. Although still primarily rational and analytic in decision-making, the learner is largely led by
guidelines that are specific to the given context. In other words, through deliberate planning and
judgment, the trainee can see the larger context and handle complex situations.24 Trainees recognize
what they know, for example, the limits of what they are able to troubleshoot on their own, and also
know when to ask for guidance or help (conscious competence).25 Safely progressing in a high-stakes
environment while knowing when to slow down or stop is indicative of being able to reflect while in
the moment. A competent level learner will reflect on actions and develop long-term goals.
Educators recognize that learners are able to complete an entire procedure independently to an
optimal level. Nevertheless, educators still provide direct supervision to guide refinement, efficiencies,
and standardization of procedures. With increasingly complex skills, educators will model specific
methods. Learners at the competent stage ask for feedback and the response of the educator becomes
less about general principles and more about fostering specific opportunities for individualized growth.
While still under direct supervision, individualized instruction allows faculty to release greater degrees
of responsibility for the full spectrum of patient care to residents/fellows so they can begin to take
ownership and think ahead in developing a care plan.
Proficient
The proficient level represents a learner who sees context, actions, and interactions holistically.
Physician core competencies (e.g., Patient Care and Professionalism), as outlined by the ACGME, are
understood and enacted in an integrated way into the roles and responsibilities of the learner.6 It is in
46
seeing the bigger picture that the trainee is able to filter out extraneous materials and focus on essential
information that results in less labored decision-making and consistently high levels of performance.24
Residents/fellows are able to apply the depth of knowledge they have acquired in their specialty and
increasingly become more intuitive with less dependence on rules (unconscious competence).25 Trainees
continue to be guided by maxims and rationale approaches to address unusual problems or deviations
from expected patterns. The trainee reflects on personal performance with the goal of being able to
efficiently merge intuitive and rationale approaches in complex situations.
Proficient residents/fellows have demonstrated that they reliably perform at an acceptable standard;
therefore, there is a greater degree of indirect supervision. The role of faculty is to provide
opportunities for learners to take full responsibility for performing a procedure, as well as work
through uncommon cases. The feedback provided to learners is specific and formative (i.e., not scored)
in helping them reach self-identified goals, as well as extend their critical thinking to unique problems
and situations.
Expert
At the expert level, individuals have deep holistic understanding in their specialty. Depth of knowledge
has provided them with intuitive understanding, confidence in decision-making, and ability to
successfully manage complex situations with ease.24 When faced with novel situations, they are able to
seamlessly proceed with alternative approaches, consciously draw on guidelines and maxims, and
consider innovative possibilities. Internal creative inquiry challenges these individuals to raise questions
to themselves, put the mental brakes on what is familiar, and set goals that extend the field in new
directions.26 Experts are thought to be authorities in their specialties.
Individuals at this level rarely receive feedback unless they ask for it.27 They adjust and adapt their
learning with regular review of current literature, participating in CME, and pursuing and publishing
research. As surgeons who independently perform procedures without any supervision, experts also rely
on patient outcomes – by reflecting in action (e.g., adapting to unexpected conditions) and reflecting on
action (e.g., follow-up care with patient) – as forms of feedback to inform practice.13,28 The expert level
does not represent completion in learning, rather it signifies that a learner has the skills to continue to
stay informed through workplace-based learning. This transition into habitual, ongoing, life-wide
learning illustrates that a learner has solidified skills for lifelong learning.
SELF-REGULATED LEARNING AND LIFELONG LEARNING IN

SURGERY EDUCATION
3 4 The purpose of this discussion is to show that skills for self-regulated learning can be learned,
developed, and transformed into lifelong learning. The Dreyfus model provides an accessible model for
visualizing the development and progression of skills from self-regulated learning into lifelong learning.
The implications for overlooking development of lifelong learning skills are less obvious while under
the observation and guidance of a Surgery Education program. However, if the goal of Surgery
Education programs is to produce surgeons who are able to practice independently, actively pursue safe
patient care with up-to-date knowledge and skills, then the development of skills for lifelong learning
cannot be easily overlooked while still in training. As such, the role of faculty educators to model and
explicitly teach about self-regulated learning and lifelong learning is essential.
Educators of residents/fellows at early levels of skill development must be explicit and concrete when
explaining how to set independent goals for advancing abilities, as well as provide specific instructions
on how to pursue inquiry on their own. As trainees deepen their skills and apply those more routinely,
the responsibility for stimulating habitual inquiry begins to shift from the faculty to the trainee. The
faculty now looks for the ways in which surgeons in training seek, receive, and provide feedback as
indicators of the awareness learners have about where they need to focus their attention for growth.29
With still further development of self-regulated learning, learners will likely transition into lifelong
learners.
5 When advancing in training and moving into careers as experts, there is a great deal of familiarity
with procedures, processes, and knowledge. When there is unconscious competence or deep
understanding, automaticity sets in. Individuals at this level have ingrained skills and habits that
routinely incite internal creative inquiry causing them to challenge these familiar patterns. The lifelong
learner purposefully “makes unconventional linkages (…) in order to reveal unseen aspects.”26 The
47
lifelong learner also seeks, applies, and makes new meaning. These are the surgeons who are prepared
to deal with the problems of today, but even better prepared to deal with complexities that are yet to
be encountered.
References
1. ACGME. The ACGME 2011 Duty hour standard: enhancing quality of care, supervision and resident
professionalism development. 2011. Available from:
http://www.acgme.org/acgmeweb/Portals/0/PDFs/jgme-monograph%5b1%5d.pdf. Accessed May
27, 2016.
2. Nasca TJ, Heard JK, Commentary: trust, accountability, and other common denominators in
modernizing medical training. Acad Med 2010;85(6):932–934.
3. Are American Patients Getting Sicker? 2012. Available from:
http://www.aha.org/research/reports/tw/12dec-tw-ptacuity.pdf.
4. Arora S, Thornton K, Komaromy M, et al. Demonopolizing medical knowledge. Acad Med
2014;89(1):30–32.
5. ACGME. ACGME common program requirements. 2013. Available from:
https://www.acgme.org/acgmeweb/Portals/0/PFAssets/ProgramRequirements/CPRs2013.pdf.
Accessed May 27, 2016.
6. ACGME. Milestones. 2011. Available from:
https://www.acgme.org/acgmeweb/tabid/430/ProgramandInstitutionalAccreditation/NextAccreditationSystem
7. ACGME. Thoracic surgery milestones. 2012. Available from:
https://www.acgme.org/acgmeweb/Portals/0/PDFs/Milestones/ThoracicSurgeryMilestones.pdf.
8. ACGME. The plastic surgery milestone project. 2013. Available from:
https://www.acgme.org/acgmeweb/Portals/0/PDFs/Milestones/PlasticSurgeryMilestones.pdf.
9. ACGME. The pediatric surgery milestone project. 2014. Available from:
https://www.acgme.org/acgmeweb/Portals/0/PDFs/Milestones/PediatricSurgeryMilestones.pdf.
10. ACGME. The hand surgery milestone project. 2013. Available from:
https://www.acgme.org/acgmeweb/Portals/0/PDFs/Milestones/HandSurgeryMilestones.pdf.
11. Zimmerman BJ. Becoming a self-regulated learner: which are the key subprocesses? Contemp Educ
Psychol 1986;11(4):307–313.
12. White CB, Gruppen LD, Fantone JC. Self-regulated learning in medical education. In: Swanwick T,
ed. Understanding Medical Education: Evidence, Theory and Practice. 2nd ed. Oxford: John Wiley &
Sons, Ltd; 2013:201–211.
13. Embo MP, Driessen E, Valcke M, et al. Scaffolding reflective learning in clinical practice: a
comparison of two types of reflective activities. Med Teach 2014;36(7):602–607.
14. Kirby JR, Knapper C, Lamon P, et al. Development of a scale to measure lifelong learning. Int J
Lifelong Educ 2010;29(3):291–302.
15. Dreyfus SE. The five-stage model of adult skill acquisition. Bull Sci Technol Soc 2004;24(3):177.
16. Dreyfus S, Dreyfus H. A five stage model of the mental activities involved in directed skill
acquisition. Operations Research Center University of California, Berkeley [monograph on the
Internet]; 1980. Available from: http://www.dtic.mil/docs/citations/ADA084551.
17. Batalden P, Leach D, Swing S, et al. General competencies and accreditation in graduate medical
education. Health Aff (Millwood) 2002;21(5):103–111.
18. Flyvbjerg, B. Making social science matter: why social inquiry fails and how it can succeed again.
Cambridge: Cambridge University Press; 2001 (trans. Steven Sampson).
19. Dreyfus SE. Formal models vs. human situational understanding: inherent limitations on the
modeling of business expertise. Office Technology People 1982;1(2/3):133–165.
20. Dreyfus H, Dreyfus S. Putting computers in their proper place: analysis versus intuition in the
48
classroom. Teach Coll Rec 1984;85(4):578–601.
21. Institute of Conservation. PACR Professional Standards. 2008. Available from:
http://www.collectionstrust.org.uk/events/item/882-pacr-professional-standards. Accessed May 27,
2016.
22. Stan Lester Developments. Novice to expert: the dreyfus model of skill development. 2005.
Available from: http://devmts.org.uk/dreyfus.pdf. Accessed May 27, 2016.
23. Honken N. Dreyfus five-stage model of adult skills acquisition applied to engineering lifelong
learning. 120th American Society for Engineering Education. 2013. Available from:
http://www.google.com/url?
url=http://www.asee.org/public/conferences/20/papers/6110/download&rct=j&frm=1&q=&esrc=s&sa=U
24. Carraccio CL, Benson BJ, Nixon LJ, et al. From the educational bench to the clinical bedside:
translating the Dreyfus developmental model to the learning of clinical skills. Acad Med
2008;83(8):761–767.
25. Robinson WL. Conscious competency - the mark of a competent instructor. Pers J 1974;53(7):538.
26. Wagoner B. Commentary: making the familiar unfamiliar. Cult Psychol 2008;14(4):467–474.
27. Finkelstein SR, Fishbach A. Tell me what I did wrong: experts seek and respond to negative
feedback. J Cons Res 2012;39(1):22.
28. Schon D. Educating the reflective practitioner. 1987. Available from:
http://resources.educ.queensu.ca/ar/schon87.htm.
29. Delva D, Sargeant J, Miller S, et al. Encouraging residents to seek feedback. Med Teach
2013;35(12):e1625–e1631.
49
Chapter 2
Principles of Intermediary Metabolism

Steven E. Raper
Key Points
1 Intermediary metabolic pathways – the metabolic manipulation and balancing of ingested

carbohydrate, fat, and protein – can process essentially all nutrients to acetyl coenzyme A (CoA) for
energy production predominantly through aerobic glycolysis, the citric acid cycle, and oxidative
phosphorylation.
2 Glucose must always be available for brain function; if not available directly from the diet, it can be
mobilized for a brief period from glycogen stores and then derived from proteins in the liver and
kidneys.
3 Free fatty acids are a direct source of energy for cardiac and skeletal muscles.
4 Hepatic protein synthesis, when excess amino acids are available, includes albumin, fibrinogen, and
apolipoproteins and can reach 50 g/day.
5 The citric acid cycle includes a series of mitochondrial enzymes that transform acetyl CoA – itself
derived from pyruvate or fatty acyl CoA – into water, carbon dioxide, and hydrogen-reducing
equivalents. Each molecule of acetyl CoA that enters the citric acid cycle yields 12 molecules of
adenosine triphosphate (ATP).
6 Oxidative phosphorylation converts the energy from NADH and FADH2 into ATP by the electron
transport chain and ATP synthase with a process called the proton motive force.
7 Biotransformation of potentially toxic, often hydrophobic, compounds into hydrophilic, excretable
compounds occurs mainly in the liver by the cytochromes P-450, the uridine diphosphate-glucuronyl
(UDP-glucuronyl) transferases, the glutathione (GSH) S-transferases, and the sulfotransferases.
INTERMEDIARY METABOLISM: AN OVERVIEW

Introduction
Intermediary metabolism – derived from the Greek word for change – is predominantly the fate of
dietary carbohydrate, fat, and protein in a series of life-sustaining cellular chemical transformations.
Although admittedly intricate, all surgeons should be familiar with the basics of the biochemistry by
which nutrients are converted to energy. Understanding the major biochemical pathways is a
prerequisite to making use of the rapid – and exciting – expansion of medical knowledge directed at
managing human metabolic derangement and improving health by beginning at the cellular level.
1 Intermediary metabolic pathways – the metabolic manipulation and balancing of ingested
carbohydrate, fat, and protein – can process essentially all nutrients to acetyl coenzyme A (CoA) for
energy production predominantly through aerobic glycolysis, the citric acid cycle, and oxidative
phosphorylation. The major intermediary metabolites are glucose, fatty acids, glycerol, and amino
acids. Glucose is metabolized to pyruvate and lactate by glycolysis. Aerobic metabolism allows
conversion of pyruvate to acetyl CoA. Acetyl CoA enters the citric acid cycle resulting in carbon dioxide,
water, and hydrogen-reducing equivalents (a major source of adenosine triphosphate [ATP]). In the
absence of oxygen, glycolysis ends in lactate. Glucose can be stored as or created from glycogen.
Glucose can also enter the phosphogluconate pathway, where it is converted to reducing equivalents for
fatty acid synthesis and ribose five-carbon sugars important in nucleotide formation. Glucose can be
converted into glycerol for fat formation and pyruvate for amino acid synthesis. Gluconeogenesis allows
synthesis of glucose from lactate, amino acids, and glycerol.
With regard to lipid metabolism, long-chain fatty acids arise from dietary fat or synthesized from
acetyl CoA. Fatty acids can be oxidized to acetyl CoA by the process of beta-oxidation or converted to
50
acylglycerols (fat) for storage as the main energy reserve. In addition to the fats noted previously,
acetyl CoA can be used as a precursor to cholesterol and other steroids and in the liver can form the
ketone bodies, acetoacetate and 3-hydroxybutyrate, which are critical sources of energy during periods
of starvation.
Proteins are degraded in two major ways: an energy independent path, usually in lysosomes, and an
energy requiring path, usually through the ubiquitin pathway. About three-fourths of the amino acids
generated in protein catabolism are reutilized for protein synthesis and one-fourth is deaminated to
form ammonia and subsequently urea. Amino acids may be divided into nutritionally essential and
nonessential. Nonessential amino acids require fewer enzymatic reactions from amphibolic
intermediates or essential amino acids. Each day, humans turn over 1% to 2% of total body protein.
CARBOHYDRATE METABOLISM
The products of intestinal carbohydrate digestion are glucose (80%) and fructose and galactose (20%).
Fructose and galactose are rapidly converted to glucose, and the body uses glucose as the primary
molecule for transport and uptake of carbohydrates by cells throughout the body. Despite wide
fluctuations in dietary intake, blood glucose levels are tightly regulated by the liver. About 90% of
portal venous glucose is removed from the blood by liver cells through carrier-facilitated diffusion.
Large numbers of carrier molecules on the sinusoidal surface of the hepatocyte are capable of binding
glucose and transferring it to the cytoplasm. The rate of glucose transport is enhanced (up to 10-fold) by
insulin. Given the critical role of glucose in survival, complex metabolic pathways have evolved for the
storage of glucose in the fed state, the release of glucose from glycogen, and the synthesis of new
glucose.
Blood glucose is stored, primarily in liver and muscle, as glycogen. Glycogen is a complex polymer of
glucose with an average molecular weight of 5 million. The liver can convert up to 100 g of glucose
into glycogen per day by glycogenesis. The liver can also release glucose into the blood by
glycogenolysis, (breakdown of glycogen), or gluconeogenesis, (formation of new glucose from
substrates such as alanine, lactate, or glycerol). Hormones play a key role in the hepatic regulation of
glycogen balance. Insulin, for example, stimulates glycogenesis and glycolysis; glucagon stimulates
glycogenolysis and gluconeogenesis through cyclic adenosine monophosphate (AMP) and protein kinase
A.1
Glycogenesis and Glycogenolysis

2 Glucose must always be available for brain function; if not available directly from the diet, it can be
mobilized for a brief period from glycogen stores and then derived from proteins in the liver and
kidneys. The first step in glycogen storage is the transport of glucose through the plasma membrane.
Once in the hepatocyte, glucose and ATP are converted by the enzyme glucokinase to glucose-6-
phosphate (G6P), the first intermediate in the synthesis of glycogen (Fig. 2-1). Because complete
oxidation of one molecule of G6P generates 37 molecules of ATP, and storage uses only one molecule of
ATP, the overall efficiency of glucose storage as glycogen is a remarkable 97%.
Glycogenolysis does not occur by simple reversal of glycogenesis. Each glucose molecule on a
glycogen chain is released by glycogen phosphorylase (Fig. 2-2). Eventually, G6P is reformed. G6P
cannot exit from cells and must first be converted back to glucose. The conversion of G6P to glucose is
catalyzed by glucose-6-phosphatase, which exists only in hepatocytes, kidney, and intestinal epithelial
cells. Brain and muscle both use glucose as a primary fuel source and do not contain the phosphatase
enzyme. This lack of glucose-6-phosphatase ensures a ready supply of glucose for the energy needs of
brain and muscle. Liver uses glucose primarily as a precursor for other molecules and not for fuel.
Glycolysis
Glycolysis is the mammalian cellular pathway by which glucose is converted to pyruvate or lactate (Fig.
2-3). The glycolytic pathway is interesting in that glucose can be metabolized in the presence (aerobic)
or absence (anaerobic) of oxygen. Aerobic glycolysis is one of four stages in the oxidation of glucose
and the only stage that occurs in the cytosol. As will be discussed below, stages II to IV occur in
mitochondria; the citric acid cycle, electron transport generation of the proton motive force, and ATP
synthase leading to generation of ATP.
51
Figure 2-1. The chemical reactions of glycogenesis and glycogenolysis. Glucose-6-phosphatase allows hepatic glucose to be
transported out of the hepatocyte for use in other tissues. Glucose-6-phosphate, in red, plays a central role in carbohydrate
metabolism.
Figure 2-2. Glucagon-stimulated enzyme cascade, responsible for the control of glycogen metabolism. Inactive forms are shown in
black, active forms in blue.
The aerobic conversion of glucose to pyruvate has three effects: (a) a net gain of two ATP molecules,
(b) generation of two reducing equivalents of the nicotinamide adenine nucleotide (NADH + H+), and
usually, (c) conversion of pyruvate to acetyl CoA with subsequent conversion of acetyl CoA in the
mitochondria to ATP. The conversion of glucose to pyruvate is regulated by three enzymes: hexokinase
(glucokinase), phosphofructokinase, and pyruvate kinase, which are nonequilibrium reactions and as
such, functionally irreversible.
Under anaerobic conditions, NADH cannot be reoxidized by transfer of reducing equivalents through
the electron transport chain to oxygen. Instead, pyruvate is reduced by NADH to lactate. Glycolysis
takes place in the cytoplasm, in contrast to the citric acid cycle and oxidative phosphorylation which are
mitochondrial processes. During times of glucose excess, as in the fed state, hepatic glycolysis can
generate energy in the form of ATP, but the oxidation of ketoacids is a preferred energy source in liver.
The conversion of lactate (through pyruvate) to glucose – a process possible only in the presence of
oxygen – is an important means of preventing severe lactic acidosis. Active skeletal muscles and
erythrocytes form large quantities of lactate. In patients with large wounds, lactate also accumulates.
The liver is exceptionally efficient at converting lactate to pyruvate through the Cori cycle (Fig. 2-4). As
a result, one would expect that only significant liver dysfunction would affect the Cori cycle and lead to
hyperlactatemia. However, lactate levels are now widely used to assess shock – septic and otherwise.2
52
The hypothesis is that circulatory hypoperfusion impairs tissue oxygen delivery with resultant
mitochondrial hypoxia. In the absence of adequate oxygen, mitochondria switch to anaerobic glycolysis
and oxidative phosphorylation stops. As a result, serum lactate concentrations appear proportional to
ongoing tissue oxygenation deficits; thus improved lactate clearance can be used as a surrogate for
success of sepsis therapy.3 Serum lactate can also be used to assess prognosis and triage patients to ICU
level care.4
Figure 2-3. The glycolytic pathway. There is a net gain of two ATP molecules per glucose molecule. Phosphofructokinase is the
key regulatory enzyme in this pathway; however, all the enzymes in red catalyze irreversible reactions. The pathway shown here is
active only in the presence of aerobic conditions.
In erythrocytes, a unique variant of glycolysis enhances oxyhemoglobin dissociation. The first site in
glycolysis for generation of ATP is bypassed, leading to the formation of 2,3-bisphosphoglycerate by an
additional enzyme called bisphosphoglycerate mutase. Kinetics of the mutase present in erythrocytes
allow the presence of high concentrations of 2,3-bisphosphoglycerate to build up. The 2,3-
bisphosphoglycerate displaces oxygen from hemoglobin, allowing a shift of the oxyhemoglobin
dissociation curve to the right.
Gluconeogenesis
There is an absolute minimum requirement for glucose in humans. Below a certain blood glucose
concentration, brain dysfunction causes coma and death. When glucose becomes scarce, as in the fasting
state, glycogenolysis occurs. Once glycogen stores have been depleted, the liver and kidneys are capable
of synthesizing new glucose by the process of gluconeogenesis. Glucagon is produced in response to low
blood sugar levels and stimulates gluconeogenesis.
53
Figure 2-4. The gluconeogenesis pathway. The irreversible nature of the glycolytic pathway means that a different sequence of
biosyntheses is required for glucose production. The enzymes in red catalyze irreversible reactions that are different from those in
glycolysis. In mammals, glucose cannot be synthesized from acetyl coenzyme A, only from cytosolic pyruvate.
Gluconeogenesis is not a simple reversal of the glycolytic pathway. In glycolysis, as noted previously,
the conversion of glucose to pyruvate is a one-way reaction. As a result, four separate, functionally
irreversible enzyme reactions are required to convert pyruvate into glucose (Fig. 2-5). These enzymes
are pyruvate carboxylase, phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, and
glucose-6-phosphatase. Other enzymes are shared with the glycolytic pathway.
About 60% of the naturally occurring amino acids, glycerol, or lactate can also be used as substrates
for glucose production. Alanine is the amino acid most easily converted into glucose. Simple
deamination allows conversion to pyruvate, which is subsequently converted to glucose. Other amino
acids can be converted into three-, four-, or five-carbon sugars and then enter the phosphogluconate
pathway (next section). Gluconeogenesis is enhanced by fasting, critical illness, and periods of anaerobic
metabolism.
Figure 2-5. The Cori cycle, an elegant mechanism for the hepatic conversion of muscle lactate into new glucose. Pyruvate plays a
key role in this process.
54
Phosphogluconate Pathway
When glucose enters the liver, glycogen is formed until the hepatic glycogen capacity is reached (about
100 g). If excess glucose is still available, the liver converts it to fat by the phosphogluconate pathway
(also known as the pentose phosphate pathway) (Fig. 2-6). The cytosolic phosphogluconate pathway can
completely oxidize glucose, generating CO2 and nicotinamide adenine dinucleotide phosphate (NADPH)
through what is known as the oxidative phase. Hydrogen atoms released in the phosphogluconate
pathway combine with oxidized nicotinamide adenine dinucleotide phosphate (NADP+) to form reduced
nicotinamide adenine dinucleotide phosphate (NADPH − H+).5 The oxidative phase is present only in
tissues, such as the adrenal glands and gonads, that require reductive biosyntheses such as
steroidogenesis or other forms of lipid synthesis. Essentially, all tissues contain the nonoxidative phase,
which is reversible and produces ribose precursors for nucleotide synthesis. In erythrocytes, the
phosphogluconate pathway provides reducing equivalents for the production of reduced glutathione by
glutathione reductase. Reduced glutathione can remove hydrogen peroxide, which increases the
conversion of oxyhemoglobin to methemoglobin and subsequent hemolysis.
LIPID METABOLISM
Lipid Transport
Lipid transport throughout the body is made complicated by the fact that lipids are insoluble in water.
To overcome this physicochemical incompatibility, dietary triglycerides are first split into
monoglycerides and fatty acids by the action of intestinal lipases. After absorption into small intestinal
cells, triacylglycerols are reformed and aggregate into chylomicrons, which then enter the bloodstream
by way of lymph. Chylomicrons are removed from the blood by the liver and adipose tissue. The
capillary surface of the liver contains large amounts of lipoprotein lipase, which hydrolyzes triglycerides
into fatty acids and glycerol. The fatty acids freely diffuse into hepatocytes for further metabolism.
Similar to chylomicrons, very low-density lipoproteins (VLDLs) are synthesized by the liver and are the
main vehicle for transport of triacylglycerols to extrahepatic tissues. The intestines and liver are the
only two tissues capable of secreting lipid particles. In addition to chylomicrons and VLDLs, there are
two other major groups of plasma lipoproteins: low-density lipoproteins (LDLs) and high-density
lipoproteins (HDLs). LDLs and HDLs contain predominantly cholesterol and phospholipid.
Figure 2-6. The phosphogluconate pathway. One of the major purposes of this pathway is to generate reduced nicotinamide
adenine dinucleotide, which can serve as an electron donor and allow the liver to perform reductive biosynthesis. Glucose-6-
phosphate, in red, plays a central role in carbohydrate metabolism.
The structure of all classes of lipoproteins is similar. There is a core of nonpolar lipids, either
triacylglycerols or cholesteryl esters, depending on the particular lipoprotein. This nonpolar core is
coated with a surface layer of amphipathic phospholipid or cholesterol oriented so that the polar ends
are in contact with the plasma. A protein component is also present. The A apolipoproteins occur in
55
chylomicrons and HDLs. The B apolipoproteins come in two forms: B-100 is the predominant
apolipoprotein of LDLs, whereas the shorter B-48 is located in chylomicrons. The C apolipoproteins can
transfer between VLDLs, LDLs, and HDLs. Apolipoproteins D and E also exist. Apolipoproteins have
several functions in lipid transport and storage. Some, such as the B apolipoproteins, are an integral part
of the lipoprotein structure. Other apolipoproteins are enzyme cofactors, such as C-II for lipoprotein
lipase. Lastly, the apolipoproteins act as ligands for cell surface receptors. As an example, both B-100
and E serve as ligands for the LDL receptor.6
Plasma variations in LDL cholesterol, HDL cholesterol, and triglycerides affect risk for atherosclerotic
cardiovascular disease. As dyslipidemias are being identified and studied, new therapeutic approaches
are needed. A convergence of human genetics and functional biology has led to recent advances in the
study of lipoprotein metabolism. Genome-wide association studies have identified about 100 genes
associated with plasma lipid phenotypes – many of which were not previously known to be associated
with lipids. These genes are now being functionally validated through human genetic analysis such as
deep targeted resequencing of kindreds with Mendelian lipid abnormalities or gene manipulation (over-
or underexpression) in cultured cells and animal models.7
FATTY ACID METABOLISM

Most human fatty acids in plasma are long-chain acids (C-16 to C-20). Because long-chain fatty acids are
not readily absorbed by the intestinal mucosa, they must first be incorporated into chylomicrons. In
contrast, short-chain and medium-chain fatty acids are absorbed directly into the portal circulation and
are avidly taken up by the liver. Free fatty acids in the circulation are noncovalently bound to albumin
and are transferred to the hepatocyte cytosol by way of fatty acid–binding proteins. Fatty acid-CoA
esters are synthesized in the cytosol after hepatic uptake of fatty acids. These fatty acid-CoA esters can
be converted into triglyceride, transported into mitochondria for the production of acetyl CoA and
reducing equivalents, or stored in the liver as triglycerides. The rate-limiting step in the synthesis of
triglyceride is the conversion of acetyl CoA to malonyl CoA. Malonyl CoA, in turn, inhibits the
mitochondrial uptake of fatty acid-CoA ester, favoring triglyceride synthesis. The liver also contains
dehydrogenases that can unsaturate essential dietary fatty acids. Structural elements of all tissues
contain significant amounts of unsaturated fats, and the liver is responsible for the production of these
unsaturated fatty acids. As another example, dietary linoleic acid is elongated and dehydrogenated to
the prostaglandin precursor arachidonic acid.
56
Figure 2-7. Diagram of hepatic fatty acid metabolism. Both dietary and newly synthesized fatty acids are esterified and
subsequently degraded in the mitochondria for energy, first as reducing equivalents, then adenosine triphosphate via the electron
transport chain. Acetyl CoA, in red, plays a central role in lipid metabolism.
3 Free fatty acids are a direct source of energy for cardiac and skeletal muscles and under basal
conditions, most free fatty acids are catabolized for energy. Under conditions of adipocyte lipolysis, the
liver can take up and metabolize fatty acids. Although fatty acid synthesis occurs in the cytosol, fatty
acid oxidation occurs in the mitochondria. Fatty acid-CoA esters bind carnitine, a carrier molecule, and
in the absence of cytosolic malonyl CoA, they enter the mitochondria, where they undergo beta-
oxidation to acetyl CoA and reducing equivalents (Fig. 2-7). Acetyl CoA can then take one of the
following routes: (a) enter the tricarboxylic acid cycle and be degraded to carbon dioxide, (b) be
converted to citrate for fatty acid synthesis, or (c) be converted into 3-hydroxy-3-methylglutaryl CoA
(HMG-CoA), a precursor of cholesterol and ketone bodies. The mitochondrial hydrolysis of fatty acids is
a source of large quantities of ATP. The conversion of stearic acid to carbon dioxide and water, for
instance, generates 136 molecules of ATP and demonstrates the highly efficient storage of energy as fat.
By a process called beta-oxidation, acetyl-CoA molecules are cleaved from fatty acids. The acetyl CoA is
then metabolized through the citric acid cycle under normal circumstances.
In times of significant lipolysis – starvation, uncontrolled diabetes, or other conditions of triglyceride
mobilization from adipocyte stores – the predominant ketone bodies 3-hydroxybutyrate and
acetoacetate are formed in hepatic mitochondria from free fatty acids and are a source of energy for
extrahepatic tissues. Ketogenesis is regulated primarily by the rate of mobilization of free fatty acids.
Once in the liver mitochondria, the relative proportion of acyl CoA destined to undergo beta-oxidation
is limited by the activity of an enzyme, carnitine palmitoyltransferase-1. Lastly, there are mechanisms
that keep the levels of acetyl CoA entering the citric acid cycle constant, so that only at high
mitochondrial levels will acetyl CoA be converted to ketone bodies. Even the brain, in times of
starvation, can use ketone bodies for half of its energy requirements. At some point, however, the
ability of liver to perform beta-oxidation may be inadequate. Under such circumstances, hepatic storage
of triglyceride or fatty infiltration of the liver can be significant, leading to the development of
nonalcoholic steatohepatitis. Triglyceride storage by itself does not appear to be a cause of hepatic
fibrosis, but fatty infiltration may be a marker for the derangement of normal processes by alcohol or
57
drug toxicity, diabetes, or long-term total parenteral nutrition. A specific type of microvesicular fatty
accumulation is also seen in a variety of diseases, such as Reye syndrome, morbid obesity, and acute
fatty liver of pregnancy.
Figure 2-8. The LDL receptor, an example of a transmembrane receptor that participates in receptor-mediated endocytosis. The
LDL receptor specifically binds lipoproteins that contain apolipoprotein B-100 or E. Once internalized, the lipoproteins are
degraded. AA, amino acids; EGF, epidermal growth factor.
As noted above, fatty acids are critical elements of all mammalian cells; as energy substrate, in
cellular structure, and for intracellular signaling. Evolutionarily, storage of excess fat in adipose tissue
mitigated starvation. But in most modern societies the ready availability of calorie-dense foods has led
to an epidemic of obesity as is discussed in detail in other chapters. In terms of intermediary
metabolism, excess dietary fatty acids are now known to cause insulin resistance in muscle through
intramyocellular triglyceride content leading to type II diabetes. This effect is likely due to intracellular
perturbations in active lipid metabolites such as diacylglycerols or ceramides. Other studies have
documented mitochondrial abnormalities possibly through interference with serine kinases.8
CHOLESTEROL METABOLISM
Cholesterol is an important regulator of membrane fluidity and is a substrate for bile acid and steroid
hormone synthesis. Cholesterol may be available by dietary intake or by de novo synthesis. In
mammals, mostly new cholesterol is synthesized in the liver from its precursor, acetyl CoA. Dietary
cholesterol intake can suppress endogenous synthesis by inhibiting the rate-limiting enzyme in the
cholesterol biosynthetic pathway, HMG-CoA reductase. A competitive antagonist, lovastatin, can also
block HMG-CoA reductase and effectively lower plasma cholesterol by blocking cholesterol synthesis,
stimulating LDL receptor synthesis, and allowing an increased hepatic uptake and metabolism of
cholesterol-rich LDL lipoproteins. The structure of the LDL receptor is known and serves as a model for
the structure and function of other cell membrane receptors (Fig. 2-8).
Cholesterol is lipophilic and hydrophobic, and most plasma cholesterol is in lipoproteins esterified
with oleic or palmitic acid. The liver can process cholesterol esters from all classes of lipoproteins.
Hepatocytes can also take up chylomicron remnants containing dietary cholesterol esters. Abnormally
elevated levels of cholesterol in VLDLs or LDLs are associated with atherosclerosis, whereas high HDL
levels are protective. Newly synthesized hepatic cholesterol is also used to synthesize bile acids for
further intestinal absorption of dietary fats. A large proportion of the bile acids secreted by the liver
58
into bile are returned to the liver via the enterohepatic circulation (Fig. 2-9).
Phospholipids
The three major classes of phospholipids synthesized by the liver are lecithins, cephalins, and
sphingomyelins. Although most cells in the body are capable of some phospholipid synthesis, the liver
produces 90%. Phospholipid formation is controlled by the overall rate of fat metabolism and by the
availability of choline and inositol. The main role of phospholipids of all types is to form plasma and
organelle membranes. The amphiphilic nature of phospholipids makes them essential for reducing
surface tension between membranes and surrounding fluids. Phosphatidylcholine, one of the lecithins, is
the major biliary phospholipid and is important in promoting the secretion of free cholesterol into bile.
Thromboplastin, one of the cephalins, is needed to initiate the clotting cascade. The sphingomyelins are
necessary for the formation of the myelin nerve sheath.
Figure 2-9. The enterohepatic circulation of bile acids. The primary bile acids, cholic acid, and chenodeoxycholic acid, are
synthesized in the liver from cholesterol. Deoxycholic acid and lithocholic acid are formed in the colon (blue lines) during bacterial
degradation of the primary bile acids. All four bile acids are conjugated with glycine or taurine in the liver. Most of the lithocholic
acid is also sulfated, which decreases reabsorption and increases fecal excretion. Bile acids are absorbed passively in the epithelium
of the small and large intestine and actively in the distal ileum.
PROTEIN METABOLISM
Formation and Catabolism of Plasma Proteins
4 Hepatic protein synthesis, when excess amino acids are available, includes albumin, fibrinogen, and
apolipoproteins and can reach 50 g/day. Of the total hepatic protein synthesized, 75% is destined for
export in plasma. Most newly synthesized proteins are not stored in the liver, and the rate of protein
synthesis is primarily determined by the intracellular levels of amino acids. The tertiary structure of
many proteins undergoes posttranslational modification after they have been synthesized in the liver’s
rough endoplasmic reticulum (ER). Glycosylation, or the addition of carbohydrate moieties, occurs in
the smooth ER. Sialation, or the addition of sialic acid, occurs in the Golgi. Glycosylation is important in
allowing some proteins to bind with specific receptors for subsequent hepatic uptake and processing.
Removal of sialic acid residues, or desialation, from the terminal galactose molecules of glycoproteins
allows them to bind to the asialoglycoprotein (ASGP) receptor in the liver and undergo degradation.
Desialation, therefore, is important in the clearance of senescent proteins from the plasma.
Intracellular proteases hydrolyze proteins into peptides, and the peptides are in turn hydrolyzed by
peptidases. Ultimately, free amino acids are generated. Unlike carbohydrate and lipids, excess amino
acids are degraded if they are not immediately reincorporated into new proteins. Protein degradation
occurs primarily by one of two routes. ASGPs are internalized into lysosomes via receptor-mediated
endocytosis. The lysosomal enzymes do not require ATP and are nonselective in their activities; more
than 20 known hydrolytic enzymes are present in lysosomes. A second pathway involves the covalent
attachment of ubiquitin, named for the fact that it exists in all mammalian cells, targeting proteins for
destruction. This pathway is ATP dependent and generally is used for proteins with shorter half-lives.9
Amino Acid Synthesis

Essentially, all the end products of dietary protein digestion are amino acids, which are absorbed by the
enterocytes into the portal circulation in an ionized state. Liver amino acid uptake occurs by one of
several active transport mechanisms. Amino acids are not stored in the liver but are rapidly used in the
production of plasma proteins, purines, heme proteins, and hormones. Under certain conditions, the
59
amine group is removed from amino acids, and the carbon chain is used for carbohydrate, lipid, or
nonessential amino acid synthesis.10
Ten nutritionally essential amino acids must be obtained from dietary intake (Table 2-2). However,
human tissues contain transferases, which convert the α-keto acids of leucine, valine, and isoleucine so
that the corresponding α-keto acids can be used as dietary supplements. The remaining nutritionally
nonessential amino acids can be synthesized in one to three enzyme-catalyzed reactions. Hydroxyproline
and hydroxylysine do not have a corresponding tRNA and arise by posttranslational modification of
proline or lysine by mixed function oxidases. Glutamate, glutamine, and proline are derived from the
citric acid cycle intermediate α-ketoglutarate. Aspartate and asparagine are synthesized from
oxaloacetate. Serine and glycine are synthesized from the glycolysis intermediate 3-phosphoglycerate.
Cysteine and tyrosine are formed from essential amino acids (methionine and phenylalanine,
respectively).11
Table 2-1 Amino Acids Required by Adult Humans
Catabolism of Amino Acid Nitrogen

Ammonia, derived largely from the deamination of amino acids, is toxic to all mammalian cells. The
ammonia formed as a result of the deamination of amino acids is detoxified by one of two routes.12 The
most important pathway involves the conversion of ammonia to urea by enzymes of the Krebs–
Henseleit, or urea cycle, which occurs only in the liver (Fig. 2-10). A second route of ammonia
metabolism involves synthesis of L-glutamine from ammonia and glutamate by renal glutamine
synthetase.
CELLULAR ENERGY GENERATION

Overview and Stage I
5 The citric acid cycle includes a series of mitochondrial enzymes that transform acetyl CoA – itself
derived from pyruvate or fatty acyl CoA – into water, carbon dioxide, and hydrogen-reducing
equivalents. Each molecule of acetyl CoA that enters the citric acid cycle yields 12 molecules of ATP.
The fundamental mechanism by which mammalian cells generate energy is the aerobic conversion of
sugars and fatty acids into ATP. There are four stages with stage I – glycolysis – (see glycolysis above)
beginning in the cytosol, converting glucose into two molecules of pyruvate. Also, cytosolic fatty acids
are converted to fatty acyl CoA. Pyruvate and fatty acyl CoA are transported to the mitochondrial
matrix and converted to acetyl CoA; generating the electron carriers NADH or FADH2 as well as CO2. In
stage II, mitochondrial acetyl CoA enters the citric acid cycle further generating NADH, FADH2,
additional CO2, and GTP. In stage III, oxygen is reduced to water via the electron transport chain using
previously generated molecules of NADH and FADH2 as electron donors. The electron transport chain
causes hydrogen ions to move from the mitochondrial matrix to the intermembrane space generating a
proton motive force. Lastly, in stage IV, ATP synthase uses energy generated by the proton motive force
to generate large amounts of ATP.13
Stage II: The Citric Acid Cycle: Integration of Metabolic Pathways and Oxidation of Acetyl
60
CoA
One major function of the citric acid cycle (also known as the Krebs cycle or the tricarboxylic acid
cycle) is to act as a common pathway for the oxidation of carbohydrate, lipid, and protein and generate
energy in the form of ATP. Conversely, the citric acid cycle is important in gluconeogenesis,
lipogenesis, and amino acid metabolism. In the fed state, a large proportion of ingested energy from
foodstuffs is converted to glycogen or fat. The metabolism of sugars, fats, and proteins, then, allows
adequate fuels for all tissue types under conditions from fed to fasting to starvation. The body
accomplishes production of fuel substrates for organs and regulates intestinally absorbed nutrients for
tissue consumption or storage by integrating three key metabolites: G6P, pyruvate, and acetyl CoA (Fig.
2-11). Each of these three simple chemical molecules can be extensively modified to allow a large
number of metabolites.
Figure 2-10. The urea cycle. Ammonia entering the urea cycle is derived from protein and amino acid degradation in tissues
(endogenous) and the colonic lumen (exogenous).
G6P can be stored as glycogen or converted into glucose, pyruvate, or ribose-5-phosphate (a

nucleotide precursor). Pyruvate can be converted into lactate, alanine (and other amino acids), and
acetyl CoA, or it can enter the tricarboxylic acid cycle by conversion to oxaloacetate. Acetyl CoA is
converted to HMG-CoA (a cholesterol and ketone body precursor) or citrate (for fatty acid and
triglyceride synthesis), or it is degraded to carbon dioxide and water for energy. In humans, acetyl CoA
cannot be converted into pyruvate due to the irreversible reaction of pyruvate dehydrogenase. Thus,
lipids cannot be converted into either carbohydrates or glucogenic amino acids.
Probably the most important citric acid cycle function is to oxidize acetyl CoA into CO2. The citric
acid cycle is composed of a series of enzyme reactions that occur in the mitochondrial matrix and inner
membrane. Here, acetyl CoA combines with oxaloacetate to form citrate. Through a series of
subsequent enzymatic reactions involving both dehydrogenases and decarboxylases, citrate is
catabolized to result in the generation of hydrogen-reducing equivalents and carbon dioxide (Fig. 2-12).
With each revolution of the citric acid cycle, a molecule of acetyl CoA generates three molecules of the
reduced coenzyme NADH, one molecule of the reduced coenzyme FADH2, and one molecule of GTP.
The reduced coenzymes NADH and FADH2 are charged with high-energy electrons that subsequently
drive the electron transport chain of stage III to generate a hydrogen ion gradient. These reducing
equivalents are transported to the inner mitochondrial membrane and the electron transport chain to
generate more ATP. Each molecule of NADH is oxidized to yield three molecules of ATP, and each
molecule of FADH2 is oxidized to yield two molecules of ATP. One molecule of ATP is generated at the
substrate level in the conversion of succinyl CoA to succinate; thus, the total molecule of ATP generated
per molecule of acetyl CoA is 12.
61
Stages III and IV: Oxidative Phosphorylation
6 Oxidative phosphorylation converts the energy from NADH and FADH2 into ATP by the electron
transport chain and ATP synthase with a process called the proton motive force. The covalent bond
energy in glucose and fatty acids is transferred into high-energy electrons in stages I (glycolysis) and II
(citric acid cycle). Flow of these high-energy electrons from NADH and FADH2 to oxygen, creating
water, is coupled to transport of protons across the mitochondrial inner membrane from the matrix to
the intermembrane space. Originally called Mitchell’s chemiosmotic hypothesis, many researchers now
refer to this process as the proton motive force. The voltage gradient caused by the transport of these
protons, and the ATP subsequently generated is the process known as oxidative phosphorylation. Below
is an admittedly simplified explication of a complex process, and the stoichiometry of the reactions has
been modified for clarity. Anyone interested in the precise biochemistry should consult the relevant
sources (Fig. 2-13).
Two high-energy electrons carried by NADH or FADH2 pass through three of four major multiprotein
complexes: I – NADH-CoQ reductase; II – succinate-CoQ reductase; III – CoQH2-cytochrome c reductase;
and, IV – cytochrome c oxidase. The paths of NADH and FADH2 are different initially. NADH electrons
are transferred through complex I – NADH-CoQ reductase – to flavin mononucleotide (FMN), seven
iron–sulfur clusters (Fe-S), and then coenzyme Q (CoQ) to create CoQH2. Four protons are transported
from the mitochondrial matrix as a result of the actions of complex I. Unlike NADH, FADH2 is oxidized
by complex II – succinate-CoQ reductase. The two FADH2 electrons are transferred to succinate
dehydrogenase-bound FAD when succinate is oxidized to fumarate, then an iron–sulfur cluster, and
finally to CoQ creating CoQH2.
Figure 2-11. Summation of the key regulatory molecules used by the liver during diverse metabolic functions. Essentially, any
compound found in the body can be synthesized in the liver from glucose-6-phosphate, acetyl coenzyme A, or pyruvate. As a
consequence of the inability of mammalian liver to convert acetyl coenzyme A to pyruvate, fats cannot be converted to
carbohydrates.
62
Figure 2-12. The citric acid cycle. Reduced nicotinamide adenine dinucleotide and reduced flavin adenine dinucleotide, formed in
the citric acid cycle, are subsequently oxidized in mitochondria by means of the electron transport chain to generate ATP. Acetyl
CoA plays a key role.
CoQH2 from NADH or FADH2 is shuttled to complex III – CoQH2-cytochrome c reductase – within the
inner membrane. The two electrons are further transferred to cytochromes bL and bH, resulting in
pumping of two additional hydrogen ions into the intermembranous space. Electrons are further
transferred to another iron–sulfur cluster, cytochrome c1, and ultimately the intermembranous space
protein cytochrome c, pumping two additional hydrogen ions. Complex II catalyzes the conversion of
fatty acyl CoA to acetyl CoA for further metabolism through the citric acid cycle. Cytochrome c shuttles
the two electrons through the intermembranous space to complex IV – cytochrome c oxidase –
reoxidizing the cytochrome c molecule, transferring the electrons to copper containing Cua, the heme
moiety of cytochrome a3, Cub, cytochrome a3, and ultimately to oxygen, yielding water.
The net result of the electron transport chain is the pumping of ten H+ ions into the intermembranous
space for two electrons flowing from NADH to O2, and six H+ ions for each two electrons from FADH2
to O2. This generates the proton motive force; a voltage gradient across the inner mitochondrial
membrane that directly provides energy for ATP generation in stage IV. ATP synthase harnesses the
voltage gradient of protons across the inner membrane by interconverting the chemical potential energy
into phosphoanhydride bonds of ATP. ATP synthase is composed of two main complexes: F0,, consisting
of three types of membrane proteins, and F1, a five-polypeptide complex protruding into the matrix.
Alternative Fuels
Regardless of the fed state of the human body, there is a requirement for glucose utilization. The
nervous system and erythrocytes have an absolute requirement for glucose. Glucose is a source of
glycerol-3-phosphate for adipose tissue, and most other tissues for integrity of the citric acid cycle. To
maintain adequate glucose for survival, other fuels can be used depending on environmental conditions.
Under conditions of carbohydrate shortage, ketone bodies and free fatty acids are utilized to spare
oxidation of glucose in muscle. These alternate fuels increase intracellular citrate, which inhibits both
phosphofructokinase and pyruvate dehydrogenase. In starvation, fatty acid oxidation results in the
production of glycerol, which, along with gluconeogenesis from amino acids, is the only source of the
63
required glucose. Ultimately, even the brain can substitute ketone bodies for about half of its energy
requirements.
The preferred energy substrates for liver are ketoacids derived from amino acid degradation even in
well-fed states. This is designed to allow the consumption of glucose by obligate tissues. Glucose
produced by the dephosphorylation of G6P rapidly diffuses out of the cell and is taken up by the brain,
muscles, and other organs. Hepatic glycolysis is used primarily for the production of intermediates of
metabolism and not for energy. Hepatic fatty acid degradation for energy is also inhibited under most
circumstances and occurs only during adipocyte lipolysis. By way of clinical relevance, alterations in
liver mitochondrial function are now known to be important in two common diseases. Patients with
type 2 diabetes have reduced ATP synthesis and abnormal ATP repletion in response to substrate-
induced ATP depletion. Nonalcoholic fatty liver disease is also associated with lowered ATP repletion in
response to oxidative stress.14
Most short-, medium-, and long-chain fatty acids (C8 to C20) are metabolized by mitochondria to
generate ATP. Mitochondria cannot metabolize fatty acids with acyl chains greater than 20, and these
very long-chain fatty acids are metabolized in peroxisomes, predominantly in the liver. Peroxisomes do
not contain elements of the citric acid cycle or electron transport chain and thus do not generate ATP.
Most of the energy is released as heat.15
Adipocyte Phenotype, Thermogenesis, and Obesity

Epidemic obesity has created a surge of interest in the adipocyte, or fat cell. There are three basic types
of adipocytes; white, brown, and beige. White adipocytes differentiate for the storage of fat and contain
few mitochondria. The traditional view is that adult human fat is comprised predominantly of white
adipocytes. These adipocytes accumulate lipid in times of over feeding leading to obesity and insulin
resistance.8
Brown adipocytes are so named because of the brown color created by a high density of cellular
mitochondria. Unlike the mitochondria of other organs, the mitochondria of brown adipocytes contain
uncoupling protein-1 which can catalyze a protein leak across the inner membrane uncoupling electron
transport from ATP synthesis. This results in the dissipation of energy as heat, or thermogenesis. Brown
adipocytes were thought to be present only in human infants, and rare circumstances such as cold-
climate outdoor workers or pheochromocytoma patients. Recently, the identification of “beige”
adipocytes has led to the realization that the adipocyte may be a target for therapy of obesity. Beige
adipocytes appear capable of switching from a white phenotype to brown, and the hope that adipocytes
could be switched to utilize excess calories for thermogenesis rather than storage as fat.16
64
Figure 2-13. The electron transport chain. A: NADH pathway. Electrons flow through complex I to complex III via the lipid soluble
molecule CoQ. From complex III, the electrons are transported through the intermembrane space by cytochrome c to complex IV.
For every two electrons that flow from NADH to O2, 10 protons are pumped to the intermembranous space. B: FADH2-succinate
pathway. Electrons flow through complex II to complex III via the lipid soluble molecule Coenzyme Q (CoQ). From complex III,
the electrons are transported through the intermembranous space by cytochrome c to complex IV. For every two electrons that
flow from FADH2 and succinate to O2, six protons are pumped to the intermembranous space.
BIOTRANSFORMATION
Biotransformation is defined as the intracellular metabolism of endogenous organic compounds (e.g.,
heme proteins and steroid hormones) and exogenous compounds (e.g., drugs and environmental
65
compounds). Most biotransformation occurs chiefly in the liver, which contains enzyme systems that
can expose functional groups, such as hydroxyl ions (phase I reactions), or alter the size and solubility
of a wide variety of organic and inorganic compounds by conjugation with small polar molecules (phase
II reactions). A general strategy is to convert hydrophobic, potentially toxic compounds into hydrophilic
conjugates that can then be excreted into bile or urine.
7 Biotransformation of potentially toxic, often hydrophobic, compounds into hydrophilic, excretable
compounds occurs mainly in the liver by the cytochromes P-450, the uridine diphosphate-glucuronyl
(UDP-glucuronyl) transferases, the GSH S-transferases, and the sulfotransferases. Biotransforming
enzymes are not distributed uniformly within the cells of the hepatic lobule. This heterogeneity may
account for the ability of some drugs to cause damage preferentially in zone 3 hepatocytes (those
nearest the central venule).
Cytochromes P-450
The cytochromes P-450 are named for their ability to absorb light maximally at 450 nm in the presence
of carbon monoxide. These enzymes are bound to the ER and collectively catalyze reactions by using
NADPH and oxygen. The P-450 isozymes present in mammalian liver catalyze reactions such as
oxidation, hydroxylation, sulfoxide formation, oxidative deamination, dealkylation, and dehalogenation.
Such reactions allow further phase II conjugation with polar groups such as glucuronate, GSH, and
sulfate. The cytochromes P-450 can also create potentially toxic metabolites. Drugs such as
acetaminophen, isoniazid, halothane, and the phenothiazines can be converted into reactive forms that
cause cellular injury and death. The cytochromes also are responsible for the formation of organic free
radicals, reactive metabolites that can directly attack and injure cellular components or act as haptens in
the generation of an autoimmune response. Several of the most potent known carcinogens are aromatic
hydrocarbons, which are modified by cytochromes P-450.
Uridine Diphosphate-glucuronyl Transferases

Glucuronidation is the conjugation of UDP-glucuronic acid to a wide variety of xenobiotics by either
ester (acyl) or ether linkages. The transferases catalyzing these reactions reside in the ER. Many
common compounds are metabolized in this way, including bilirubin, testosterone, aspirin,
indomethacin, acetaminophen, chloramphenicol, and oxazepam. Clinically significant loss of activity can
occur with acute ethanol exposure or acetaminophen overdose, when formation of UDP-glucuronic acid
from UDP-glucose is outstripped by use. Some acyl linkages lead to the generation of electrophilic
centers that can react with other proteins. The covalent linkage of conjugated bilirubin to albumin is
believed to occur by this mechanism.
Glutathione S-transferases
The GSH transferases are more selective in the biotransformations they perform. GSH conjugation
occurs only with compounds that have electrophilic and potentially reactive centers. The role of GSH
conjugation catalyzed by the GSH S-transferases is demonstrated by acetaminophen. In metabolism of
this drug, cytochromes P-450 create an electrophilic center that reacts with protein thiol groups or
GSH.17 The presence of GSH S-transferase allows the preferential detoxification of acetaminophen rather
than its potentially injurious binding to thiol groups. A class of GSH S-transferases, known as ligandins,
appears to facilitate the uptake and intracellular transport of bilirubin, heme, and bile acids from plasma
to liver. In addition to the detoxification of potential toxins, GSH is a substrate for GSH peroxidase, an
enzyme important in the metabolism of hydrogen peroxide.
Sulfotransferases
The sulfotransferases catalyze the transfer of sulfate groups from 3'-phosphoadenosine-5'-phosphosulfate
(PAPS) to compounds such as thyroxine, bile acids, isoproterenol, α-methyldopa, and acetaminophen.
They are located primarily in the cytosol. Although many P-450 derivatives can be further conjugated
by either the sulfotransferases or the glucuronyl transferases, a limited ability of the liver to synthesize
PAPS makes glucuronidation the predominant mechanism.
HEME AND PORPHYRIN METABOLISM

Heme is formed from glycine and succinate and is the functional iron-containing center of hemoglobin,
66
myoglobin, cytochromes, catalases, and peroxidases. From glycine and succinate precursors, δ-
aminolevulinic acid (δ-ALA) is synthesized by the rate-limiting enzyme ALA synthase. The
porphyrinogens are intermediates in the pathway from δ-ALA to heme, and porphyrins are oxidized
forms of porphyrinogen (Fig. 2-14). Inherited enzyme defects in the heme synthetic pathway cause the
overproduction of various porphyrinogens, which can in turn cause clinical manifestations known as the
porphyrias.18 Acquired porphyria can be caused by heavy metal intoxication, estrogens, alcohol, or
environmental exposure to chlorinated hydrocarbons.
Bilirubin IXa is the predominant heme degradation product in humans and is derived mostly from
hemoglobin. The enzyme heme oxygenase, located in cells of the reticuloendothelial system, is
primarily responsible for this conversion. Heme oxygenase resides in the ER and requires NADPH as a
cofactor. Hepatic processing of bilirubin is further detailed in the section on bile formation.
METAL METABOLISM
Iron uptake appears to occur by two distinct processes: (a) receptor-mediated endocytosis of iron–
transferrin complexes and (b) facilitated diffusion across the plasma membrane. More iron is taken up
and stored by the liver than by any other organ, with the exception of the bone marrow. Transferrin is
synthesized in the liver and has specific plasma membrane receptors on a number of different tissues.
After endocytosis, the transferrin and iron dissociate and the transferrin and transferrin receptors return
to the cell surface for recycling. A pathway appears to involve the dissociation of iron and transferrin at
the plasma membrane and subsequent internalization by carrier-mediated diffusion. Once internalized,
iron is stored and forms a complex with apoferritin. Each apoferritin molecule is capable of storing
several thousand iron molecules. The iron–apoferritin complex, called ferritin, is responsible for iron
storage under physiologic conditions. Iron storage in a protein-bound form is essential because free iron
can catalyze free radical formation, leading to cell injury.19
Figure 2-14. The heme biosynthetic pathway. Inherited defects of each of the heme biosynthetic enzymes except δ-aminolevulinic
acid synthase have been described and lead to the clinical disorders known as the porphyrias.
Copper is transported to the liver bound to albumin or histidine and enters the hepatocytes by a
process of facilitated diffusion. Once inside the cell, copper can bind to several intracellular proteins for
storage or as a necessary enzyme cofactor. Copper-binding proteins include metallothionein,
monoamine oxidase, cytochrome c oxidase, and superoxide dismutase. Ceruloplasmin is a liver-derived
protein that binds hepatic copper for transport to other tissues. The low levels of ceruloplasmin seen in
patients with Wilson disease suggest a pathogenetic defect.
Zinc is taken up by and competes for the same binding sites as copper. In hepatocytes, zinc binds
predominantly to metallothionein and is excreted into bile, in which it enters the enterohepatic
circulation. Other metals, usually found in trace amounts, are lead, cadmium, selenium, mercury, and
nickel. These metals are usually bound to metallothionein or GSH, and intoxication is associated with
free radical formation and liver injury.
SUMMARY
67
The broad brush-stroke fundamentals of intermediary metabolism have been known for years, however,
knowledge on the details expands at an ever-increasing rate. A working understanding of the
fundamental biochemical reactions by which substrates are metabolized is important for all surgical
disciplines. Advanced knowledge of the genetics, cellular biology, bioenergetics, and molecular biology
is being exploited to support and perhaps enhance general and specialized cellular function, combat
disease, and improve health.
References
1. Lodish H, Berk A, Kaiser CA, et al., eds. Molecular Cell Biology. 7th ed. New York, NY: WH Freeman;
2013:699–704.
2. The ProCESS Investigators; Yealy DM, Kellum JA, Huang DT, et al. A randomized trial of protocol-
based care for early septic shock. N Engl J Med 2014;370:1683–1693.
3. Jones AE, Shapiro NI, Trzeciak S, et al. Lactate clearance vs central venous oxygen saturation as
goals of early sepsis therapy. JAMA 2010;303(8):739–746.
4. Whittaker SA, Fuchs BD, Gaieski DF, et al. Epidemiology and outcomes in patient with severe sepsis
admitted to the hospital wards. J Crit Care 2015;30(1):78–84. Available from:
http://dx.doi.org/10.1016/j.jcrc.2014.07.012. Accessed May 27, 2016.
5. Berg JM, Tymoczko JL, Stryer L, et al., eds. Biochemistry. 7th ed. New York, NY: WH Freeman;
2012:601–605.
6. Botham KM, Mayes PA. Lipid transport and storage. In: Murray RK, Bender DA, Botham KM, et al.,
eds. Harper’s Illustrated Biochemistry. 29th ed. New York, NY: McGraw-Hill; 2012:237–249.
7. Bauer RC, Stylianou IM, Rader DJ. Functional validation of new pathways in lipoprotein
metabolism identified by human genetics. Curr Opin Lipidol 2011;22:123–128.
8. Turner N, Cooney GJ, Kraegen EW, et al. Fatty acid metabolism, energy expenditure and insulin
resistance in muscle. J Endo 2014;220:T61–T79.
9. Römisch K. Endoplasmic reticulum-associated degradation. Annu Rev Cell Dev Biol 2005;21:435–456.
10. Brosnan JT. Interorgan amino acid transport and its regulation. J Nutr 2003;133(6 suppl 1):2068S–
2072S.
11. Berg JM, Tymoczko JL, Stryer L, et al., eds. Biochemistry. 7th ed. New York, NY: WH Freeman;
2012:711–722.
12. Ah Mew N, Lanpher BC, Gropman A, et al. Urea Cycle Disorders Overview. In: Pagon RA, Adam
MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington;
2003:1993–2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1217/. Accessed May
27, 2016.
13. Lodish H, Berk A, Kaiser CA, et al., eds. Molecular Cell Biology. 7th ed. New York, NY: WH Freeman;
2013:517–552.
14. Koliaki C, Roden M. Hepatic energy metabolism in human diabetes mellitus, obesity, and non-
alcoholic fatty liver disease. Mol Cell Endo 2013;379:35–42.
15. Chapter 12: cellular energetics. In: Lodish H, Berk A, Kaiser CA, et al., eds. Molecular Cell Biology.
7th ed. New York, NY: WH Freeman; 2013:531–532.
16. Rosen ED, Spiegelman BM. What we talk about when we talk about fat. Cell 2014;156:20–44.
17. Riddick DS. Drug biotransformation. In: Kalant H, Grant DM, Mitchell J, eds. Principles of Medical
Pharmacology. 7th ed. Toronto: Saunders-Elsevier; 2007.
18. Bonkovsky HL, Guo JT, Hou W, et al. Porphyrin and heme metabolism and the porphyrias. Compr
Physiol 2013;3(1):365–401.
19. Winter WE, Bazydlo LA, Harris NS. The molecular biology of human iron metabolism. Lab Med
2014;45(2):92–102.
68
Chapter 3
Surgical Nutrition and Metabolism

George Kasotakis
Key Points
1 Starvation and systemic inflammatory response result in erosion of the fat-free mass and body
weight (malnutrition) and are indicators for nutrition support if present.
2 Inflammation increases energy utilization and alters the metabolism of glucose, protein, fat, and
trace minerals.
3 Hypermetabolism is seen in numerous disease states, and not merely in trauma and sepsis.
4 Numerous methods exist to aid assessment of patients’ nutritional status, each with its own
advantages and disadvantages.
5 A strong relation between protein depletion and postoperative complications has been demonstrated
in nonseptic, nonimmunocompromised patients undergoing elective major gastrointestinal surgery.
6 The main goal of perioperative or posttraumatic nutritional support is repletion or maintenance of
protein, energy stores, and other nutrients to allow rapid and full recovery from illness.
7 Whenever providing nutritional support, supply caloric intake in the form of carbohydrate and fat in
a 2:1 ratio, if no contraindications exist.
8 Enteral nutritional support is always preferable than parenteral nutrition, in the presence of a
functioning gastrointestinal tract.
9 The maintenance of an intact brush border and intercellular tight junctions prevents the movement
of toxic substances into the intestinal circulation and minimizes bacterial translocation. These
functions may be affected in critical illness. Enteral nutrition helps restore them.
10 Allow hypocaloric enteral feedings in the acute phase of critical illness for up to 5 to 7 days in
previously well-nourished patients. Start as early as feasible.
11 Routine glutamine supplementation is not supported during critical illness.
12 Supply micronutrients to prevent refeeding syndrome, and monitor electrolytes, liver function tests,
and triglyceride levels as needed.
13 The adequacy of nutritional support should be reassessed frequently and adjustments made as
needed until full convalescence.
INTRODUCTION
Patients undergoing gastrointestinal procedures with evidence of malnutrition at baseline are more
likely to suffer postoperative morbidity, mortality, and require longer hospital stays compared to their
well-nourished counterparts.1,2 The problem is greater than most realize, with up to 14% of patients
scheduled for elective gastrointestinal tract procedures found to be malnourished and up to 40% of
those with gastrointestinal disease found to be at risk for malnutrition.3 It has been shown that poor
nutritional status can detrimentally affect postoperative outcomes,4 and in a consensus review of
Enhanced Recovery After Surgery, it was recommended that patients receive carbohydrate loading 24
hours preoperatively and nutritional supplements, from the day of surgery, until oral intake is
achieved.5
In addition to patients undergoing elective surgery, severe injury and critical illness are associated
with a hypermetabolic state that can increase energy expenditure dramatically and complicate the
resuscitation and recovery of the critically ill or severe injury victim. Over the last few years,
aggressive nutritional support has been underlined as an integral part of the caring of the critically ill
surgical patient, and the Society for Critical Care Medicine (SCCM) and the American Society for
Parenteral and Enteral Nutrition (ASPEN) have made recommendations toward providing early,
69
aggressive nutritional support that enables patients to preserve their immune function, maintain lean
body mass, and minimize metabolic complications.6,7 This chapter addresses the areas of nutritional
assessment and management of the surgical patient, reviewing key metabolic principles and providing
an overview of pertinent literature.
BASIC METABOLIC PRINCIPLES

Body Composition
Total body mass is composed of aqueous and nonaqueous components, with the former constituting
approximately 55% to 60% of total body mass (total body water, TBW). Mineralized bone and adipose
tissue make up the majority of the nonaqueous component. The relationship between total body mass
and TBW is relatively constant for an individual and typically reflects the amount of body fat. Solid
organs and muscle contain a higher proportion of water than bone and fat, therefore young lean males
have a higher proportion of their total body mass as water, compared to obese or elderly individuals.
Obesity, older age, and female gender shift the body composition to a greater fat mass (Fig. 3-1).8
The aqueous portion is divided into three functional fluid compartments: plasma (5% of body
weight), interstitial or extracellular fluid (ECF; 15% of body weight), and intracellular fluid (ICF; 40%
of body weight) (Fig. 3-2). In a typical 70-kg male, there are approximately 3.5 L of plasma, 10.5 L of
interstitial fluid, and 28 L of intracellular volume, while the remainder 28 kg represent the nonaqueous
portion. Of the above, the body cell mass constitutes the metabolic engine of the body, while the
extracellular component forms the supporting “scaffolding” for the body cell mass.
Figure 3-1. Body composition as a function of gender and age. (Data from Cohn SH, Vaartsky D, Yasumura S, et al. Compartmental
body composition based on total-body nitrogen, potassium, and calcium. Am J Physiol 1980; 239:E524–E530.)
In clinical practice, body composition is inferred indirectly using the body mass index (BMI; kg/m2),
which reflects the fatty proportion of the total body weight. According to the Centers for Disease
Control and Prevention, a BMI between 25 and 29.9 kg/m2 is indicative of being overweight, whereas
an individual with a BMI of ≥30 kg/m2 is considered obese.
Body composition may change acutely after trauma or major surgery.9 These changes are
characterized by a rapid loss of lean body mass and expansion of the ECF compartment, the latter
manifesting clinically as edema. The underlying changes in body cell mass and fat mass are difficult to
recognize until much later in the process, when they manifest as temporal or extremity wasting. Tools
to assess changes in body composition during critical illness have been described (arm circumference
and tissue bioelectrical impedance), but their use and utility in daily clinical practice are limited.10–12
Energy and Substrate Metabolism

Energy Production and Measurement
The human body functions much like an engine, in that it uses oxygen to burn fuel (carbohydrate, fat,
and protein) and generate energy, excreting the byproducts of this combustion (carbon dioxide, water,
urea, and heat) to the environment (Fig. 3-3). This energy, which is necessary for numerous functions of
the human body, both on micro- (molecular synthesis and transport) and macroscopic (breathing and
mobility) levels, is derived from the energy present in the chemical bonds of the nutrients consumed.
70
When no nutrition is provided, such as during periods of starvation or immediately after surgery or
trauma, the body oxidizes stored fuel to generate energy.
Figure 3-2. Aqueous and nonaqueous body composition.
The energy production process is relatively inefficient, as approximately half of the nutrient-
containing energy is eventually converted to heat, instead of all of it being utilized for work. Some of
this heat is used to help maintain body temperature (via meticulously regulated hypothalamic
mechanisms), while the remainder is released to the environment – mostly through the skin. During
illness, or following surgery or trauma, the central temperature regulating mechanisms become reset,
leading to the development of fever, usually an appropriate response to a physiologic stressor. This
increase in body temperature typically intensifies the rate of enzymatic-facilitated chemical reactions
that are essential to the inflammatory response.
All energy produced by the human body comes from oxidation of fuel via a series of
decarboxylation/dehydrogenation reactions. The fuel undergoing oxidation is derived from food or
mobilization of fuel stores. The energy released by these reactions is captured in adenosine triphosphate
(ATP), the human body’s energy “coin,” via a series of redox reactions. In the final step of energy
production from carbohydrates or fat, hydrogen is combined with oxygen to form water. The oxygen
required and the carbon dioxide produced in this process are transported by the circulatory system and
exchanged with the environment by the lungs. Protein oxidation is a special case, in which nitrogen is a
byproduct, in addition to carbon dioxide and water. This nitrogen is removed by the kidneys, after
conversion to urea by the liver.
Energy is measured in joules or calories. The joule is the SI unit of energy and is defined as the
energy required to exert a force of 1 N for a distance of 1 m (unit of measure is kg/m2/s2). In the
United States, energy is most commonly measured in g-calories (gram-calories) or kg-calories (kilo-
calories or kcal). A g-calorie is the amount of heat required to raise the temperature of 1 g of water
from 14.5°C to 15.5°C at the pressure of one standard atmosphere, whereas the kg-calorie is the amount
of heat needed to increase the temperature of 1 kg of water under the same circumstances. Joules and
g-calories are very small units of energy (1 J is expended by a resting person every hundredth of a
second), therefore megajoules (MJ) and kilocalories are far more commonly used to describe energy
produced from human nutrition. A megajoule is equivalent to 106 J, while a kilocalorie is equivalent to
103 calories. One megajoule corresponds to 239 kcal.
Figure 3-3. Fuel utilization in human metabolism.
CLASSIFICATION
Table 3-1 Fuel Reserves of a Healthy, 70-kg Adult Male
71
Body Fuels
Human metabolism is organized in such a way, so that fuel consumption occurs in a hierarchical way
when more than one energy source is present, with excess stored for the postprandial or fasting period.
In the postprandial state, the body contains fuel reserves that it can also mobilize in an orderly fashion,
as fasting is prolonged. The same fuel reserves are accessed during stress metabolism, although in a less
orderly fashion (Table 3-1).
Calorically dense fat is by far the largest energy repository, providing 9 kcal/g when mobilized and
oxidized. The ability of the body to store fat is essentially limitless. Protein comprises the next largest
energy store in the human body, yet amino acids when oxidized yield 4 kcal/g. And unlike fat, protein
plays both a structural and functional role in the body, thus, in severe protein loss, major functional
consequences can be expected. In malnutrition, proteolysis frees up amino acids to be used for
gluconeogenesis to produce glucose, which in turn can be used as fuel. Carbohydrate reserves are
minimal and exist in the form of glucose or glycogen in the liver. These can be depleted quickly,
typically within 12 hours, unless replenished through nutrition. Carbohydrates, like protein, also yield
approximately 4 kcal/g when mobilized for energy production (Table 3-2).
Carbohydrates. Carbohydrates are the most commonly used fuel by the human body, providing
frequently over 45% to 60% of daily energy requirements. Each gram of carbohydrate that is
administered enterally yields approximately 4 kcal when broken down, whereas intravenously
administered carbohydrates (such as dextrose-containing solutions) provide slightly less (approximately
3.4 kcal/g).
Table 3-2 Energy Value of Various Energy Sources
The basic unit of carbohydrate metabolism in humans is glucose, and nearly all dietary carbohydrates
are converted to glucose for energy production. Digestion of carbohydrates begins as proximally as the
oral cavity with food ingestion, where salivary amylase breaks down polysaccharides into smaller oligo-
and disaccharides. This process continues in the duodenum and proximal jejunum with the pancreatic
amylase. Oligosaccharidases that are present in the brush border of the proximal small bowel further
hydrolyze oligosaccharides into di- or monosaccharides, most commonly glucose, to be absorbed by the
gut mucosa. Once glucose reaches the bloodstream, it stimulates secretion of insulin from the endocrine
pancreas (beta cells), which has major anabolic effects and stimulates protein synthesis, inhibits
lipolysis, and upregulates glycogen production. Conversely, during stress, pancreatic glucagon exerts
opposite effects: it promotes breakdown of glycogen, but also fat and protein, to be used as additional
energy sources during a time when energy requirements are maximal. Deficiencies in carbohydrate
digestion are rare in surgical patients, even in patients in whom the pancreatic exocrine function is
significantly decreased. Patients with pre-existing celiac or Whipple disease may, however, have limited
capacity to absorb carbohydrates.
The human central nervous system and circulating blood cells require glucose constantly for their
energy requirements. In periods of extended fasting, after the liver has used up its stores of glycogen,
the human body breaks down protein and uses the resulting amino acids to generate glucose, and even
converts fat into ketones that can partly substitute glucose as an energy source. When glucose is
reinstated through nutrition, these metabolic adaptations are completely reversed. During stress,
72
gluconeogenesis and glycogen breakdown is accelerated and ketone production minimized, leading to
an abundance of glucose for use as the human body mounts an inflammatory response.
Lipids. Lipids are the second most commonly used fuel for energy by the human body, accounting for
35% to 45% of daily caloric intake. Each gram of fat yields approximately 9 kcal of energy when
oxidized. When lipids enter the proximal small bowel, cholecystokinin and secretin are released, which
make the gallbladder contract and release bile into the duodenum. Bile salts contained in bile are
necessary for lipid absorption, especially the long-chain fatty acids that are found in a typical western
diet, which occurs mostly in the distal ileum. Surgical resection of the distal ileum may lead to depletion
of the bile salt pool and fat malabsorption.
Lipids are most commonly classified by the length of their contained hydrocarbon chains. Short-chain
fatty acids typically refer to lipids containing 2 to 5 carbon length chains and are a product of dietary
fiber fermentation in the colon by the intestinal flora. They are absorbed by and are the preferred fuel
for the colonocytes. Medium-chain fatty acids (6 to 9 carbon length chains) are also not typically found
in the human diet, but are commonly used in numerous enteral nutrition formulas, as they are easier to
digest, compared to longer chain triglycerides. They are water soluble, and hence require no
emulsification or micelle formation for transport. Lipase is not required. The medium-chain triglycerides
are absorbed directly into the portal circulation. Unlike the short- and medium-chain fatty acids which
can be produced from other dietary substrates, two long-chain fatty acids (>9 carbon length chains),
linoleic and linolenic acids, are essential for human nutrition. These are not water soluble and require
bile salts for emulsification as stated above, lipase for digestion, and micelle/chylomicron formation for
transport. They gain access to the bloodstream via the lymphatic system (thoracic duct). Insufficient
intake of these essential fats can lead to fatty acid deficiency, which can be prevented with provision of
at least 3% to 4% of the daily calories as linoleic and linolenic acids. These two fatty acids are also a
precursor of eicosanoids, significant mediators of the inflammatory response. On a cellular level,
lipoprotein lipase is necessary for intake, and carnitine for transport from the cytosol into the
mitochondria for oxidation. Long-chain triglycerides are the main form of energy storage in the human
body, given the numerous high-energy bonds they contain.
Protein. Protein is different from carbohydrate and lipids in that it contains nitrogen that neither fatty
acids nor glucose do. It is also a key structural component, and there are no inactive protein stores.
Essentially all proteins are either functional or structural in the human body.
Proteins are polypeptides, containing numerous amino acids as their building blocks, and yield 4
kcal/g when used for energy production. Dietary protein is broken down into amino acids and smaller
peptides by gastric pepsin and pancreatic proteases, the latter activated by enterokinase in the
duodenum. These amino acids and oligopeptides get absorbed mostly in the proximal gastrointestinal
tract and travel to the liver, where they are recycled to synthesize new protein. In a healthy, 70-kg
weighing adult male over 300 g of protein are recycled daily. The branched-chain amino acids (BCAAs;
leucine, isoleucine, and valine) are transported to muscle unaltered, while other amino acids are
distributed to the intra- and extracellular pool for protein synthesis as needed. Excess amino acids are
usually converted to glycogen or free fatty acids.
In addition to the dietary protein, intracellular proteins are continuously recycled, and the resulting
free nitrogen is excreted, mostly through urine. Most of the urine nitrogen is in the form of urea (85%),
with smaller amounts excreted as creatinine and ammonia. Urinary nitrogen decreases significantly with
protein-free diets (decreased intake), but increases during stress (greater turnover).
Amino acid metabolism generates ammonia, a highly toxic compound, which is converted into urea
(nontoxic) in the liver. Glutamine and alanine serve as ammonia-transporting vehicles in a nontoxic
form from the metabolically active peripheral tissues to the viscera. There, ammonia is resynthesized
and either excreted (by the kidneys, where it also acts as a buffering system) or detoxified to urea
(liver). Diseases that affect the functional capacity of either the kidneys or the liver can lead to
significant ammonia build up in the body, with potentially toxic consequences to the central nervous
system.
Other Nutrients
To maintain health, in addition to energy, numerous other nutrients are required for the numerous
metabolic functions of the human body. These include nucleotides, vitamins, and trace elements. The
former are increasingly identified as important for the nutrition of the critically ill patient, whereas
vitamins and trace elements are important for numerous anabolic functions.
73
Nucleotides. Nucleic acids are the building blocks for DNA and RNA, and are not typically considered
essential for a balanced nutrition in healthy adults. However, dietary requirements become significant
during severe stress and critical illness, as nucleic acids are necessary for rapidly proliferating cells, such
as the cells participating in the immune function. Diets augmented with RNA or the nucleotide uracil
have been shown to restore delayed hypersensitivity and improve the lymphoproliferative response. As
such, they have been included in enteral nutrition formulas, where they may aid recovery from severe
infections.13
Vitamins. Vitamins A, D, E, and K are fat soluble and are absorbed in the small bowel in association
with long-chain fatty acids. From there, they are transported to the liver (vitamins A and K) or the skin
and subcutaneous tissue (vitamins D and E) for storage. Fat-soluble vitamins are required for normal
immune function and play a significant role in wound healing. Daily vitamin A intake in patients on
chronic corticosteroid regimens may counteract most of steroid-mediated adverse effects of wound
healing.
Unlike vitamins A, D, E, and K, vitamins B1, B2, B6, and B12, along with vitamin C, niacin, folate,
biotin, and pantothenic acid are water soluble and are absorbed in the proximal small bowel. From
there, they are transferred to the liver with the portal circulation for use or storage. Water-soluble
vitamins are required for normal amino and nucleic acid metabolism.
Electrolytes and Trace Elements. Electrolytes are important components of both the intra- and
extracellular compartment, where they play a major role in maintaining electrical and osmotic balance
across the body’s plasma membranes. Such electrolytes include sodium (Na+), potassium (K+), calcium
(Ca2+), magnesium (Mg2+), chloride (Cl−), and are cations (with a positive charge) or anions (with a
negative charge), due to uneven distribution of electrons. Sodium is the main extracellular electrolyte
and is important in maintaining volume homeostasis and blood pressure control. Conversely, potassium
is one of the key intracellular cations. The role of electrolytes is diverse, and includes functions as
varied as the conduction of electric signals, cotransport of larger molecules against their concentration
gradient, muscular contraction, and participation in numerous essential biochemical reactions.
Trace elements play an important role in numerous metabolic, immunologic, and healing functions
and eight minerals have been identified as “essential.” These include iron, iodine, zinc, chromium,
copper, selenium, manganese, and molybdenum.
Iron is an integral component of the heme core in hemoglobin and of the mitochondrial cytochrome
complex. Subtle impairments in central nervous, musculoskeletal, and immune system function can be
identified in patients with iron deficiency, before microcytic anemia becomes clinically evident.
Impaired cerebral, muscular, and immunologic function can occur in patients with iron deficiency before
anemia becomes clinically evident. Particular attention has to be paid to pregnant and lactating females,
in whom iron requirements are even greater than the rest of the population.
Iodine is a key component of the thyroidal hormonal system. Deficiencies are rare in the western
world, due to widespread use of iodinated salt. However, chronically malnourished patients can develop
significant iodine deficiency, which can typically manifest clinically as diffuse goiter and
hypothyroidism.
Zinc deficiency can manifest with skin discoloration and perioral rash, neuritis, hair loss, and
alterations in taste and smell. Chromium deficiency presents as impaired glucose tolerance during
prolonged fasting and is fairly common with total parenteral nutrition (TPN). Copper deficiency
presents with microcytic anemia, typically unresponsive to iron, abnormal skin keratinization, and, in
its most severe cases, pancytopenia. Selenium deficiency, which can similarly be identified in cases of
prolonged TPN administration, manifests as neuromuscular dysfunction or cardiac conduction defects,
which in the most severe cases can lead to heart failure. Manganese deficiency can be identified as the
underlying cause in a syndrome presenting as unintentional weight loss, hair color changes, and
hypolipidemia. Molybdenum deficiency is associated with hypomethioninemia and hypouricemia,
resulting in nausea and vomiting, tachycardia, and nonfocal central nervous system dysfunction (Table
3-3).
Nutritional Assessment
Metabolism is altered to varying degrees by stress, namely surgical injury, critical illness, infection, and
physical trauma. In most cases, these alterations are short lived and reversible in a previously well-
nourished individual, even if fasting is superimposed during acute illness. However, pre-existing
74
malnutrition, even if mild, and prolonged post-stressor fasting, intentional or not, can adversely affect
healing, recovery, and overall outcomes after injury or surgery.14–20 In addition, the nutritional needs of
a patient recovering from severe infection, injury, or a major operation are different than those of
nonstressed individuals and aggressive postoperative or postinjury nutritional regimens are associated
with improved outcomes.21 This recognition has led nutrition science to become an integral part of
modern medicine and critical care, and nutritional support to continue to gain ground as primary
therapy in the care of the surgical and critically ill patient.
Table 3-3 Summary of the Daily Requirements of Vitamins, Electrolytes, and Trace
Elements in a per os Diet by Healthy Adults
Subjective Global Assessment

12 Subjective global assessment of a patient’s nutritional status is commonly utilized to assess the
presence and degree of malnutrition in surgical patients. It is one of the few clinical methods that has
been validated as a reproducible method assessing a patient’s nutritional status and has been
consistently associated with clinical outcomes. This global assessment utilizes numerous variables,
including physical examination and anthropometric measurements such as weight, height, and weight
loss history; dietary questionnaires and portion size analyses; along with pertinent past medical history
to classify patients in three distinct categories: class A is assigned to individuals with no evidence of
malnutrition; class B to patients with moderate or indeterminate malnutrition; and class C to patients
with definitive malnutrition. Patients in this last category typically present with recent history of
unintentional weight loss and signs of tissue wasting (temporal and/or extremity most commonly).
While the subjective global assessment can provide coarse information about the severity of
malnutrition, it rarely yields clues pertaining to the underlying etiology (starvation vs. inflammation).
Similar methods of assessing overall nutritional status encompassing dietary history, baseline health,
anthropometric and laboratory measurements have been described and used in certain patient
subpopulations. These include the mini-nutritional assessment, the malnutrition universal screening tool,
the instant nutritional assessment, the geriatric nutritional risk index, among others.
75
Anthropometric Measurements and Nutritional Indices
Anthropometric measurements have been used extensively to provide information regarding lean body
mass, total fat stores, and overall nutritional health. Body composition studies aid in determining TBW,
fat, and nitrogen. These anthropometric measurements can be easily performed at the bedside or an
ambulatory setting, and may include an individual’s height and weight (which allow calculation of the
BMI), triceps skinfold, midhumeral circumference, and other body part summations. The BMI is widely
used as a measure of overnutrition (a BMI of 25 to 29.9 suggests overweight status, whereas a BMI
>30 defines obesity). The BMI is calculated from an individual’s height and weight using the formula:
More advanced techniques and measurements include x-ray absorptiometry that allows a more
accurate assessment of total fat and lean body mass. With the exception of the BMI, most
anthropometric measurements are operator dependent, and skill and experience are important in order
to obtain accurate studies.
Nutritional indices provide a means of risk-stratifying and objectively comparing individuals, as well
as to guide nutritional support. The BMI is one of the most commonly utilized nutritional indices. It
provides information on normal, overweight, or obese status. It also provides information on degree of
protein–calorie malnutrition in underweight individuals. Other commonly used indices include the
prognostic nutritional index (PNI), the nutritional risk index (NRI), and the creatinine height index
(CHI).
These are calculated with the following formulas respectively:
Serum Protein Levels. An ideal biochemical marker of malnutrition would be one that is highly
sensitive and specific to nutrition intake. Although a single laboratory biomarker that could effectively
describe a patient’s nutritional status is lacking, numerous freely circulating serum transport proteins
have been used. The most commonly utilized ones are albumin, prealbumin, transferrin, and retinol-
binding protein (RBP), each with its own advantages and disadvantages. Many nutrition-unrelated
parameters, most commonly inflammation, dilution secondary to large volume resuscitation, and
chronic liver failure, affect the levels of these serum markers. Although it is customary for markers of
inflammation, usually the C-reactive protein, to be measured with the aforementioned biomarkers (most
commonly prealbumin), little data exist to support this practice.22,23
Albumin. Albumin is a serum protein synthesized in the liver with a long half-life (approximately 20
days) and a relatively large total pool size. Only 5% of total body albumin is produced daily. Its main
function is to carry molecules in the bloodstream and to help maintain intravascular oncotic pressure.
Due to its large pool, long half-life, and relative slow turnover, it has been used as an indirect marker of
protein intake, hepatic synthetic ability, and chronic nutritional status. Unfortunately, it is a negative
acute–phase reactant, decreasing during the acute-phase response, and numerous nutrition-unrelated
factors may affect its levels in either direction (Table 3-4). Albumin is neither a sensitive nor specific
marker for malnutrition, as patients with even severe starvation can have normal levels.24–26 In critical
care, hypoalbuminemia more commonly reflects illness acuity, especially during the acute phase, due to
its function as a negative acute–phase reactant, its redistribution to the interstitial space, and dilution
secondary to large volume resuscitation.27
Prealbumin. Prealbumin, also known as transthyretin or transthyretin-bound prealbumin, similar to

albumin, is a visceral protein synthesized in its majority by the liver, and to a smaller extent by the
choroid plexus in the central nervous system. Its name prealbumin was originally given because it ran
faster than albumin on electrophoretic gels. Its main function is to transport thyroxine (T4) and retinol
(vitamin A) in the bloodstream. As a visceral protein, it is a small part of the total body protein pool,
which includes serum and intracellular proteins. Consequently, it is similarly affected by many of the
same factors that affect serum albumin concentrations. The main advantage of prealbumin over albumin
76
is its shorter half-life (2 to 3 days) which makes it more sensitive and rapidly adaptable to acute, short-
lived changes in nutrient intake. Like albumin, prealbumin is also a negative-phase reactant, with values
decreasing during the acute inflammatory response. Therefore, rising prealbumin levels may reflect
improvement in nutritional status or resolution of the inflammatory condition. Prealbumin is commonly
measured along C-reactive protein, and low levels of the former accompanied by high levels of the
latter are commonly seen in inflammatory conditions, as opposed to malnutrition. While this practice is
not well validated, a better use for prealbumin as a marker of overall nutritional status is to monitor
trends.28,29
Retinol-Binding Protein. The majority of retinol-binding protein (RBP) is present in the bloodstream
in the form of retinol-circulating complex that includes prealbumin, retinol (vitamin A), and RBP. It is
catabolized in the kidneys and its levels may be elevated in end-stage renal failure. RBP is dependent on
vitamin A and zinc, as low levels of these conutrients inhibit mobilization of RBP in the liver.30 Due to
its extremely short half-life (approximately 12 hours) and typically expensive laboratory level
assessment, it is rarely used as a malnutrition marker.
Transferrin. Transferrin has also been identified and used as a nutrition biomarker. It has a half-life
between that of albumin and prealbumin (8 to 10 days) and fairly small total body pool size. However,
because it plays a key role in iron transport, its levels are affected by iron status. Iron deficiency may
lead to increased levels secondary to greater iron absorption. Under these circumstances, it may be a
better marker of total iron-binding capacity, rather than malnutrition.
Nitrogen Balance
Nitrogen balance is another marker for overall nutritional status. It is an indicator of whether protein
intake and catabolism are in balance, and along with trends in prealbumin levels, it is a commonly
employed method to assess progress in patients on nutritional support. Nitrogen balance is calculated
from the amount of nitrogen entering minus the amount leaving the human body over a 24-hour period.
Nitrogen intake is estimated from total protein intake divided by 6.25 (the average nitrogen content of
human protein is approximately 16%). The main route of nitrogen excretion is the urine (90% or more).
Nitrogen is also lost through the skin and stool, but this loss is usually small (<2 g/day), difficult to
measure, and therefore typically accounted for with a constant of 2 in the nitrogen balance equation.
Total urinary nitrogen (TUN) is ideally measured, but is frequently substituted by urine urea nitrogen
(UUN), because it is easier to estimate. In the latter case, an additional 2 to 3 g are typically added to
the output side of the nitrogen balance equation to account for the unmeasured losses. The nitrogen
balance equations are as follows:
Table 3-4 Serum Proteins Used in Nutritional Status Assessment
Nitrogen balance (g/day) = Protein intake/6.25 - (TUN + 2)
77
Nitrogen balance (g/day) = Protein intake/6.25 - (UUN + 2 + 3)
A nitrogen balance of –2 to +2 g/day indicates nitrogen equilibrium, and typically represents the
goal in medically indicated nutritional support. More negative balances are managed with increases in
protein intake, while more positive values typically reflect anabolism in recovering patients, or simply
errors in measurement in the acutely ill (a positive nitrogen balance implies anabolism, but bedridden
patients with active inflammation are not anabolic). Achievement of a positive balance has been
associated with improved outcomes in certain critically ill patients.31 Limitations of the nitrogen balance
assessment include false-negative results in overfed patients; long time for the equation to re-
equilibriate after adjustments in nutritional support; and renal insufficiency and upper gastrointestinal
bleeding may invalidate results (due to incomplete excretion of urea nitrogen and due to excess urea
nitrogen production respectively).
Indirect Calorimetry
Resting energy expenditure can be measured at the bedside with indirect calorimetry. This method,
based on thermodynamic principles, calculates heat produced through the measurement of oxygen
consumed and carbon dioxide exhaled. Patients must be either sedated or able to tolerate a respiration
chamber placed over their heads that allows collection of exhaled air. (A less commonly utilized method
is direct calorimetry, in which the patient is placed inside the calorimeter for measurement.) Intubated
patients must have a fraction of inspired oxygen of <60%, while spontaneously breathing patients must
be on room air. No air leaks (that would allow heat to escape the collection chamber) can be present.
Numerous protocols have been developed to measure resting energy expenditure with as little as 5-
minute testing sessions.32
Metabolic Energy Expenditure

In most cases, energy expenditure is not measured, but estimated, on the basis that all metabolic
activity occurs within the fat-free body mass. Fat-free mass is a function of body weight, height, age,
and gender, and therefore, resting energy expenditure can be predicted quite reliably from these
variables. In obesity, where adipose tissue becomes hypertrophic and hyperplastic, most of these
relationships are preserved, but carry a weaker predictive ability. Several equations that predict basal
energy expenditure, and hence daily caloric requirements, have been developed from the
aforementioned variables, with the Harris–Benedict one being among the most widely used (Table 3-
5).33
Once the basal metabolic rate has been calculated, minor adjustments based on exercise frequency
and intensity can be made for estimation of the daily caloric requirement for an adult to maintain
current weight.33
Table 3-5 The Harris–Benedict Equation and Adjustment Using the Harris–
Benedict Principle
The Mifflin–St. Jeor equation appears to be even more accurate in estimating basal metabolic rate in
healthy individuals34:
78
For critically ill, or patients with highly inflammatory conditions, the estimated basal metabolic rate
is adjusted upward. Not surprisingly, basal energy requirements increase significantly with an active
inflammatory response, but minimally after elective surgery. The largest increases in energy
expenditure are seen in patients with severe polytrauma or major burns.35
Other Parameters for Nutritional Assessment

In addition to the aforementioned methods of assessment of nutritional status, many more
anthropomorphic, clinical and laboratory parameters have been described. These include total
lymphocyte count (<2,000/mm3), CHI (<80%), ideal body weight (<90%), weight loss over time
(>10%/6 months), and skin antigen testing (<3/4 reactive sites over number placed). The numbers in
the parentheses are suggestive of malnutrition.
OVERFEEDING AND MALNUTRITION

Overfeeding
While adequate caloric intake is necessary to maintain weight and promote health, overprovision of
calories can lead to overfeeding and obesity. Excess calories, especially as carbohydrates, can lead to
increased carbon dioxide production (which may prolong ventilatory weaning), hyperglycemia (which
can contribute to immunosuppression and increase the risk for infectious complications), lipogenesis
(indicated by a respiratory quotient >1), and hepatic steatosis (which can interfere with normal liver
function). Additionally, excessive nutritional support, may lead to mineral or vitamin poisoning, and
severe electrolyte imbalances, with hypophosphatemia being the most common. To avoid overfeeding,
specifically in critically ill patients with numerous active medical conditions, indirect calorimetry may
be indicated to accurately estimate energy expenditure during the various stages of disease.
Malnutrition
Starvation
3 During short periods of fasting, insulin levels drop and glucagon levels rise in the plasma, while
glycogen is being broken down in the liver to release glucose. Liver glycogen stores are typically
depleted within 24 hours of fasting. After carbohydrate stores are used up, caloric needs are met by
protein and fat degradation. During starvation, down-regulated insulin results in net muscle wasting, as
protein is broken down to release amino acids. These amino acids – most commonly alanine and
glutamine – are used for gluconeogenesis in the liver. The resulting glucose is used primarily by the
central nervous system and the hemopoietic system that rely heavily on glucose metabolism for their
energy requirements. Hepatic gluconeogenesis itself also requires energy, which is typically supplied by
the free fatty acid oxidation. The drop in circulating insulin levels, along with the concomitant rise in
plasma glucagon, activates hormone-sensitive lipase in fatty tissue that hydrolyzes triglycerides to
release free fatty acids, which in turn help generate energy for the aforementioned gluconeogenesis.
Both gluconeogenesis and fatty acid oxidation require the permissive effect of cortisol and thyroxine.
During starvation, the human body attempts to recycle energy sources to the greatest extent possible.
Lactate produced by the white blood cells or the muscles during anaerobic metabolism is recycled back
to glucose in the liver, through the Cori cycle. BCAAs, unlike glutamine and alanine, which are taken up
by the liver, are secreted by the gland, in order to provide skeletal and cardiac muscles an energy
substrate. Once BCAAs are oxidized for energy, their residual amino groups are utilized to recycle
alanine and glutamine, which in turn return to the liver to allow further gluconeogenesis. However
efficient this conservation of energy and substrates may seem, gluconeogenesis from amino acids in the
liver results in a significant loss of lean body mass, which may reach fatal levels after approximately 4
weeks. The brain adapts to prolonged starvation after about 7 to 10 days (chronic starvation) to use
ketones derived from fat, as its primary energy source. At this stage, the basal metabolic rate decreases
by as much as 30%, and all functions requiring significant amounts of energy expenditure slow down,
including voluntary muscle activity and cardiac function.
79
Starvation versus Inflammation as the Cause of Malnutrition
Both starvation and the systemic inflammatory response result in lean body mass loss, which should
indicate nutritional support.1–4 However, the two processes have key dissimilarities that differentiate
one from the other. On one hand, starvation leads to progressive loss of both lean mass and body fat,
preservation of serum protein levels, and reversal of the metabolic response with feeding. The most
common causes of starvation in the surgical patient are functional, and include nausea and emesis, ileus,
dysphagia, and malabsorption. On the other hand, during a significant inflammatory response, the basal
metabolic rate increases significantly (both anabolism and catabolism) and becomes relatively
insensitive to feeding, and levels of acute-phase proteins change. Inflammation may additionally worsen
malnutrition by interfering with caloric intake acutely (anorexia of acute illness) or in the chronic state
(cancer cachexia). The key differences between the metabolic response to simple starvation and injury
are summarized on Table 3-6.
Table 3-6 Metabolic Differences Between the Response to Simple Starvation and
Stress
METABOLIC RESPONSE TO STRESS

Neuroendocrine and Cytokine-Mediated Response to Stress
4 After injury, two distinct phases of a neurohumoral response that affect metabolism can be identified.
A shorter, early “ebb” or shock phase, which typically lasts 12 to 24 hours, occurs immediately
following injury. During this early phase, cardiac output, body temperature, oxygen consumption, and
therefore overall metabolism are reduced. These events are often associated with blood loss and
commonly lead to anaerobic metabolism and lactic acid synthesis. With restoration of the blood volume,
metabolism accelerates, and is associated with increased cardiac output, altered glucose metabolism,
faster tissue catabolism, and greater urinary nitrogen losses. During the “flow” phase, the basal
metabolism increases to greater rates than what would be predicted on the basis of age, gender, and
body size in a healthy individual. The degree of hypermetabolism is generally related to the severity of
the original insult, and hence the intensity of the inflammatory response. This delayed “flow” phase
response to injury is not dissimilar to what occurs following elective surgery. The response to injury,
however, is usually much more intense and extends over longer periods of time.
The response to accidental injury or elective surgery, with both its phases, comprises two
components: a neuroendocrine response and an inflammatory response. Catecholamines, corticosteroids,
and glucagon play a principal role in the neuroendocrine response. Cytokines, complement, eicosanoids,
and platelet-activating factor are key mediators of the inflammatory response. During elective surgery,
the inflammatory response is typically local and confined to the surgical wound. Following a major
accidental injury, extensive uncontrolled tissue damage triggers an inflammatory response and release
of mediators that commonly spills over into the systemic circulation.
The hormonal response to stress appears to be the result of extensive neuroendocrine stimulation.
Glucagon along with insulin resistance has potent glycogenolytic and gluconeogenic effects on the liver,
which signal the hepatocytes to produce glucose from hepatic glycogen stores and gluconeogenic
precursors. These gluconeogenic precursors are typically amino acids (alanine and glutamine) released
from muscle. This action is facilitated by thyroid hormone. Catecholamines also stimulate hepatic
glycolysis and gluconeogenesis and increase lactate production from peripheral tissues (skeletal muscle).
Catecholamines additionally increase metabolic rate and stimulate lipolysis (Fig. 3-4).
80
The inflammatory portion of the response is arbitrated by a host of mediators, including cyto- and
chemokines, complement, and eicosanoids. The initial trigger stimulates local mast cells to release
numerous mediators, with pro- or anti-inflammatory properties.36 The intermediaries that promote
inflammation usually predominate early (tumor necrosis factor [TNF], interleukin [IL]-1, IL-6,
prostaglandin-E2 [PGE2], leukotriene-4 [LT4]), whereas anti-inflammatory effectors are released later,
as the body is trying to control the inflammatory response. The TNF and IL-1 stimulate IL-6 release. One
of the effects of IL-6 is to reduce the level of insulin-like growth factor 1 (IGF-1), which promotes
proteolysis and amino acid release from muscle. Cytokines act in concert with catecholamines, cortisol,
and thyroid hormone to mobilize amino acids from skeletal muscle. As the inflammatory stimulus is
controlled and eliminated, the anti-inflammatory cytokines (IL-4, IL-10, and IL-13) and eicosanoids
(PGE3 and LT5) begin to predominate, and bring the inflammatory response to a conclusion. This is not
to say that only pro- or anti-inflammatory mediators are being expressed, a balance between the two
sets of factors favors a pro- or anti-inflammatory state at any given time, depending on the presence of
ongoing stimulation.
This combined neuroendocrine- and cytokine-based response provides key nutrients to support
cellular metabolism at a time when enteral nutrition typically cannot be acquired. The primary
metabolic component of the acute-phase response affected by IL-6 is a qualitative alteration in hepatic
protein synthesis with a resulting alteration in plasma protein composition. Characteristically, proteins
acting as serum transport and binding molecules (albumin and transferrin) are reduced, and acute-phase
proteins (fibrinogen and C-reactive protein) are increased. While the role of many acute-phase proteins
remains unclear, many act as opsonins, antiproteases, or coagulation and wound-healing factors, with
the greater aim to minimize tissue destruction associated with inflammation. For example, fibrinogen
promotes thrombus formation to control bleeding, while antiproteases lessen tissue damage caused by
proteases released by dying cells. C-reactive protein has scavenger function and its serum levels have
been identified to be a measure of the inflammatory response.
This inflammatory response occurs at various levels. Small-scale localized inflammatory changes can
be identified frequently in minor illness with no major systemic consequences, and the neuroendocrine
component is only minimally, if at all, activated. In fact, these responses may be an important
mechanism through which the body allows controlled exposure of the immune system to antigen.
Moderate inflammation is still localized, but its effects are more obvious. Severe accidental injury or
major surgery triggers a hyperactive inflammatory reaction, along with the full neuroendocrine
response, the systemic effects of which are more readily identifiable (hypermetabolism, body protein
catabolism, insulin resistance, fever, and acute-phase protein response). Occasionally, such an exuberant
response leads to multiorgan failure, in which widespread endothelial damage, metabolic derangements,
immune function collapse, and, finally, end-organ dysfunction occur.37 This type of inflammation-driven
illness is a major cause of death in the intensive care unit (ICU). Significant lean body mass loss is seen
in survivors, however, when convalescence is under way, the inflammatory-driven metabolic changes
abate, and the body can be repleted with appropriate nutritional support and exercise.
Inflammation, for reasons not fully understood, can occasionally become a chronic condition in
survivors, in which impairments in metabolism typically seen in the acute phase endure, and cachexia
sets in.38,39 This form of chronic inflammation is maladaptive and a common feature in many chronic
disease states, inflammatory or not (renal, hepatic, or cardiac failure, many autoimmune diseases,
cancer), and is increasingly identified in ICU survivors after prolonged and complicated ICU stays.38,39
81
Figure 3-4. The neuroendocrine response to stress stimulates proteolysis and lipolysis, promotes gluconeogenesis and leads to
glucose intolerance.
Substrate Metabolism Changes during Stress

5 During the neuroendocrine response to stress, metabolism of commonly used nutritional substrates
undergoes significant changes.
Altered Carbohydrate Metabolism

Hyperglycemia occurs commonly after injury, and its intensity generally reflects the severity of the
stressor. During the ebb phase, insulin levels are low and glucose production is only minimally elevated.
During the flow phase, hepatic gluconeogenesis occurs at a faster pace from peripheral tissue-released
precursors and hyperglycemia persists, while insulin levels are normal or elevated. This phenomenon
suggests relative insulin resistance.
Altered Protein Metabolism

After major injury, nitrogen losses increase. These correlate to the extent of trauma and the injury
victim’s pre-existing nutritional status. In patients not receiving nutrition, protein breakdown exceeds
synthesis, and negative balance results. Providing exogenous calories is important to maintain a neutral
nitrogen balance.23 Skeletal muscle is the chief source of the nitrogen lost in urine following extensive
injury and it appears that amino acid release from muscle is heavily skewed toward glucogenetic
precursors (alanine and glutamine), even though these comprise less than 5% of muscle total protein.
In addition to skeletal muscle, the kidneys and the gastrointestinal tract also release alanine, which
may be used for glucogenetic purposes, even though the majority enters metabolic pathways that favor
the production of urea and ammonia, to be excreted from the body.
Altered Lipid Metabolism

To support the increased metabolic rates after injury or elective surgery, triglycerides are released from
adipose tissue for energy production. Glucose administration minimally affects this lipolysis, which
appears to be a result of continuous neuroendocrine stimulation. Although mobilization and oxidation of
free fatty acids are accelerated in injured subjects, ketone synthesis is minimal and occurs independently
of protein catabolism. When severely injured patients remain unfed, their fat and protein stores become
depleted rapidly, and the resultant malnutrition increases their susceptibility to infectious complications,
multiple organ system failure, sepsis, and ultimately death.
Stressor-Dependent Adjustments to the Metabolic Response

Response to Elective Surgery and Accidental Injury
82
One of the earliest consequences of major surgery is the rise in levels of circulating cortisol in response
to a sudden release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. This
cortisol remains elevated for 24 to 48 hours after operation. Cortisol has generalized effects on tissue
catabolism and mobilizes amino acids from skeletal muscle that provide substrates for wound healing
and serve as precursors for the hepatic synthesis of acute-phase proteins or new glucose, as delineated
earlier (Fig. 3-5). Associated with the activation of the adrenal cortex is stimulation of the adrenal
medulla through the sympathetic nervous system, with release of epinephrine and norepinephrine.
These circulating neurotransmitters play an important role not only in increasing vascular tone, which
may be lessened from circulating cytokines, but also in promoting amino acid release from skeletal
muscle, lipolysis in adipose tissue, and gluconeogenesis in the liver.
The neuroendocrine response to surgical trauma can also modify the various mechanisms that
regulate salt and water excretion. Alterations in serum osmolarity and body fluid tonicity due to
anesthesia, operative stress, and fluid resuscitation, stimulate antidiuretic hormone (ADH) and
aldosterone secretion. ADH and aldosterone promote water and sodium reabsorption in the renal
tubules respectively. Thus weight gain from salt and water retention is not uncommon after major
surgery. Edema occurs to a varying extent in all surgical wounds secondary to local cytokine release
that increases vascular permeability, and this local water accumulation is proportional to tissue trauma.
This extravasated fluid eventually returns to the circulation as the postoperative inflammatory response
subsides and diuresis commences, typically 2 to 3 days after surgery.
Figure 3-5. During sepsis, metabolism shifts to greater glucose synthesis and utilization, likely mirroring the greater metabolic
needs of the pathogens and the mobilized host white blood cells.
Table 3-7 Differences Between Elective Surgery and Accidental Injury
83
Glucagon from the endocrine pancreas is also released at greater rates postoperatively, while insulin
levels decrease. This response appears to be associated with the increased sympathetic activity that
typically follows surgical trauma. The rise in glucagon and the corresponding fall in insulin act as potent
signals accelerating hepatic glucose synthesis.
This postoperative catabolic period, which may be worsened by inadequate caloric intake, has been
termed the “adrenergic–corticoid phase,” which generally lasts 1 to 3 days and is followed by the
“adrenergic–corticoid withdrawal phase,” which may last an additional 1 to 3 days. An anabolic phase
ensues, which can occur at a variable time during a surgical patient’s convalescence. In general, in the
absence of significant postoperative complications, this stage starts 3 to 6 days after major abdominal
surgery, usually when the bowel function returns and an oral diet is initiated. This phase is
characterized by positive nitrogen balance and weight gain. Protein is synthesized at an increased rate,
and return of lean body mass and muscular strength ensues.
Whether the body is injured within the carefully monitored confines of the operating room or
accidentally, the response to tissue trauma is similar, although key differences exist. In accidental
injury, tissue damage is uncontrolled and happens in a contaminated environment. The associated
volume loss can be substantial and life-threatening. Pain and the sympathetic nervous system
overexcitation are heightened and uncontrolled. As a consequence, the magnitude of the physiologic
response to major accidental injury is considerable. In contrast, the elective tissue trauma inflicted
occurs in a planned and monitored setting, and the team caring after the surgical patient perioperatively
ensures appropriate resuscitation designed to attenuate such changes. Hydration during and after
surgery is common, and the latter typically happens in a clean field. At the same time, the
anesthesiologist provides medications to minimize anxiety and fear, to minimize the sympathetic
nervous system response. Appropriately selected pharmacologic agents are used to minimize undesirable
cardiovascular responses, and analgesic techniques are employed to minimize postoperative pain. As a
result, the physiologic responses to elective surgery are generally of lesser magnitude than those
following major accidental injury and are typically tolerated better (Table 3-7).
Metabolic Adaptations to Sepsis

The metabolic changes following invasive infection are not dissimilar to those seen after elective
surgery and accidental trauma, although they are typically less predictable. Severe infection is
characterized by fever, hypermetabolism, diminished protein economy, altered glucose dynamics, and
accelerated lipolysis, much like the injured patient. Anorexia that commonly follows systemic infection
is an added factor contributing to the loss of lean body mass.
Hypermetabolism and increased oxygen consumption are additional traits, with the latter reaching
peak levels that may be 50% to 60% higher compared to baseline in severe sepsis. A portion of this
metabolic acceleration can be attributed to the escalation in enzymatic reaction rates associated with
fever. It is estimated that the base metabolic rate rises by 10% to 13% for every 1°C rise in central
temperature. Glucose metabolism is increased to much greater levels in systemically infected subjects,
compared to trauma victims. As an example, burn patients synthesize glucose at a rate approximately
50% above normal. If superinfection ensues, hepatic glucose production doubles, and it appears that the
additional glucose requirements correlate with the bacterial burden and white blood cell activation (Fig.
3-5).
Increased proteolysis and nitrogen excretion leading to negative nitrogen balance typically occur
84
following invasive infection, in a pattern that is similar to that described for injury. Visceral amino acid
uptake is accelerated during sepsis, and this is matched by faster amino acid efflux from skeletal muscle.
In infected burn patients, splanchnic amino acid uptake is amplified over 50% above rates in uninfected
burn victims with comparable injuries. These amino acids serve either as glucose precursors, or building
blocks for acute-phase protein synthesis.
Fat is another major fuel utilized for energy in infected patients. Increased fat catabolism is
particularly profound in patients during periods of inadequate nutritional support or relative starvation.
Lipolysis is accelerated among other reasons by a heightened sympathetic activity, and serum
triglyceride levels reflect the balance between synthesis in the liver and storage in the peripheral
adipose tissue. Marked hypertriglyceridemia has been associated with certain gram-negative infections,
but frequently triglyceride concentrations are normal or low, indicating enhanced utilization and
clearance by other organs. Infected patients cannot convert fatty acids to ketones as efficiently in the
liver, and do not adapt to starvation as well as their fasted, unstressed counterparts. It is postulated that
the low ketone state of infection is a consequence of the hyperinsulinemia, which in turn follows insulin
resistance in high-degree catabolic states.
Trace elements and electrolytes (zinc, iron, potassium, magnesium, and inorganic phosphate)
typically follow alterations in nitrogen balance. Although the iron-binding capacity of transferrin
typically remains unchanged in early infection, free iron cannot be found in the plasma of patients with
severe pyrogenic infections. Similar changes are seen in zinc levels. These decreases cannot be totally
accounted for by total body losses, rather an accumulation of these elements appears to occur in the
liver, through not yet elucidated mechanisms. Unlike iron and zinc, serum copper levels generally rise,
seemingly due to greater ceruloplasmin synthesis in the liver.
Metabolic Response to Cancer and Acquired Immunodeficiency Syndrome

Patients with cancer and acquired immunodeficiency syndrome (AIDS) have similar metabolic states,
characterized by chronic malnutrition, typically a result of anorexia and treatment side effects, and
prolonged low-grade inflammatory changes. Cancers of the aerodigestive tract interfere with taste,
swallowing and/or digestion, precluding adequate caloric and/or protein intake. Supplementation with
zinc and B vitamins may help taste-related symptoms, and soft mechanical diets may allow greater
caloric intake in patients with swallowing difficulties or proximal gastrointestinal tract malignancies.
The aggressive management of nausea and vomiting, may also afford greater interest in food.
Cancer- and AIDS-related cachexia is seen in the later stages of disseminated disease and represents a
chronic catabolic state due to unrelenting inflammation that is difficult to reverse, even with adequate
caloric and protein supplementation. Proinflammatory cytokines (TNF, IL-1, and IL-6) are constantly
released in response to the tumor or an infectious source in AIDS, respectively, and lead to a chronic
state of muscle wasting and fat loss. The cachexia of cancer and AIDS is difficult to manage, as
removing the inflammatory stimulus can prove elusive. However, mitigation of the chronic, low-grade
inflammatory response may be useful, and so can aggressive nutritional supplementation and appetite
stimulants.40
Another practice that is becoming increasingly popular is the repurposing of the dietary balance of n-6
to n-3 fatty acids. Thirty eight fatty acids from the diet eventually become incorporated into cells’
plasma membranes, influencing their function and characteristics, and act as precursors for eicosanoid
synthesis.39 The eicosanoids produced depend on the type of fatty acids found in plasma membranes.
The n-6 fatty acid linoleic acid is converted to arachidonic acid, which in turn gives rise to
proinflammatory eicosanoids PG2 and LT4. The n-3 fatty acid linolenic, eicosapentaenoic, and
docosahexaenoic acids yield more anti-inflammatory PG3 and LT5. These eicosanoids interrupt the
release of IL-6, thus potentially allowing IGF-1 levels to normalize in cachectic patients.40 While a
typical Western diet is high in n-6 to n-3 fatty acids ratio (∼15:1), more therapeutic ratios of 2:1 to 4:1
can be targeted, in addition to maximizing protein and caloric intake. Such efforts have been met with
improving clinical outcomes in patients with pancreatic cancer41 or generalized malignancies.42
Stimulants of the Stress Response

Hypovolemia and End-Organ Hypoperfusion
Following hemorrhage, pressure receptors in the aortic arch and carotid, and volume (stretch) receptors
in the left atrial wall detect the acute drop in circulating blood volume and pressure and respond by
signaling the central nervous system. Activation of the sympathoadrenergic axis leads to a rise in stroke
volume to maintain a perfusing pressure, at the expense of tachycardia. ADH and aldosterone are also
85
released, in an attempt to restore circulating plasma volume. ADH is released by the posterior pituitary
in response to hypotonicity and increases water reabsorption in the renal tubular apparatus. Aldosterone
is produced through activation of the renin–angiotensin system, when the renal juxtaglomerular
apparatus senses a drop in the renal perfusion pressure, and also increases reabsorption of sodium and
water. These mechanisms are only partly effective and, if bleeding is not controlled surgically and
resuscitation inadequate, peripheral tissue oxygenation does not suffice to meet metabolic demands and
metabolism switches to anaerobic metabolism, leading to lactate production and lactic acidosis.
Tissue Damage
Tissue damage appears to be one of the principal factors that can set the stress response into motion.
Hypovolemia itself is rarely an adequate stimulus to trigger a hypermetabolic response, unless
associated with extensive tissue damage or infection. However, if hypoperfusion is prolonged, cellular
death may ensue, which in turn will lead to release of toxic products that can initiate the “stress”
response.
Pain
Pain can be an important activator of the sympathoadrenergic response and lead to a catecholamine
surge with the metabolic effects described earlier. Local tissue destruction is sensed as pain centrally,
which triggers numerous efferent pathways preparing the body for what is termed the “fight or flight”
response.
Determinants of the Host Response to Stress

Each individual, depending on their genetic traits and certain environmental parameters may respond
differently to similar tissue injury patterns. The idiosyncratic nature, intensity, and duration of the
stress response may vary extensively in numerous ways in individuals with certain similar genetic and
body composition characteristics.
Body Composition
Body composition is a major determinant of the metabolic response seen in the acute phase after
surgical or accidental trauma. Posttraumatic nitrogen excretion is directly proportional to the size of the
lean body mass. The balance between nitrogen intake and output is a useful marker of protein
metabolism. A greater muscle mass due to greater long-term physical activity may also confer an
advantage during acute surgical illness and starvation, as the ability of the lean body mass to provide
amino acids for gluconeogenesis during acute illness when it is needed the most, is optimal. Conversely,
excessive adiposity may affect outcomes after intense stress, and this is likely due to an abundance of
proinflammatory precursors.43
Baseline Nutritional Status

A strong relationship exists between preoperative protein depletion and postoperative complications.4
Protein-depleted patients have lower pulmonary muscle strength and reserve, and are more susceptible
to infectious complications, including of the respiratory tract, as well as of the surgical site. Patients
with poorer baseline nutrition also experience impaired wound healing and are subject to longer
postoperative hospital stays.
Age and Gender

Certain patterns in the metabolic response to surgical pathology that occur with aging can be attributed
to alterations in body composition. Although weight remains roughly stable, fat mass tends to increase
with age, while lean body mass tends to decline. The loss of strength that accompanies immobility,
starvation, and acute surgical illness may have significant consequences. Although the increased energy
requirements after elective surgery occur essentially independent of age, the capacity of muscle to serve
as a source of amino acids may be limited during acute surgical illness in the elderly, and muscle
strength may rapidly become inadequate for respiratory function.
In addition to a smaller muscle mass, older age is commonly associated with a greater prevalence of
cardiovascular and pulmonary disease. Relatively decreased arterial compliance, lower baroreceptor
sensitivity, and a blunted response to the catecholamine surge may impair the cardiovascular
homeostatic response during acute surgical illness. Thus, tissue oxygenation may not be able to meet the
heightened demand.
Gender, in addition to age, may affect the body’s ability to adapt to surgical stress. Observed
86
differences in the metabolic response between men and women in general reflect differences in body
composition. Lean body mass, as a proportion of total body weight, is lower in women than in men.
This difference is thought to account for the lower net loss of nitrogen after major elective abdominal
surgery in women. Women in general, have approximately half the skeletal muscle mass of men of the
same age. Therefore, young muscular men experience the greatest nitrogen losses during acute surgical
illness, as opposed to elderly, sedentary women.8
NUTRITIONAL SUPPORT
Nutritional Support in Elective Surgery
Most patients undergoing elective operations are adequately nourished, and are typically only fasted the
evening before surgery. Unless the patient has suffered significant preoperative malnutrition (subjective
global assessment class C) or has a major intraoperative or postoperative complication, intravenous
solutions containing 5% dextrose may be administered for up to 5 to 7 days with no detrimental effect
on clinical outcomes. In patients who present with the evidence of starvation-related malnutrition,
preoperative addition of balanced macronutrient, and high-protein supplementation could be useful.
This preoperative support should be initiated as far in advance as possible, even though it is estimated
that the minimum time required to derive any benefit from this support is in the range of 2 to 4
weeks.44 During this period, electrolyte abnormalities should be addressed, and early involvement of a
nutritionist would be advisable.
Bowel function typically returns within the first 5 to 7 postoperative days in the majority of surgical
patients, and an oral diet or enteral feedings can be resumed. The increased cost of feedings and the
potential complications associated with parenteral nutrition cannot be justified. Conversely, in patients
who are malnourished preoperatively or prolonged postoperative ileus has rendered them unable to be
fed enterally for more than 5 to 7 days, nutritional support should be considered. The nutritional status
should be assessed early, so this piece of information can be integrated into decision-making and
nutrition care planning. Enteral feedings are superior and always preferred to parenteral nutrition in
patients who can tolerate an enteral diet. Standard high-protein feeding formulas are adequate. The
choice of product and volume of feeding are based on the results of the nutrition assessment. The
majority of tube feeding formulas today are rich in water-soluble dietary fiber, which is considered
standard in the nutritional care of the surgical patient. Specific adjustments can be undertaken, if special
considerations (e.g., cardiac failure, renal failure, diabetes, etc.) have to be made. Preoperative addition
of a balanced macronutrient high-protein supplement is useful to initiate as far in advance of surgery as
possible, although in this severely malnourished population, the time needed to see benefit from
supplementation is unknown (estimated minimum of 2 to 4 weeks).
6 One of the best studies to date evaluating the efficacy of preoperative TPN was published by the
Veterans Affairs Total Parenteral Nutrition Cooperative Study Group.4 Over 3,000 patients requiring
mostly elective gastrointestinal procedures were randomized to receive parenteral nutritional support
for at least 7 days preoperatively versus none, if they were deemed to be malnourished preoperatively.
Patients with severe malnutrition (>15% weight loss and serum albumin <2.9 mg/dL) preoperatively
had fewer noninfectious complications (impaired wound healing), if they were provided TPN before
surgery, however, infectious complications (pneumonia, surgical site infections, and line infections)
were more common in the TPN group. This study strongly suggests that preoperative TPN should be
considered only to severely malnourished patients who cannot be fed via the enteral route.
Numerous studies that have followed have reached similar conclusions, and have led the SCCM and
ASPEN to recommend targeted preoperative nutritional support for those deemed malnourished. This
support should ideally be oral, enteral, or in rare circumstances parenteral and with therapeutic intent.6
In fact, while initial guidelines advocated the use of artificial nutrition if preoperative weight loss
>10% has occurred or oral intake is not deemed achievable for more than 7 days postoperatively,
interest in supporting all surgical patients perioperatively has been on the rise, regardless of baseline
nutritional status.45
Nutritional Support in Critical Care

7 While resuscitation, bleeding control and preservation of the vital body functions, such as
maintenance of gas exchange and supporting of adequate cardiac output, remain immediate priorities
for survival in any critically ill surgical patient, it is increasingly recognized that nutritional support is
87
an integral part of the metabolic care of the critically ill, and aggressive pursuit of target energy
requirements is associated with optimal wound healing, recovery, and rehabilitation. Critically ill
patients commonly have anorexia that can be adaptive or maladaptive and may be unable to be fed by
mouth volitionally for periods, which can range from days to months, and severe malnutrition can
complicate their course and adversely affect outcomes, unless they are provided with enteral or
parenteral nutrition.46 Several studies have underlined the association between energy deficit in critical
illness and longer ICU stays, greater incidence of infectious complications, and even mortality.47–50 The
finding that enteral nutrients exert a trophic effect on the cellular integrity and function of the gut
mucosa has provided the rationale for initiating enteral feedings early in the course of critical illness. In
fact, evidence from observational studies appears to support that critically ill patients who were fed
earlier had better overall outcomes compared to those that did not,51 and these improved outcomes
have led critical care nutrition to be at the forefront of ongoing research worldwide. Therefore,
regardless of baseline nutritional status, any critically ill patient who is not expected to resume an oral
diet within 3 to 4 days should have nutritional support instituted as soon as technically and logistically
feasible, ideally within 24 to 48 hours after admission, and have their blood glucose levels maintained
<140 mg/dL.52 Patients on enteral nutrition, should have their head of bed elevated at 45 degrees, or
be in steep reverse Trendelenburg position if spinal precautions preclude this measure, to minimize
aspiration risk.18,20
The optimal method of estimating daily energy requirements in the critically ill remains a subject of
debate. It would be ideal if energy requirements were calculated precisely on a daily basis using indirect
calorimetry, as this method appears to lead to greater energy provision than less precisely calculated
energy targets, even though this practice was associated with a greater incidence of infectious
complications and a longer overall ICU length of stay.53 Indirect calorimetry, however precise, can be
impractical, if not even impossible to apply in certain critically ill individuals.54 Additional challenges
facing critical care nutrition include the frequent interruptions in nutrition delivery for a variety of
reasons, including delayed gastric emptying and transfers outside the ICU for diagnostic or therapeutic
procedures. When protocols to aggressively advance nutrition are in place, it appears that critically ill
patients are able to achieve their caloric goals earlier, even though these practices may not necessarily
translate to better overall outcomes.55–57 With regard to delayed gastric emptying, which is commonly
cited as a reason for slow advancement of enteral feedings, it appears that advancing tube feedings
without measuring or accepting residual volumes as high as 500 cc/4 hours results in quicker attainment
of the caloric goals, with no concomitant rise in the incidence of nutrition-related adverse events.58 The
use of prokinetic agents (erythromycin may be more effective than metoclopramide), as well as
postpyloric feeding delivery has also been advocated to minimize the issue of delayed gastric emptying,
however, other than achievement of nutritional goals being slightly earlier in the course of critical
illness, no definitive improvement in outcomes has been demonstrated.59–62 There is some divergence
on whether immune- or inflammation-modulating feeding formulas are indicated in some critically ill
patients. There is at least one quality study that has been published since the guidelines that support the
use of such feedings in patients with sepsis and risk for acute respiratory distress syndrome or acute
lung injury.63
Access Routes for Nutrition

Enteral or Parenteral
8 An issue with reliance solely on enteral nutrition is that attaining caloric targets may prove elusive,
due to a partly functional gastrointestinal tract or side effects associated with enteral feedings. While
enteral feedings are always preferable to parenteral nutrition in general, the timing of initiation of TPN
in patients unable to tolerate or with contraindications for enteral feedings remains controversial.
European guidelines recommend early initiation of TPN to minimize nutritional deficits, while North
American guidelines favor hypocaloric enteral nutrition for up to 1 week in patients with good
nutritional baseline before considering TPN.48,49 The rationale on the delay in TPN administration is
based on complications associated with the use of TPN, such as infections, hyperglycemia,
hypertriglyceridemia, and liver function abnormalities.64–67 The latter seems to be supported by more
recent high-quality data that demonstrate that patients receiving partial enteral nutrition demonstrate a
lower incidence of ICU-acquired weakness, spend less time in the ICU and the hospital, and require
shorter length of vital-organ support, and incur less costs, compared to their counterparts in whom
partial enteral nutrition was supplemented with TPN.68–71 However, conflicting data exist on the effect
of nutritional supplementation with TPN on infectious outcomes in patients receiving hypocaloric
88
enteral feedings from more recent trials.68,69,72 In critically ill patients with a relative contraindication
(e.g., gastric residual volumes >500 mL or postoperative ileus) for early enteral nutrition, it appears
that early TPN helps decrease total length of stay on mechanical ventilation.73 Whether early parenteral
nutrition is beneficial in patients with an absolute or prolonged contraindication for enterally
administered nutrition remains a topic of debate, even though it is fairly well established that the
greater incidence of infectious complications may outweigh the benefits of early achievement of
nutritional goals in patients in their first 5 to 7 days in the ICU.68,74
Total Parenteral Nutrition Considerations

As the term implies, and due to the high osmolarity of its content, TPN must be delivered centrally to
minimize the risk of venous sclerosis. Patients on TPN therapy should be monitored regularly by
measuring blood sugar, serum electrolytes, and liver function tests, as abnormalities in these
laboratories are common. TPN-related complications can be broadly categorized into those that are
access related, metabolic, and infectious. A list of these is summarized on Table 3-8.
Table 3-8 TPN-Related Complications
9 Hyperglycemia is common in surgical patients, especially during high-stress periods, or they were
relatively glucose intolerant or frankly diabetic at baseline. This side effect of TPN can generally be
controlled with subcutaneous or intravenous insulin administration if mild or moderate–severe
respectively, and eventually by adding insulin to the TPN formulation, once the daily insulin
requirements have been calculated. It has been shown that stressed individuals can maximally oxidize
up to 4 to 5 mg of glucose/kg/min. For a 70-kg man, this is equal to approximately 400 to 500 g/day
(1,600 to 2,000 kcal/day). Therefore it is common for patients to receive up to two-thirds of their daily
caloric needs in carbohydrate form through TPN. Excess glucose can result in hyperglycemia and
glycosuria, can be converted to fat, and deposited in the liver. Glycosuria with its osmotic load can lead
to osmotic diuresis, which can be misinterpreted as a sign of adequate resuscitation status or transition
to recovery phase, while the patient may actually be clinically worsening.
Fat is an important fuel for the critically ill, as stressed patients preferentially utilize endogenous fat
as an energy source. Fat oxidation is only minimally affected by carbohydrate administration during
stress, unlike traditional starvation, and glucose infusion above certain levels may lead to hepatic
steatosis. Lipids are commonly added to TPN formulations to help meet the caloric requirements, as
well as to provide the essential fatty acids and to minimize complications associated with the infusion of
large amounts of carbohydrate-containing fluids. Lipid emulsions for TPN solutions are mostly vegetable
fat based, and contain primarily long-chain fatty acids. Inclusion of lipids in the TPN provides the
essential linoleic acid, inhibits lipogenesis from carbohydrates, and helps lower the respiratory quotient
89
(RQ), which may benefit patients with carbon dioxide retention. However, formulations with a high n-6
polyunsaturated fatty acid content (linoleic acid in particular) may attenuate acute lung injury,75 and by
affecting plasma membrane fluidity, the ability to phagocytose bacteria may be impaired. Newer
nutritional methods of modifying the catabolic response to injury and infection propose the use of n-3
fatty acids, which may decrease eicosanoid synthesis and thereby diminishing the vasoconstriction,
platelet aggregation, and immunosuppression that may occur when n-6 derivatives are given. Studies
suggest that n-3 fatty acids may be of benefit to the critically ill patient.76
The amounts of the various electrolytes provided to patients receiving TPN vary, depending on
previous volume status and preexisting electrolyte abnormalities. Careful monitoring of serum
electrolyte levels is critical, especially during the acute phase of disease or in severely malnourished
individuals, because as metabolism switches to the anabolic phase, potassium and phosphate can move
rapidly into the intracellular compartment, leading to potentially fatal hypokalemia or
hypophosphatemia, in what is known as the refeeding syndrome.77 Vitamin and trace mineral levels,
although not as life-threatening, should also be occasionally monitored. The composition of a standard
TPN solution is shown in Table 3-9.
A significant downside of TPN is that the gastrointestinal tract goes into misuse, and evidence
suggests that this may exacerbate intestinal microflora translocation from the gut lumen to the
mesenteric lymph circulation, worsening total bacterial load and stress during an already compounded
clinical situation. Clinical evidence suggests that TPN, under certain circumstances, may accentuate
stress, and predispose to gut-derived infectious complications, and even multiple organ failure,78,79
while compared to enteral nutrition, it may minimize episodes of hypoglycemia and vomiting.80
Enteral Nutrition Considerations

10 11Enteral nutrition is safer and less expensive than parenteral nutrition, and numerous studies have
demonstrated the superiority of enteral nutrition compared to parenteral, in decreasing postoperative
infectious complications and increasing collagen deposition at anastomotic sites, improving wound
tensile strength.81 The gastrointestinal tract can be used for administration of complex nutrients that
cannot be provided as readily intravenously, such as polypeptides and fiber. Gut processing of many of
these nutrients stimulates hepatic protein synthesis, while intravenous administration bypasses the
portal circulation altogether. In addition to the systemic benefits of enteral nutrition, enteral feedings
afford significant local benefits on the gut mucosa itself. Enterocytes are being fed directly, and the
absorptive surface of the mucosa is stimulated and maintained. Luminal nutrients, such as glutamine and
short-chain fatty acids, are used as fuel by small bowel enterocytes and colonocytes respectively.82 The
trophic effects of luminal nutrition are well documented, even if small amounts of enteral feedings are
provided, and a growing body of evidence suggests that earlier enteral nutrition is preferable.83–85 An
additional immunologic benefit of enteral nutrition is that complex polypeptides and long-chain fatty
acids stimulate the production of gut-derived immunoglobulin A, which is important in reducing
bacterial translocation. Luminal nutrients also help maintain a normal pH and flora, thus diminishing
the risk of opportunistic bacterial overgrowth in the bowel. In addition to the physiologic, metabolic,
and immunologic benefits of enteral nutrition, safety and cost benefits also exist. Enteral feedings are
considered safer than parenteral nutrition. The latter places patients at a greater risk for hyperglycemic
events, which may partly inhibit neutrophil-mediated immune function, and may be the reason why
TPN-nourished patients may be at a greater risk for infectious complications, even though this risk may
be eliminated with tight glucose control.80 Finally, there are obvious cost benefits, as tube feedings are
in general cheaper than parenteral nutrition formulations.
Table 3-9 Composition of a Standard Total Parenteral Nutrition Formulation
90
Although enteral nutrition is the preferred method for nutritional support in malnourished patients, or
subjects at risk for developing malnutrition and have an intact gastrointestinal tract, a problem surgical
patients are commonly facing is intestinal inactivity, especially after gastrointestinal procedures.
Postoperative ileus is frequent, reflects functional immobility of the gastrointestinal tract, and is
typically proportional to the amount of manipulation the bowel sustained during the surgical
intervention. Patients who are either unable to meet their daily caloric and nutrient needs are
candidates for enteral support. Factors that can help determine the timing of initiation of enteral
nutrition include preexisting malnutrition, current illness acuity and duration, estimated catabolic
activity, and anticipated return to per os intake. Contraindications to enteral feedings are usually
relative or temporary, and include short, obstructed, or perforated bowel, a gastrointestinal tract in
discontinuity, protracted vomiting, fistulas, or active gastrointestinal ischemia. While gastrointestinal
bleeding or worsening hemodynamic instability has been traditionally quoted as additional
contraindications, it appears that enteral nutrition can be safely administered during these.86–88
Despite the numerous benefits of enteral nutrition, it is not completely free of complications. These
can be categorized in access related, functional, and metabolic, and are summarized in Table 3-10. In
general, these can be avoided with meticulous care while inserting and maintaining feeding tubes,
considering using nasal bridles,89 ensuring head of bed elevation to minimize risk of aspiration, using
motility agents when gastric motility is suboptimal, closely monitoring patients’ metabolic profile and
adjusting content, or adding bulking agents if osmotic diarrhea develops.
Enteral feedings are generally categorized into intact or polymeric (protein, carbohydrate, and lipid
molecules exist in an unaltered form – usually given to patients without absorption or digestion
difficulties), hydrolyzed or monomeric (contain predigested proteins, simple sugars, and medium-chain
triglycerides – are a good option for patients with impaired digestive capacity), and modular (typically
contain one type of fuel, carbohydrate, lipids or fat, and can be combined to address each patient’s
specific needs). Some of the most commonly used enteric feeding formulas and their metabolic
characteristics are shown on Table 3-11.
Table 3-10 Enteral Nutrition-Related Complications
91
Table 3-11 Commonly Used Enteral Nutrition Formulations
92
Macro- and Micronutrient Selection
An additional topic of debate is whether selection of specific macro- and micronutrients to be included
in nutritional formulas, be it enteral or parenteral, can afford specific benefits to patients receiving
them, depending on the underlying pathology. Gluconeogenesis from amino acids (glutamine and
alanine) released from muscle protein breakdown cannot be fully suppressed with exogenous glucose
and insulin administration, due to the complex hormonal stress response the human body elicits during
critical illness, which results in relative insulin resistance. It was postulated, therefore, that exogenous
amino acid and oligopeptide infusion would help minimize lean body mass erosion. However, even
though the total nitrogen equilibrium appears to be shifted toward a more positive balance when this
practice is employed, it does not translate to better outcomes.90 Therefore, the optimal protein to total
energy ratio in critical illness remains largely unknown.
12 Glutamine is the most abundant nonessential amino acid and in humans it is predominantly
released with skeletal muscle proteolysis. It is one of the key precursors for hepatic gluconeogenesis at
times of stress, and low glutamine levels have been associated with poor outcomes in critical illness, as
it is an important nutrient necessary for the function of immune cells, enterocytes, and hepatocytes. It
has been postulated that low glutamine levels are a consequence of muscle wasting, and a meta-analysis
of early randomized controlled trials suggested that glutamine supplementation may help decrease
infectious complications, hospital length of stay, and even mortality.91 However, this finding has not
been replicated in newer, higher-quality studies, and in fact, it appears that aggressive glutamine
supplementation may increase risk of death in patients with organ failure.92–94 These findings do not
support glutamine supplementation routinely. Its supplementation may be beneficial when depletion is
severe or when the intestinal mucosa is damaged by chemo- and/or radiation therapy.95 Similarly,
arginine supplementation may be associated with a lower infectious risk and shorter hospital length of
stay, however, no currently available evidence support its use during critical illness.96
The n-3 fatty acids (present in fish oil preparations) have been shown to have anti-inflammatory
effects, while n-9 fatty acids (present in olive oil) have a neutral effect on inflammation, and n-6 fatty
acids (in soybean oil) appear to be proinflammatory.97 On the basis of low levels of n-3 fatty acids in
acute lung injury patients and the proinflammatory properties of n-6 fatty acids, the lipid profile of such
patients was hypothesized to contribute to worsening acute lung injury, and some initial studies
suggested that administration of high n-3 to n-6 fatty acid ratio formulas may benefit critically ill
patients.98,99 However, more recent, higher-quality studies have failed to show a beneficial effect of rich
in n-3 fatty acid preparations in either enteral or parenteral nutrition formulations.100,101 Currently, the
lack of high-quality evidence precludes any recommendation on the use of specific lipids in critically ill
patients.
13 Micronutrients, as electrolytes, vitamins and trace elements are generally termed, are
administered in critical illness to prevent deficiencies and associated complications. With repletion of
micronutrient stores after starvation, refeeding syndrome can occur, which typically unmasks severe
deficiencies in potassium, phosphate, and thiamine. This can be life-threatening and present with lactic
acidosis, cardiac arrhythmias, worsening respiratory failure, and even heart failure. Therefore, routine
administration of micronutrients during critical illness is commonly warranted. Provision of therapeutic
doses of trace elements (selenium, copper, zinc, and iron) and vitamins (E, C, and beta-carotene) with
antioxidant activity has also been proposed,102 however, recent randomized controlled data failed to
demonstrate a benefit.93 Selenium supplementation may also be beneficial in subjects with selenium
deficiency, and the potential benefit is supported by a recent meta-analysis.103
Current recommendations for nutritional support during critical illness are summarized on Table 3-12.
Access Routes
TPN solutions are administered through a central venous catheter, generally inserted in the subclavian
or internal jugular vein, or through peripherally inserted central catheters (PICCs) that are typically
inserted in veins of the antecubital fossa and have their ends reach the atriocaval junction.
Administration of TPN through femoral venous catheters is avoided as possible, due to the greater
incidence of infectious complications this access site entails. Central lines are preferred when short-term
central venous access is indicated, and are commonly inserted by surgeons, intensivists, or
interventional radiologists. In contrast, PICC lines are placed by specially trained nursing staff or
interventional radiologists, and the logistics of insertion (scheduling, availability, and workload of the
practitioners placing them) must be considered. The major benefit of PICCs is that patients can be
discharged from the hospital with them, if prolonged access is required, and their safer insertion profile,
93
while the major advantage of traditional central venous catheters is that they allow infusion of
vasoactive medications, and can be used for resuscitative purposes (administration of large volume of
crystalloids rapidly) and advanced hemodynamic monitoring (measurement of central venous pressure).
Both carry multiple ports, and it is a common practice to save one of these for nutrition access alone, as
the high-carbohydrate concentration of nutrition solutions can act as a nidus for infection, if the same
port is used both for TPN administration and is frequently accessed for blood draws. Both devices can
also be used for administration of medications toxic to the peripheral venous system (e.g., hypertonic
saline, vancomycin, and other hyperosmolar solutions), and allow an easy access route for repeat
venous sampling, which can be convenient in patients requiring frequent laboratory draws. Routine
exchange of uncomplicated central or PICC lines is not advocated, and both types of catheters should be
removed when the indication for their placement ceases to exist, to minimize infectious and thrombotic
complications.
Table 3-12 Recommendations for Clinical Nutritional Practice in the ICU
Peripheral parenteral nutrition (PPN) can be infused through peripheral venous cannulas. Peripheral
intravenous feedings may be used for infusion of protein, lipid, and lower concentration dextrose
solutions. PPN is limited in caloric delivery, due to the large volumes it would require to meet daily
demands, but it avoids central venous cannulation, which has considerable complications. It can be
considered for short-term parenteral nutrition, for example, in the case of postoperative patients with
ileus expected to resolve in a few days.
Enteral feedings are typically administered through oro/naso-, -gastric or -enteric feeding tubes in the
acute phase of disease. The stomach is easily accessed with a soft flexible feeding tube. Intragastric
feedings provide several advantages compared to more distal gastrointestinal tract feedings, as the
stomach has the capacity and reservoir for bolus feedings. Feeding into the stomach stimulates the
biliary and pancreatic axis, with trophic benefits for the entire small bowel. Finally, gastric secretions
exert a dilutional effect on tube feeding osmolarity, reducing the risk of diarrhea. An important risk of
intragastric feedings is regurgitation of gastric contents with possible aspiration into the
tracheobronchial tree. This risk is highest in patients with altered mental status or who are paralyzed.
Placement of the feeding tube through the pylorus further down into the small bowel reduces the risk of
regurgitation. Nasoduodenal/nasojejunal tubes are smaller in caliber and therefore more comfortable
for patients, however, they are more prone to clogging. Patients who repeatedly remove their catheters
may be candidates for feeding tube bridles. Placement of nasogastric or nasoduodenal tubes should
always be confirmed radiographically prior to initiation of feedings.
Patients with chronically impaired mental status (such as those with severe traumatic brain injury),
an inadequate swallowing mechanism or dysphagia, and those with oropharyngeal or proximal
gastrointestinal tract pathology or recent/anticipated surgical procedure may be candidates for longer
term transabdominal gastrointestinal access. This access is typically provided through temporary Stamm
gastrostomies, in which a small laparotomy incision is made, and the gastric lumen in the midportion of
the gastric body is accessed, while a transabdominal large-bore feeding tube is secured in place with
concentric purse string sutures. Percutaneous endoscopic gastrostomy (PEG) tubes can be inserted and
provide access for gastric feedings, without the need for laparotomy, general anesthesia, and even a trip
to the operating room, as they can be performed at the bedside under endoscopic guidance. Using
monitored anesthesia care, a gastroscope is advanced transorally into the stomach and helps
transilluminate the anterior gastric wall through the abdominal wall. A small abdominal incision is
made over the area of maximal transillumination, ideally over the midportion of the gastric body, and
through an angiocath, a wire is advanced into the gastric lumen, which is snared and pulled back out of
94
the mouth with the gastroscope. The wire is looped around the PEG tube and pulled through the
abdominal wall in an antegrade fashion, until only the head of the feeding tube remains in the stomach,
with the rest of it being extracorporeal. The inner part of the PEG tube is confirmed to be in correct
position and the feeding tube is secured in place. This technique may be difficult in obese patients,
whose abdominal walls can be hard to transilluminate. Modified laparoscopy-assisted techniques have
also been described.
Feeding jejunostomies can be considered following any major abdominal procedure, if the need for
prolonged enteral nutrition is anticipated. A loop of proximal small bowel, typically 20 to 40 cm distal
to the ligament of Treitz is elevated and secured against the abdominal wall fascia of the left upper or
lower quadrant and is accessed transabdominally with a feeding tube. The tube can be covered for a
short distance with bowel serosa (Witzel jejunostomy). Laparoscopic feeding jejunostomies have also
been described, as well as the passage of jejunostomy tubes through percutaneously placed gastrostomy
tubes.
ADDITIONAL NUTRITIONAL CONSIDERATIONS

Infectious Processes and Fever
As mentioned earlier, with core temperature elevations, such as those that occur with fever during
infectious or other inflammatory processes, the base metabolic rate increases. Total energy
requirements can be calculated using the aforementioned equations, multiplying by appropriate factors:
mild to moderate infections increase energy requirements by 20% to 30%, and severe infection with
fever increases caloric needs by over ∼50% above basal levels. Even though weight gain and anabolism
are difficult to achieve during the septic response, the astute clinician should be mindful of these
associations and adjust nutritional support accordingly in persistently febrile patients.
Respiratory Failure
A condition commonly complicating surgical patients is respiratory failure with the need for prolonged
mechanical ventilation. The main concern in mechanically ventilated patients is adequate gas exchange,
which includes oxygen and carbon dioxide transport across the capillary–alveolar membrane. Not
uncommonly the indication for ventilatory support is pulmonary infection, which along with a
postoperative status, contributes to the overall hypermetabolism. Hypermetabolism is accompanied by
increased oxygen consumption, which drives carbon dioxide production, as more substrate must be
oxidized to support the greater energy requirements. While nutrition commonly takes lower priority in
ventilated patients, in whom all efforts are directed toward managing the underlying etiology for the
respiratory insufficiency, consideration should be given to the content of the nutritional support, as they
may facilitate or prolong weaning, especially in those with chronic CO2 retention. The RQ of a specific
nutrient denotes the carbon dioxide produced over oxygen consumed, and adjustments in feedings from
high RQ (e.g., carbohydrates, RQ = 1) to lower RQ (e.g., fat, RQ = 0.7), and avoidance of overfeeding
should be considered in patients difficult to wean due to CO2 retention. These adjustments have to be
considered carefully, as increased fat intake, especially mixtures high in n-6 fatty acids, may exacerbate
lung injury.
Renal Failure
Renal failure affects the body’s ability to clear the byproducts of protein metabolism, but does not
change the catabolic rate or the protein requirements. Therefore, a careful balance needs to be achieved
between the need for protein and to limit uremia. When acute surgical stress is superimposed,
consideration for potentially earlier or more aggressive renal support should be given, so that the body
is not restricted of protein, which is critical during the hypermetabolic phase of acute disease. TPN with
amino acids of high biologic value may improve survival in patients with acute renal failure.104 The use
of solutions containing high-quality amino acids can improve nitrogen balance and minimize urea
production. This translates into a decreased frequency of dialysis.
Liver Failure
Patients with liver disease may be malnourished secondary to excessive alcohol intake, diminished food
intake, or persistent inflammatory state from viral infection. These individuals are protein depleted, yet
95
tolerate protein poorly, due to their likelihood to become encephalopathic with high-nitrogen intake.
Due to liver damage and portosystemic shunting, these patients develop derangements in circulating
levels of amino acids. The plasma aromatic-to-branched chain amino acid ratio is increased, favoring the
transport of aromatic amino acids across the blood–brain barrier. These amino acids are precursors of
neurotransmitters that can worsen encephalopathy and lethargy. Using solutions enriched in BCAAs and
deficient in aromatic amino acids in liver failure patients enhances protein tolerance and potentially
improves in clinical encephalopathy.
Heart Failure
Myocardial dysfunction can be seen as part of the critical illness cardiomyopathy (circulating cytokines
TNF and IL-1 appear to have a direct myocardial depressant activity) in patients with sepsis or those
with preexisting congestive cardiac failure who undergo surgery. Patients with surgical emergencies
commonly third space and require significant amounts of crystalloid resuscitation, which may
exacerbate their pre-existing volume overload. When considering nutritional support of these patients,
efforts should be made to minimize the total fluid volume, and nutrition formulas should be
concentrated if possible.
Bariatric Surgery
Bariatric patients pose a special challenge, given their chronically overnourished status and their altered
gastrointestinal tract, if they have undergone weight loss surgery. The latter are at increased risk for
several macro- (usually protein) and micronutrient deficiencies (most commonly vitamins D and B12,
calcium, iron, folic acid, zinc, and selenium),105–107 and the clinician should be mindful of these
potential complications. Nutritional support of the obese or postweight loss surgery patient is
particularly complex because of the balance needed between minimizing overfeeding and avoiding the
hypercatabolic state. Despite the excessive fat stores, critically ill obese patients should receive early
and timely nutrition, as protein–calorie malnutrition does occur, and consideration for indirect
calorimetry, which allows accurate estimation of the caloric requirements, and early involvement of a
nutritionist should be considered. Hyperglycemia is an additional concern in obese patients, as glucose
intolerance or frank diabetes may first manifest in acute illness, and should be addressed whenever
identified.108
Geriatric Patients
Attention to appropriate nutritional support of the geriatric patient is of paramount importance, both in
the perioperative stage, as well as in the ICU, given the multiple physiologic alterations seen in older
age, including greater ratio of fat-to-muscle mass, decreased cardiac and pulmonary reserves, poor
dentition, polypharmacy, and high incidence of malnutrition, which may be as high as 85% in nursing
home residents.109,110 In relation to preoperative preparation, elderly patients are more likely to have
numerous disease processes affecting their general nutritional status, including diabetes, cancers,
cardiac, pulmonary, and renal insufficiency. Given a certain degree of lean body mass loss is to be
expected in this demographic, a higher-protein intake (>1.5 g/kg/day) should be the goal
preoperatively in the elderly undergoing elective surgery, or early in the recovery phase after
emergency procedure or acute surgical illness.46 Toward that goal, numerous protein-rich supplements
that are commercially available to patients who can tolerate enteral feedings, or parenteral nutrition
with high-protein concentrations can be prescribed.44
Enterocutaneous Fistulas
Gastrointestinal cutaneous or gastrointestinal atmospheric fistulas with high output (commonly defined
as having output greater than 400 cc/24 hours) represent a classic indication for long-term TPN. Oral
intake in patients with such fistulas typically results in greater output, especially in fistulas involving
the proximal gastrointestinal tract, which can lead to dehydration, significant metabolic disturbances,
and adversely affect the ability of the fistula to heal. TPN has been shown to increase spontaneous rate
of closure of enterocutaneous fistulas by improving overall nutritional status in the host, or improving
perioperative outcomes in those requiring surgical therapy. Somatostatin and analogs have been used to
aid with fistulous output and spontaneous closure with varying results.
Short Bowel Syndrome
96
Patients with history of extensive small bowel resection lose a large part of the absorptive ability of the
bowel, and frequently have to rely on prolonged TPN to meet their nutritional goals. In select patients
with residual small intestine of at least 18 inches, postresection hyperplasia that can allow enteral
nutrition has been demonstrated in subjects treated with supplemental glutamine, growth hormone, and
a high-carbohydrate, low-fat TPN.111
Major Thermal Injury

Burn victims often suffer from prolonged ileus, which encumbers enteral nutritional support. Even if the
bowel is usable and patients not on mechanical ventilation, they are frequently unable to consume
adequate calories, due to anorexia of severe injury and frequent npo status for repeated trips to the
operating room. Currently available data suggest that aggressive nutritional support with high-protein
intake in patients with major burns is associated with improved survival.112
Prolonged Postoperative Ileus

Patients undergoing major gastrointestinal procedures may develop prolonged ileus in the postoperative
period, which precludes the use of the intestinal tract as a feeding route. If the patient is unable to eat
by postoperative days 5 to 7, TPN should be considered. Although provision of TPN does not influence
the disease process per se, it is beneficial because it prevents further erosion of lean body mass. When
postoperative ileus of shorter duration is anticipated, patients can be bridged with PPN.
Acute Radiation and Chemotherapy Enteritis

Malnourished patients who receive abdominopelvic radiation or chemotherapy may develop mucositis
and enterocolitis that precludes using the intestinal tract for nutrition for variable periods of time. In
such individuals, parenteral nutrition should be provided, until the enteritis resolves and oral feedings
can be resumed.
References
1. Correia MI, Waitzberg DL. The impact of malnutrition on morbidity, mortality, length of hospital
stay and costs evaluated through a multivariate model analysis. Clin Nutr 2003;22:235–239.
2. Schiesser M, Muller S, Kirchhoff P, et al. Assessment of a novel screening score for nutritional risk
in predicting complications in gastro-intestinal surgery. Clin Nutr 2008;27:565–570.
3. Elia M, Russell CA, Stratton RJ. Malnutrition in the UK: policies to address the problem. Proc Nutr
Soc 2010;69:470–476.
4. The Veterans Affairs Total Parenteral Nutrition Cooperative Study Group. Perioperative total
parenteral nutrition in surgical patients. N Eng J Med 1991;325:525–532.
5. Lassen K, Soop M, Nygren J, et al. Consensus review of optimal perioperative care in colorectal
surgery: Enhanced Recovery After Surgery (ERAS) Group recommendations. Arch Surg
2009;144:961–969.
6. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of
nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM)
and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enter Nutr
2009;33:277–316.
7. Mueller C, Compher C, Ellen DM; American Society for Parenteral Enteral Nutrition (A.S.P.E.N.)
Board of Directors. A.S.P.E.N. clinical guidelines: nutrition screening, assessment, and intervention
in adults. JPEN J Parenter Enter Nutr 2011;35:16–24.
8. Cohn SH, Vartsky D, Yasumura S, et al. Compartmental body composition based on total-body
nitrogen, potassium, and calcium. Am J Physiol 1980;239:E524–E530.
9. Frankenfield D, Cooney RN, Smith JS, et al. Age-related differences in the metabolic response to
injury. J Trauma 2000;48:49–56; discussion 56–57.
10. Lamb MJ, Byrne CD, Wilson JF, et al. Evaluation of bioelectrical impedance analysis for identifying
overweight individuals at increased cardiometabolic risk: a cross-sectional study. PloS One
2014;9:e106134.
11. Mathew S, Abraham G, Viayan M, et al. Body composition monitoring and nutrition in maintenance
hemodialysis and CAPD patients–a multicenter longitudinal study. Ren Fail 2015;37(1):66–72.
97
12. Reid CL, Campbell IT, Little RA. Muscle wasting and energy balance in critical illness. Clin Nutr
2004;23:273–280.
13. Kemen M, Senkal M, Homann HH, et al. Early postoperative enteral nutrition with arginine-omega-
3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: an
immunologic evaluation of impact. Crit Care Med 1995;23:652–659.
14. Tan CS, Read JA, Phan VH, et al. The relationship between nutritional status, inflammatory
markers and survival in patients with advanced cancer: a prospective cohort study. Support Care
Cancer 2015;23(2):385–391.
15. de Luis DA, Terroba MC, Cuellar L, et al. Association of anthropometric and biochemical markers
with length of stay and mortality in the hospital. Eur Rev Med Pharmacol Sci 2013;17:1321–1325.
16. Ignjatovic AM, Cvetkovic TP, Pavlovic RM, et al. Endothelial dysfunction, inflammation and
malnutrition markers as predictors of mortality in dialysis patients: multimarker approach. Int Urol
Nephrol 2013;45:1715–1724.
17. Kattelmann KK, Hise M, Russell M, et al. Preliminary evidence for a medical nutrition therapy
protocol: enteral feedings for critically ill patients. J Am Diet Assoc 2006;106:1226–1241.
18. Kreymann KG, Berger MM, Deutz NE, et al. ESPEN guidelines on enteral nutrition: intensive care.
Clin Nutr 2006;25:210–223.
19. Heyland DK, Dhaliwal R, Drover JW, et al.; Canadian Critical Care Clinical Practice Guidelines
Committee. Canadian clinical practice guidelines for nutrition support in mechanically ventilated,
critically ill adult patients. JPEN J Parenter Enteral Nutr 2003;27:355–373.
20. ASPEN Board of Directors and the Clinical Guidelines Task Force. Guidelines for the use of
parenteral and enteral nutrition in adult and pediatric patients. JPEN J Parenter Enteral Nutr
2002;26:1SA–138SA.
21. Latifi R. Nutritional therapy in critically ill and injured patients. Surg Clin North Am 2011;91:579–
593.
22. Racca V, Castiglioni P, Ripamonti V, et al. Nutrition markers in patients after heart surgery. JPEN J
Parenter Enteral Nutr 2010;34:143–150.
23. Goulet O. Assessment of nutritional status in clinical practice. Baillieres Clin Gastroenterol
1998;12:647–669.
24. Haluzík M, Kábrt J, Nedvídková J, et al. Relationship of serum leptin levels and selected nutritional
parameters in patients with protein-caloric malnutrition. Nutrition 1999;15:829–833.
25. Nova E, Lopez-Vidriero I, Varela P, et al. Indicators of nutritional status in restricting-type anorexia
nervosa patients: a 1-year follow-up study. Clin Nutr 2004;23:1353–1359.
26. Hooker C, Hall RC. Nutritional assessment of patients with anorexia and bulimia; clinical and
laboratory findings. Psychiatr Med 1989;7:27–36.
27. Friedman AN, Fadem SZ. Reassessment of albumin as a nutritional marker in kidney disease. J Am
Soc Nephrol 2010;21:223–230.
28. Brose L. Prealbumin as a marker of nutritional status. J Burn Care Rehabil 1990;11:372–375.
29. Parrish CR. Serum proteins as markers of nutrition: what are we treating? Nutr Issues Gastroenterol
2006;43:48–64.
30. Raguso CA, Dupertuis YM, Pichard C. The role of visceral proteins in the nutritional assessment of
intensive care unit patients. Curr Opin Clin Nutr Metab Care 2003;6:211–216.
31. Frankenfield DC, Smith JS, Cooney RN. Accelerated nitrogen loss after traumatic injury is not
attenuated by achievement of energy balance. JPEN J Parenter Enteral Nutr 1997;21:324–329.
32. Compher C, Frankenfield D, Keim N, et al.; Evidence Analysis Working Group. Best practice
methods to apply to measurement of resting metabolic rate in adults: a systematic review. J Am
Diet Assoc 2006;106:881–903.
33. Roza AM, Shizgal HM. The Harris Benedict equation reevaluated: resting energy requirements and
the body cell mass. Am J Clin Nutr 1984;40:168–182.
34. Mifflin MD, St Jeor ST, Hill LA, et al. A new predictive equation for resting energy expenditure in
healthy individuals. Am J Clin Nutr 1990;51:241–247.
35. Frankenfield DC, Smith JS Jr, Cooney RN, et al. Relative association of fever and injury with
hypermetabolism in critically ill patients. Injury 1997;28:617–621.
98
36. Bessey PQ, Watters JM, Aoki TT, et al. Combined hormonal infusion simulates the metabolic
response to injury. Ann Surg 1984;200:264–281.
37. Anker SD, Coats AJ. Cardiac cachexia: a syndrome with impaired survival and immune and
neuroendocrine activation. Chest 1999;115:836–847.
38. Gentile LF, Cuenca AG, Efron PA, et al. Persistent inflammation and immunosuppression: a
common syndrome and new horizon for surgical intensive care. J Trauma Acute Care Surg
2012;72:1491–1501.
39. Vanzant EL, Lopez CM, Ozrazgat-Baslanti T, et al. Persistent inflammation, immunosuppression,
and catabolism syndrome after severe blunt trauma. J Trauma Acute Care Surg 2014;76:21–29;
discussion 9–30.
40. Ruiz Garcia V, López-Briz E, Carbonell Sanchis R, et al. Megestrol acetate for treatment of anorexia-
cachexia syndrome. Cochrane Database Syst Rev 2013;3:CD004310.
41. Barber MD, Ross JA, Voss AC, et al. The effect of an oral nutritional supplement enriched with fish
oil on weight-loss in patients with pancreatic cancer. Br J Cancer 1999;81:80–86.
42. Gogos CA, Ginopoulos P, Salsa B, et al. Dietary omega-3 polyunsaturated fatty acids plus vitamin E
restore immunodeficiency and prolong survival for severely ill patients with generalized
malignancy: a randomized control trial. Cancer 1998;82:395–402.
43. Neville AL, Brown CV, Weng J, et al. Obesity is an independent risk factor of mortality in severely
injured blunt trauma patients. Arch Surg 2004;139:983–987.
44. Enomoto TM, Larson D, Martindale RG. Patients requiring perioperative nutritional support. Med
Clin North Am 2013;97:1181–1200.
45. Smedley F, Bowling T, James M, et al. Randomized clinical trial of the effects of preoperative and
postoperative oral nutritional supplements on clinical course and cost of care. Br J Surg
2004;91:983–990.
46. Wolfe RR. Perspective: optimal protein intake in the elderly. J Am Med Dir Assoc 2013;14:65–66.
47. Alberda C, Gramlich L, Jones N, et al. The relationship between nutritional intake and clinical
outcomes in critically ill patients: results of an international multicenter observational study.
Intensive Care Med 2009;35:1728–1737.
48. Martindale RG, McClave SA, Vanek VW, et al. Guidelines for the provision and assessment of
nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine and
American Society for Parenteral and Enteral Nutrition: Executive Summary. Crit Care Med
2009;37:1757–1761.
49. Singer P, Berger MM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: intensive
care. Clin Nutr 2009;28:387–400.
50. Casaer MP, Van den Berghe G. Nutrition in the acute phase of critical illness. N Eng J Med
2014;370:1227–1236.
51. Artinian V, Krayem H, DiGiovine B. Effects of early enteral feeding on the outcome of critically ill
mechanically ventilated medical patients. Chest 2006;129:960–967.
52. Meyfroidt G, Ingels C, Van den Berghe G. Glycemic control in the ICU. N Eng J Med 2011;364:1280;
author reply 1281.
53. Singer P, Anbar R, Cohen J, et al. The tight calorie control study (TICACOS): a prospective,
randomized, controlled pilot study of nutritional support in critically ill patients. Intensive Care Med
2011;37:601–609.
54. Frankenfield DC, Ashcraft CM. Estimating energy needs in nutrition support patients. JPEN J
Parenter Enteral Nutr 2011;35:563–570.
55. Martin CM, Doig GS, Heyland DK, et al.; Southwestern Ontario Critical Care Research Network.
Multicentre, cluster-randomized clinical trial of algorithms for critical-care enteral and parenteral
therapy (ACCEPT). CMAJ 2004;170:197–204.
56. Doig GS, Simpson F, Finfer S, et al. Effect of evidence-based feeding guidelines on mortality of
critically ill adults: a cluster randomized controlled trial. JAMA 2008;300:2731–2741.
57. Rice TW, Wheeler AP, Thompson BT, et al.; National Heart Lung and Blood Institute Acute
Respiratory Distress Syndrome Clinical Trials Network. Initial trophic vs full enteral feeding in
patients with acute lung injury: the EDEN randomized trial. JAMA 2012;307:795–803.
58. Montejo JC, Minambres E, Bordeje L, et al. Gastric residual volume during enteral nutrition in ICU
99
patients: the REGANE study. Int Care Med 2010;36:1386–1393.
59. Davies AR, Morrison SS, Bailey MJ, et al. A multicenter, randomized controlled trial comparing
early nasojejunal with nasogastric nutrition in critical illness. Crit Care Med 2012;40:2342–2348.
60. Acosta-Escribano J, Fernandez-Vivas M, Grau Carmona T, et al. Gastric versus transpyloric feeding
in severe traumatic brain injury: a prospective, randomized trial. Intensive Care Med 2010;36:1532–
1539.
61. Nguyen NQ, Chapman MJ, Fraser RJ, et al. Erythromycin is more effective than metoclopramide in
the treatment of feed intolerance in critical illness. Crit Care Med 2007;35:483–489.
62. MacLaren R, Kiser TH, Fish DN, et al. Erythromycin vs metoclopramide for facilitating gastric
emptying and tolerance to intragastric nutrition in critically ill patients. JPEN J Parenter Enteral Nutr
2008;32:412–419.
63. Pontes-Arruda A, Aragao AM, Albuquerque JD. Effects of enteral feeding with eicosapentaenoic
acid, gamma-linolenic acid, and antioxidants in mechanically ventilated patients with severe sepsis
and septic shock. Crit Care Med 2006;34:2325–2333.
64. Peter JV, Moran JL, Phillips-Hughes J. A metaanalysis of treatment outcomes of early enteral
versus early parenteral nutrition in hospitalized patients. Crit Care Med 2005;33:213–220; discussion
60–61.
65. van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N
Eng J Med 2001;345:1359–1367.
66. Dissanaike S, Shelton M, Warner K, et al. The risk for bloodstream infections is associated with
increased parenteral caloric intake in patients receiving parenteral nutrition. Crit Care
2007;11:R114.
67. Grau T, Bonet A, Rubio M, et al. Liver dysfunction associated with artificial nutrition in critically ill
patients. Crit Care 2007;11:R10.
68. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill
adults. N Eng J Med 2011;365:506–517.
69. Hermans G, Casaer MP, Clerckx B, et al. Effect of tolerating macronutrient deficit on the
development of intensive-care unit acquired weakness: a subanalysis of the EPaNIC trial. Lancet
Respir Med 2013;1:621–629.
70. Vanderheyden S, Casaer MP, Kesteloot K, et al. Early versus late parenteral nutrition in ICU
patients: cost analysis of the EPaNIC trial. Crit Care 2012;16:R96.
71. Casaer MP, Wilmer A, Hermans G, et al. Role of disease and macronutrient dose in the randomized
controlled EPaNIC trial: a post hoc analysis. Am J Respir Crit Care Med 2013;187:247–255.
72. Heidegger CP, Berger MM, Graf S, et al. Optimisation of energy provision with supplemental
parenteral nutrition in critically ill patients: a randomised controlled clinical trial. Lancet
2013;381:385–393.
73. Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with
short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA
2013;309:2130–2138.
74. Braunschweig CL, Levy P, Sheean PM, et al. Enteral compared with parenteral nutrition: a meta-
analysis. Am J Clin Nutr 2001;74:534–542.
75. Battistella FD, Widergren JT, Anderson JT, et al. A prospective, randomized trial of intravenous fat
emulsion administration in trauma victims requiring total parenteral nutrition. J Trauma
1997;43:52–58; discussion 58–60.
76. Stapleton RD, Martin JM, Mayer K. Fish oil in critical illness: mechanisms and clinical applications.
Crit Care Clin 2010;26:501–514, ix.
77. Mehanna HM, Moledina J, Travis J. Refeeding syndrome: what it is, and how to prevent and treat
it. BMJ 2008;336:1495–1498.
78. Bagga D, Wang L, Farias-Eisner R, et al. Differential effects of prostaglandin derived from omega-6
and omega-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion. Proc Natl Acad Sci
U S A 2003;100:1751–1756.
79. Fong YM, Marano MA, Barber A, et al. Total parenteral nutrition and bowel rest modify the
metabolic response to endotoxin in humans. Ann Surg 1989;210:449–456; discussion 56–57.
80. Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically
100
ill adults. N Eng J Med 2014;371(18):1673–1684.
81. Kiyama T, Onda M, Tokunaga A, et al. Effect of early postoperative feeding on the healing of
colonic anastomoses in the presence of intra-abdominal sepsis in rats. Dis Colon Rectum
2000;43:S54–S58.
82. Chin KF, Townsend S, Wong W, et al. A prospective cohort study of feeding needle catheter
jejunostomy in an upper gastrointestinal surgical unit. Clin Nutr 2004;23:691–696.
83. Taylor SJ, Fettes SB, Jewkes C, et al. Prospective, randomized, controlled trial to determine the
effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients
suffering head injury. Crit Care Med 1999;27:2525–2531.
84. Cook D, Arabi Y. The route of early nutrition in critical illness. N Eng J Med 2014;371(18):1748–
1749.
85. McClave SA, Heyland DK. The physiologic response and associated clinical benefits from provision
of early enteral nutrition. Nutr Clin Pract 2009;24:305–315.
86. Flordelis Lasierra JL, Perez-Vela JL, Montejo Gonzalez JC. Enteral nutrition in the
hemodynamically unstable critically ill patient. Med Intensiva 2014;39(1):40–48.
87. Guillaume A, Seres DS. Safety of enteral feeding in patients with open abdomen, upper
gastrointestinal bleed, and perforation peritonitis. Nutr Clin Pract 2012;27:513–520.
88. Patel JJ, Kozeniecki M, Biesboer A, et al. Early trophic enteral nutrition is associated with
improved outcomes in mechanically ventilated patients with septic shock: a retrospective review. J
Intensive Care Med 2014. (PMID 25315218).
89. Seder CW, Janczyk R. The routine bridling of nasojejunal tubes is a safe and effective method of
reducing dislodgement in the intensive care unit. Nutr Clin Pract 2008;23:651–654.
90. Scheinkestel CD, Kar L, Marshall K, et al. Prospective randomized trial to assess caloric and protein
needs of critically ill, anuric, ventilated patients requiring continuous renal replacement therapy.
Nutrition 2003;19:909–916.
91. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic
review of the evidence. Crit Care Med 2002;30:2022–2029.
92. Andrews PJ, Avenell A, Noble DW, et al. Randomised trial of glutamine, selenium, or both, to
supplement parenteral nutrition for critically ill patients. BMJ 2011;342:d1542.
93. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in
critically ill patients. N Eng J Med 2013;368:1489–1497.
94. Wernerman J, Kirketeig T, Andersson B, et al. Scandinavian glutamine trial: a pragmatic multi-
centre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand 2011;55:812–
818.
95. Bollhalder L, Pfeil AM, Tomonaga Y, et al. A systematic literature review and meta-analysis of
randomized clinical trials of parenteral glutamine supplementation. Clin Nutr 2013;32:213–223.
96. Marik PE, Zaloga GP. Immunonutrition in critically ill patients: a systematic review and analysis of
the literature. Intensive Care Med 2008;34:1980–1990.
97. Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr
2007;85:1171–1184.
98. Ferrie S. Re: The use of an inflammation-modulating diet in patients with acute lung injury or acute
respiratory distress syndrome: a meta-analysis of outcome data. JPEN J Parenter Enteral Nutr
2010;34:452; author reply 453–454.
99. Pontes-Arruda A, Martins LF, de Lima SM, et al. Enteral nutrition with eicosapentaenoic acid,
gamma-linolenic acid and antioxidants in the early treatment of sepsis: results from a multicenter,
prospective, randomized, double-blinded, controlled study: the INTERSEPT study. Crit Care
2011;15:R144.
100. Umpierrez GE, Spiegelman R, Zhao V, et al. A double-blind, randomized clinical trial comparing
soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit
patients requiring parenteral nutrition. Crit Care Med 2012;40:1792–1798.
101. Manzanares W, Dhaliwal R, Jurewitsch B, et al. Parenteral fish oil lipid emulsions in the critically
ill: a systematic review and meta-analysis. JPEN J Parenter Enteral Nutr 2014;38:20–28.
102. Manzanares W, Dhaliwal R, Jiang X, et al. Antioxidant micronutrients in the critically ill: a
systematic review and meta-analysis. Crit Care 2012;16:R66.
101
103. Alhazzani W, Jacobi J, Sindi A, et al. The effect of selenium therapy on mortality in patients with
sepsis syndrome: a systematic review and meta-analysis of randomized controlled trials. Crit Care
Med 2013;41:1555–1564.
104. Abel RM, Beck CH Jr, Abbott WM, et al. Improved survival from acute renal failure after treatment
with intravenous essential L-amino acids and glucose. Results of a prospective, double-blind study.
N Eng J Med 1973;288:695–699.
105. Bal BS, Finelli FC, Shope TR, et al. Nutritional deficiencies after bariatric surgery. Nat Rev
Endocrinol 2012;8:544–556.
106. Gletsu-Miller N, Wright BN. Mineral malnutrition following bariatric surgery. Adv Nutr 2013;4:506–
517.
107. Isom KA, Andromalos L, Ariagno M, et al. Nutrition and metabolic support recommendations for
the bariatric patient. Nutr Clin Pract 2014;29(6):718–739.
108. Kaafarani HM, Shikora SA. Nutritional support of the obese and critically ill obese patient. Surg Clin
North Am 2011;91:837–855, viii–ix.
109. Morley JE. Anorexia of aging: a true geriatric syndrome. J Nutr Health Aging 2012;16:422–425.
110. Morley JE. Pathophysiology of the anorexia of aging. Curr Opin Clin Nutr Metab Care 2013;16:27–
32.
111. Wilmore DW. The effect of glutamine supplementation in patients following elective surgery and
accidental injury. J Nutr 2001;131:2543S–2549S; discussion 2550S–2551S.
112. Alexander JW, MacMillan BG, Stinnett JD, et al. Beneficial effects of aggressive protein feeding in
severely burned children. Ann Surg 1980;192:505–517.
102
Chapter 4
Obesity and Metabolic Disease

Robert W. O’Rourke and Michael W. Mulholland
Key Points
1 Obesity is a polygenic phenomenon, and up to 70% of the propensity to a specific body habitus is
due to genetic influences.
2 Epigenetics and environment interact with genetics to produce the obesity phenotype.
3 The hypothalamic feeding center is a dominant central site of control of energy homeostasis and
receives multiple afferent inputs and delivers diverse efferent outputs to all organ systems.
4 Control of food intake via satiety and hunger is a dominant mechanism of regulation of body weight,
but other processes contribute, including but not limited to metabolic rate, adipocyte physiology,
and the microbiome; alterations in the set-points and regulation of these processes have been linked
to the development of obesity.
5 Nutrient excess is a key early trigger in the development of cell stress that underlies the
pathogenesis of metabolic disease.
6 Adipose tissue acts as a critical nutrient “buffer” to protect other tissues from nutrient excess; as
adipose buffering capacity is overwhelmed, nutrient excess overflows to all tissues, inducing
metabolic disease.
7 Hepatic steatosis and peripheral and central insulin resistance are dominant features of metabolic
disease, but metabolic disease encompasses all organ systems with pleiotropic pathology.
GENETICS OF OBESITY
Metabolic thrift: Obesity is encoded within the human genome. The thrifty gene hypothesis, proposed by
geneticist James Neel, posits that humans are predisposed to a thrifty metabolism by genes selected over
eons of evolution in environments characterized by food scarcity.1 These genes were adaptive in our
ancient past but in our modern environment lead to a blossoming of obesity. In the past 50 years, the
very genes which drive us to seek out calorie-dense food have led us to create, for the first time in
human history, an obesogenic environment in which food is plentiful. While competing theories exist,
such as predation release and genetic drift, Neel’s thrifty gene hypothesis remains the basis of a modern
understanding of obesity as a genetic phenomenon.
Metabolic thrift is a feature of all life, which exists in a perpetual struggle for energy resources.
Strategies of metabolic thrift include high caloric intake, body temperature regulation, torpor, and
hibernation. Humans practice thrift by storing energy in the form of adipose tissue. Lipid is not only
energy dense, but also water insoluble, and thus can be stored in large quantities in cells without
disrupting osmotic gradients. Because of these unique characteristics, virtually all life-forms use lipid as
an energy storage molecule. Lipid droplets are found in yeast, Drosophila stores lipid in a specialized
“fat body,” and migratory geese store lipid in hepatocytes. Humans, along with many other vertebrates,
store large amounts of lipid in adipose tissue, which can provide energy for months; monitored fasts of
over a year have been documented in obese humans.2 Adipose tissue accumulation is not the only
mechanism of human metabolic thrift. Insulin resistance is thought to have evolved in humans to
protect against hypoglycemia during periods of fasting and famine. The carnivore hypothesis posits that
insulin resistance appeared in primates with the onset of the ice age when food became scarce and
primates shifted away from a carbohydrate-rich diet toward a protein-rich diet, an evolutionary heritage
that explains the link between obesity and diabetes.
1 Modern genetics and human obesity: Compelling data support the contention that obesity is rooted in
genetics. Quantitative analysis of twin studies, in which phenotypic traits of thousands of twin pairs are
analyzed using statistical methods based on Mendelian principles, is a well-accepted method for
103
quantifying the contribution of genetics to a given phenotype or disease. Multiple twin studies have
consistently demonstrated that approximately 70% of the tendency toward obesity is due to genetics,
with the remainder presumably due to environmental influences.3 Genome-wide association studies extend
these data and permit study of human genetics at the nucleotide level. These studies involve sequencing
the genomes of thousands of patients and correlating single-nucleotide polymorphisms (SNPs) with
phenotypic traits and disease states. Association studies have begun to identify the thrifty genes that
Neel postulated decades earlier. Many SNPs that correlate with obesity lie within genes that are directly
associated with body weight regulation. Others lie in genes that are not as clearly related to energy
balance, including genes that regulate neural and limb development, DNA repair, and many other
cellular functions, testament to the fact that the processes that regulate energy homeostasis overlap
with all aspects of physiology. As SNP data emerge, it has become clear that the effect size of each
individual SNP’s contribution to the obesity phenotype is small, on the order of <1% to 3%, and that
potentially hundreds of SNPs contribute to obesity. Obesity, like many chronic diseases, is a complex
polygenic phenomenon. Genetic studies have so far identified over 50 SNPs that correlate with human
obesity, and the list continues to grow.4
2 Epigenetic mechanisms contribute to obesity. The thrifty phenotype hypothesis was proposed by Hales
and Barker in 1992 to explain the observation that infants born to malnourished mothers are at
increased risk of adult obesity and metabolic disease compared to offspring born of the same mothers
during well-nourished pregnancies.5 The fetus was presumed to be responding to instability in
environmental food resources by adjusting its phenotype toward a thrifty metabolism, a phenomenon
termed fetal programming. A similar response was subsequently observed in fetuses born of obese and
diabetic mothers.6 Excess or scarcity of nutrients may be interpreted similarly by the fetus as signs of
unstable food resources, which may explain the similar effect of maternal under- and overnutrition on
offspring metabolic phenotype. Subsequent research has demonstrated that these effects are mediated
by epigenetic mechanisms which involve covalent modification of DNA independent of changes in
Watson–Crick base-pair sequence, including DNA methylation and glycosylation and histone
modification. These changes may persist for one or more generations. Research over the past two
decades has revealed that epigenetic modification of the genome is widespread, occurs primarily during
fetal development but may extend into adulthood, and regulates normal developmental and homeostatic
processes as well as pathologic responses. Epigenetics allows the fetus to respond in utero to
environmental cues delivered by changes in maternal homeostasis, the so-called “weather forecast”
model.7 Epigenetic modifications in response to fetal under- and overnutrition have been demonstrated
in animals and humans, play an important role in disease pathogenesis, and speak to the fact that
intervention must occur early, prior to birth, to prevent adult obesity and metabolic disease. The
metabolic dice are cast in utero.
Human metabolic diversity and the role of environment: The multiple thrifty SNPs in the human genome
impart marked genetic heterogeneity that underlies the intrinsic variability of the human body habitus,
with a wide range of body types from lean to obese. This heterogeneity extends to all aspect of
metabolism, with individual differences in satiety and hunger thresholds, metabolic rates, metabolic
handling of lipid and glucose, variability in adipocyte proliferation and hypertrophy capacities, and
differing propensities to insulin resistance and hyperlipidemia. This heterogeneity explains the diversity
of the obesity phenotype with its different sites of accumulation, including visceral and subcutaneous,
and its variable ages of onset, triggers, severity, and responses to diet- and surgery-induced weight loss.
The human species is highly metabolically diverse, a trait that had been critical to our success, allowing
us to adapt to a wide range of habitats as we colonized the globe. Multiple examples exist of human
subpopulations whose genetic heritages are adaptive in their native environments, but maladaptive in a
modern obesogenic environment. Polynesians provide an example of a human subpopulation with a
marked genetic propensity to obesity and insulin resistance, traits that provided a selective advantage in
the ancient South Pacific environment, which was characterized by labile food supplies and transoceanic
voyages that entailed a high risk of starvation. This genetic heritage, in our modern environment, places
Polynesians at exceptionally high risk for obesity and metabolic disease. Similar human subpopulations
metabolically adapted to specific niche environments but at high risk for metabolic disease in
industrialized society include Inuit Eskimos, Aboriginal Australians, and Pima Indians (Fig. 4-1).
Environment plays a critical role in the pathogenesis of obesity. Dominant modern environmental
contributors are an excess of processed food and a structured built environment that discourages physical
activity. Modern processed food is not only calorie dense but also highly palatable, and stimulates
central nervous system (CNS) reward centers and hunger/satiety circuits not designed for chronic
104
stimulation, thus reinforcing overeating. Physical activity is markedly decreased in our modern
environment relative to our distant past. Paleolithic humans were estimated to have consumed 30%
more calories than modern humans but engaged in significantly higher levels of physical activity.8
Other factors also contribute to a lesser extent, including disruption in Circadian rhythms, stability in
home temperatures, and assortative mating patterns. An evolving field of environmental engineering
has arisen to address these issues.
Figure 4-1. Interactions between environment and genetics dictate phenotype. A: Environment alters genetics over millennia,
while the effects of environment on epigenetics take place over generations. In the case of humans, genetics dictates our behavior
which in turn has led us to create an obesogenic environment, creating a vicious cycle that exacerbates the obesity epidemic. B:
The obesity phenotype blossoms in a modern obesogenic environment, with the population body mass index (BMI) curve
broadening and shifting rightward, with an increase in median BMI. The increase in median BMI is relatively modest, but a
substantially larger percentage of people populate overweight and obese BMI ranges. Of note, the schematic graphs shown are
similar to those that describe the shift in US population BMI National Health and Nutrition Examination Survey data from the late
1970s to the early 2000s.
PHYSIOLOGY OF OBESITY
3 The adipostat: A dominant determinant of systemic metabolic homeostasis is the quantity of existent
adipose tissue stores, the adequacy of which is determined by the hypothalamic feeding center (HFC).
The HFC receives multiple afferent neural and hormonal inputs from all organ systems, including
adipose tissue, and orchestrates a range of responses via efferent outputs that regulate all aspects of
metabolism. These multiple HFC-regulated systems monitor and maintain adipose tissue stores, and
together comprise the adipostat, the sum total of all processes that defend body weight. The amount of
adipose tissue deemed adequate by the HFC varies among individuals and is dictated by multiple poorly
understood thrifty genes. Collectively, these genes and the proteins they regulate define the adipostat
set-point, which determines the degree of metabolic thrift of an individual. The hypothalamus of a lean
person “considers” a lower amount of adipose tissue to be adequate, while the hypothalamus of an
obese person requires higher levels of baseline adipose tissue stores. Weight loss alerts the HFC to
deviation from the adipostat set-point and triggers robust compensatory metabolic responses that act to
restore adipose tissue mass to baseline levels, including but not limited to increased hunger, decreased
satiety, and decreased metabolic rate. The HFC resides deep in the midbrain, far removed from the
frontal cortex, the seat of conscious thought and what we refer to as “willpower.” HFC-mediated
metabolic responses are characterized by tight regulation; deviation outside the range of these responses
for more than limited periods of time is not possible based on conscious choice, explaining the near-
universal failure of conscious dietary efforts to lose weight. Obese patients are able to control their
weight only to a point, and only for brief periods, after which compensatory responses are activated.
These mechanisms also explain the lack of efficacy of liposuction as a tool for weight loss. Regardless of
the method, whether diet-induced or liposuction, reduction in adipose tissue mass activates
compensatory mechanisms that act to restore adipose tissue mass to set-point levels. Bariatric surgery-
105
induced weight loss is the only exception to this rule, inducing poorly understood paradoxical responses
that bypass the adipostat, including decreased satiety and increased metabolic rate.
Multiple physiologic mechanisms comprise the adipostat and regulate body weight. Most important in
humans are the collective satiety and hunger systems that regulate food intake. Less powerful but
nonetheless important are mechanisms that control metabolic rate, adipocyte physiology, and the
microbiome.
4 Satiety and hunger: Regulation of food intake is the dominant mechanism by which humans control
body weight. This is not true for all species. While food intake is an important mechanism of energy
homeostasis in mice, regulation of metabolic rate plays a greater role in mice than in humans. Food
intake in humans is controlled by a family of proteins that regulate satiety and hunger primarily by
acting on receptors within the hypothalamus. These diverse proteins are secreted by multiple organ
systems, including but not limited to adipose tissue, the gut, the liver, and the skeletal muscle.
The Ob mouse, a genetic mutant strain described in 1950, manifests an obese phenotype, along with a
range of other abnormalities related to immune, endocrine, and reproductive functions. The Ob mouse
harbors an inactivating point mutation in the leptin gene (Gr. leptos, thin). Leptin is a 16-kD satiety
hormone secreted by adipose tissue in response to a meal that in turn acts on receptors within the HFC
to induce satiety. Leptin establishes communication between adipose tissue, the gut, and the brain that
signals the status of adipose tissue stores to the brain, which in turn dictates food intake. As such, leptin
represents a paradigmatic mediator of the adipostat, and an example of the complex interorgan
communication that underlies its function (Fig. 4-2). Soon after the cloning of the leptin gene in 1994,9
rare humans with leptin mutations were identified with an Ob phenotype that was reversed with
administration of exogenous recombinant leptin. Unfortunately, similar therapy was ineffective in
common human obesity, which is not due to a single-leptin mutation, but rather is polygenic and
characterized by hypothalamic resistance to leptin satiety effects. Nonetheless, the discovery of leptin
led to an explosion of satiety and hunger research, and over the ensuing decade multiple satiety and
hunger proteins were described.
Figure 4-2. Leptin mediates communication between adipose tissue, gut, and brain. A: Signals from the gastrointestinal tract
106
triggered by a meal circulate to adipose tissue and induce adipocyte leptin secretion. Leptin circulates to the hypothalamus, where
it binds receptors in the arcuate nucleus to induce satiety, leading to decreased food intake. Leptin is one of many signals that
mediates bidirectional communication between gut, adipose tissue, and brain. Other organ systems are also involved, including
immune and reproductive systems and the liver. B: Leptin regulates allostatic control of short-term and long-term food intake.
Postprandial leptin secretion induces satiety for a period of hours, after which leptin levels and satiety wane, prompting food
intake. Similarly, leptin, along with other mediators of food intake, controls long-term weight regulation: diet-induced weight loss
leads to decreased adipose tissue mass, reducing peak postprandial leptin levels, leading to decreased postprandial satiety and
increased food intake at each subsequent meal until adipose tissue mass is restored to set-point levels. In this manner, leptin
functions as a component of the adipostat. This allostatic control provides an explanation for rebound weight gain after diet-
induced weight loss.
The control of feeding behavior and nutrient intake is a highly regulated process centered in the
hypothalamus, which integrates information regarding nutritional status, environment, and energy
expenditure via central and peripheral orexigenic and anorexigenic signals. Peripheral messengers
include signals from adipose tissue (adipokines), including leptin and adiponectin, cytokines, such as TNF-
α and interleukin (IL-6), and gut peptides. Among this diverse latter class of mediators, ghrelin is a
dominant stimulant of feeding. Ghrelin is expressed primarily by oxyntic glands in the fundus of the
stomach. Gastric ghrelin–producing cells represent about one-fourth of endocrine cells within the gastric
mucosa. Ghrelin is also produced in the hypothalamus.
Encoded by five exons, preproghrelin undergoes endoproteolytic processing and posttranslational
modification to yield des-acyl ghrelin and acyl ghrelin. Both hormones share the same amino acid
sequence, and both are detectable in blood, but acyl ghrelin, which undergoes acylation of the Ser3
residue, is the active form. Acyl ghrelin regulates feeding, metabolic activity, and insulin secretion. The
enzyme-mediating acylation is the membrane-bound ghrelin O-acyltransferase (GOAT). Genetic
disruption of the GOAT gene in mice leads to complete absence of acyl ghrelin. GOAT inhibition
improves glucose tolerance and reduces weight gain in mice. Plasma acyl-ghrelin levels increase with
fasting and decrease after feeding, a pattern indicating that ghrelin is involved in meal initiation. The
ghrelin receptor is a member of the family of G protein–coupled receptors and contains seven
transmembrane domains. Ghrelin receptors are widely distributed among both central and peripheral
tissues, including the pituitary gland, hypothalamus, pancreas, stomach, and intestine. Ghrelin causes
growth hormone secretion following peripheral or central administration, and release of growth
hormone from cultured pituitary cells.
Ghrelin is the only orexigenic hormone identified to date. The relative scarcity of orexigenic proteins
relative to anorexigenic proteins underscores an important fundamental characteristic of the global
regulation of food intake, which is biased toward chronic basal hunger regulated by multiple satiety
factors (rather than chronic basal satiety regulated by multiple hunger factors). This central feature of
food intake control systems predisposes to excess food intake and thus provides a selective advantage in
environments of food scarcity during our evolution, but leads to obesity in our modern environment. In
humans, the intravenous administration of ghrelin at physiologic concentrations induces the sensation of
hunger and stimulates oral intake. Circulating ghrelin levels peak just prior to meal initiation and
decline rapidly postprandially. Ghrelin secretion is increased by weight loss and by restriction of caloric
intake. Serum ghrelin levels are increased in anorexic individuals and depressed in obese subjects. In
animals, ghrelin administration has been found to stimulate food intake, to induce growth of adipose
tissues, and to increase body weight. The administration of ghrelin antibody or ghrelin receptor
antagonists blunts ghrelin-induced weight gain and positive energy balance. Similar molecules are under
active study as potential therapeutic agents.
Ghrelin is a circulating hormone with CNS effects. The arcuate nucleus of the hypothalamus is a
crucial site for the integration of fasting and feeding signals. Two types of neurons, with opposing
actions on feeding behavior, have been identified in the arcuate nucleus. Neurons that express
proopiomelanocortin and cocaine- and amphetamine-regulated transcript (CART) suppress food intake,
reduce body weight, and increase energy expenditure. In contrast, neurons producing neuropeptide Y
and agouti gene–related transcript (AgRP) are orexigenic. These cells act to stimulate food intake and
reduce energy expenditure. Ghrelin, as well as leptin and multiple other gut peptides, adipokines, and
cytokines, directly mediate the activities of these two types of neurons (Fig. 4-3). Direct peripheral
effects of ghrelin on peripheral tissues also contribute to the regulation of body weight and energy
homeostasis.
Leptin and ghrelin are paradigmatic adipokine and gut peptide mediators of food intake respectively,
107
but multiple other proteins contribute. Adipokines that regulate satiety include adiponectin, visfatin,
apelin, and lipocalin; gut peptides include glucose-dependent insulinotropic peptide (GIP), glucagon-like
peptide-1 (GLP-1), nesfatin-1, oxyntomodulin, pancreatic polypeptide, cholecystokinin, amylin,
glucagon, somatostatin, cholecystokinin, and insulin. Finally, cytokines, including TNF-α and IL-6, in
addition to immunoregulatory functions, also play important roles in the control of food intake. TNF-α,
for example, mediates anorexigenic responses in the context of cachexia and inflammatory states.
Virtually all adipokines, gut hormones, and cytokines have multiple overlapping functions that include
regulation of satiety and hunger, immune function, glucose homeostasis, lipid metabolism, and
endocrine and reproductive function (Fig. 4-4). This functional diversity speaks to the intimate
association of energy homeostasis with all aspects of physiology.
Genetic polymorphisms in the melanocortin 4 receptor gene, which regulates satiety and hunger
responses and the HFC set-point, are implicated in 5% of cases of human obesity. Similar
polymorphisms associated with obesity exist with the genes encoding leptin and its receptor, ghrelin,
neuropeptide Y, adiponectin, GLP-1, and other genes associated with the control of satiety and hunger.
These observations demonstrate that variability in the genes that regulate food intake, with
corresponding variability in the functional control of satiety and hunger, contribute to the development
of human obesity.
Metabolic rate: While less important than control of food intake, variability in metabolic rate
contributes to the pathogenesis of obesity. In obese subjects who lose weight with diet, total energy
expenditure is decreased up to 20% beyond that expected by loss of fat and fat-free mass alone, and is
accompanied by a corresponding decrease in voluntary physical activity.10 In contrast to diet-induced
weight loss, bariatric surgery-induced weight loss paradoxically induces increased energy expenditure,
which may explain the efficacy of surgery. In the absence of surgery however, compensatory decreases
in energy expenditure counteract caloric restriction and contribute to adipostat responses that resist
declines in adipose tissue mass. Studies of overfeeding and weight gain in obese subjects demonstrate
converse changes with a compensatory increase in total energy expenditure. Importantly, overfeeding
studies in twin cohorts demonstrate a significant genetic component to variability in energy expenditure
responses to overfeeding, suggesting that variability in metabolic rate responses to weight loss
contributes to the development of obesity in those at risk.3
Differences in sympathetic nervous system activity are observed in humans and represent a potential
mechanism underlying variability in metabolic rate. Obese humans demonstrate decreased sympathetic
nervous system activity compared to lean humans, and higher levels of sympathetic nervous system
activity predict successful diet-induced weight loss. Differences in endocrine responses also contribute,
with obese humans manifesting differences in thyroid hormone and catecholamine balance associated
with decreased metabolic rates. At the cellular level, differences in energy utilization and thermogenesis
play an important role. Skeletal muscle energy utilization efficiency is increased in humans who achieve
successful weight loss and decreased in those who gain weight. Furthermore, decreased levels of
skeletal muscle nonexercise-induced thermogenesis and diet-induced thermogenesis have been
demonstrated in obese humans.11 These observations suggest that fundamental differences in cellular
energy homeostasis contribute to obesity. The mechanisms underlying these variable cellular responses
are not fully defined, but differences in uncoupling protein (UCP) function are implicated. UCPs
uncouple oxidative phosphorylation from electron transport in mitochondria, creating a proton leak that
generates heat rather than ATP. The role of UCPs in the pathogenesis of obesity is an important area of
active research. UCP function is highly variable and genetically determined in mice, and polymorphisms
in UCP genes correlate with obesity and metabolic disease in humans, supporting a role for genetic
variability in UCP function in obesity pathogenesis. Transgenic mice overexpressing UCP-1 under
control of the adipose tissue-specific AP2 promoter are resistant to obesity, suggesting the potential
therapy for obesity based on manipulation of cellular thermogenesis and metabolic rate.
108
Figure 4-3. A simplified schematic of the hypothalamic feeding center and its primary afferent signals. A. Multiple hormones
secreted by the gastrointestinal tract and adipose tissue act as afferent signals that impact on the arcuate nucleus (ArcN) within the
hypothalamic feeding center to regulate feeding behavior. B. Peripheral afferent signals impact on first-order ArcN neurons, which
in turn communicate with second-order paraventricular nucleus (PVN) and lateral hypothalamic area (LHA) neurons to coordinate
behavioral and metabolic output. PVN signaling is primarily anorexigenic and catabolic, and is enhanced by leptin and insulin,
while LHA signaling is primarily orexigenic and anabolic and inhibited by leptin and insulin. Higher-order anorexigenic PVN
outputs include corticotropin-releasing hormone (CRH), oxytocin, and thyrotropin-releasing hormone (TRH); higher-order
orexigenic LHA outputs include melanin-concentrating hormone (MCH) and orexins A and B. Both pathways negatively regulate
the other. Other peripheral and central mediators stimulate first- and second-order neurons as well, including ghrelin, CCK, GLP-1,
serotonin, endogenous cannabinoids, and norepinephrine.
Adipocyte physiology: Adipocytes arise from mesenchyme-derived adipocyte stem cells within adipose
tissue. Nomenclature is evolving and includes the terms preadipocyte or adipocyte/adipose tissue stem cell.
Adipocyte stem cells are pluripotent, and depending on the stage of differentiation, may give rise to
adipocytes, fibroblast, myocytes, and other cell types. Multiple adipocyte stem cell subpopulations give
rise to adipocytes of variable phenotypes, including white, brown, and beige. Evidence suggests that
hematopoietic precursor cells may also give rise to adipocytes.
Until recently it was thought that adipocyte stem cell proliferation, that is, hyperplasia, did not occur
in postnatal humans, and that adipocyte hypertrophy was the primary mechanism of increased adipose
tissue mass in obesity. Recent data suggest that both hyperplasia and hypertrophy contribute to
evolving obesity, with hyperplasia predominating during childhood and hypertrophy predominating
during adulthood. These data derive in part from ingenious methods studying incorporation of C14 into
adipocyte DNA in individuals born before and after mid-20th century nuclear bomb testing, which raised
environmental C14 levels.12 Data over the last decade have demonstrated that adipocyte hyperplasia
and proliferation are highly regulated and that aberrations in these processes contribute to obesity.
Adipocyte necrosis and apoptosis as a result of hypoxia and nutrient excess (described below) are
matched by increased adipocyte stem cell proliferation and differentiation. Furthermore, adipocytes
from obese humans demonstrate increased hyperplastic and hypertrophic capacities, contributing to
increased adipose tissue mass with progressive obesity.13 The epigenetic programming of adipocyte
stem cells during fetal development may underlie some of these differences in adipocyte behavior
observed between obese and lean subjects. Defining regulatory mechanisms of adipocyte growth is an
active area of research and will lead to methods to manipulate adipocyte biology and treat obesity at its
source.
109
Figure 4-4. Primary peptide mediators of energy homeostasis. Cytokines, adipokines, and gut peptides regulate diverse aspects of
metabolism to control global energy homeostasis. Each of these proteins has dominant functions within its primary family, but also
demonstrates cross-regulatory functions in other domains. In addition, mediators participate in crosstalk at the level of cellular
receptors and downstream intracellular signaling mediators. Shown are only partial lists of peptides and the physiologic functions
they control.
The microbiome: In a very real sense, the microbiome may be considered a distinct organ system much
like cardiopulmonary, gastrointestinal, or renal systems, and like any organ system, aberrations in the
microbiome contribute to the pathophysiology of disease. The microbiome plays an important role in
energy homeostasis. Animals raised in germ-free environments manifest increased food intake but
decreased body weight and do not develop obesity and insulin resistance when fed a high-fat diet,
demonstrating that gut microbiota contribute to nutrient digestion. Gut microbiota ferment nonhost-
digestible polysaccharides into absorbable monosaccharides and short-chain fatty acids that are absorbed
by host enterocytes and colonocytes. Products of microbiota fermentation act not only as nutrients, but
also regulate host metabolism: short-chain fatty acids induce host satiety, mediated in part by increased
secretion of GLP-1 and peptide YY and decreased secretion of ghrelin. Separate data demonstrate
interactions between microbiota and adipose tissue, liver, skeletal muscle, and CNS. These effects are
mediated by short-chain fatty acids, activation of Toll-like receptors on host cells via lipopolysaccharide
and other bacterial products, regulation of host systemic and cellular metabolism, and other diverse
mechanisms, all of which affect diverse aspects of host energy homeostasis.
Alterations in microbiome–host interactions contribute to the pathogenesis of obesity and metabolic
disease. Germ-free mice, when colonized with stool from obese mice, gain more weight than mice
colonized with stool from lean mice, demonstrating an obesity-specific microbiome. The ratio of gut
Firmicutes/Bacteroidetes species is increased in obese mice and humans. Ongoing research has begun to
identify specific subspecies within these broad categories of bacteria that are altered in obesity and
metabolic disease to provide a higher-resolution picture of the microbiome in obesity. For example,
obesity in mice and humans is associated with an increase in gram-negative gut bacteria, with a
concomitant increase in lipopolysaccharide absorption from the gut, which has been postulated to
contribute to obesity-associated inflammation and insulin resistance. The tools used to evaluate the
microbiome are rapidly evolving. Sequencing of the microbial genome using ribosomal 16S is well
established, while evolving technologies include shotgun sequencing of the entire metagenome and
functional assays involving transfer of human microbiota in the form of stool into germ-free animals to
study in vivo effects. Manipulation of the microbiome holds significant promise. Prebiotic
(nondigestible bacterial nutrients) and probiotic (specific bacterial subspecies thought to confer systemic
benefits) therapies are areas of active research, while antibiotic therapy directed against gram-negative
bacteria reduces steatosis and systemic inflammation in obese rodents.
Summary: Satiety and hunger, metabolic rate, adipocyte physiology, and the microbiome are but a
few of the many processes that regulate metabolism and are dysregulated in obesity. Differences in lipid
and glucose metabolism, immune function, central and peripheral nervous system function, and multiple
other processes that impact upon energy metabolism contribute to the wide variability of the obesity
phenotype in humans. This variability is the result of genetic polymorphisms that contribute to
metabolic diversity among humans and the wide range in human body habitus. The question is often
posed as to whether obesity should be considered a disease. Rather, obesity is better thought of as a
110
maladaptive compensatory response to an environment that is radically different than that in which our
species evolved. The obesity phenotype remained relatively underexpressed in environments of food
scarcity in which we evolved, in which obesogenic genes acted to defend adipose tissue stores and
enhance survival, but blossoms in our modern environment. An understanding of this intimate interplay
between phenotype and environment will lead to novel therapy for obesity based on manipulation of
environment and genetics.
PATHOPHYSIOLOGY OF METABOLIC DISEASE

Obesity and metabolic disease: Obesity is associated with a range of pathology involving every organ
system collectively referred to as metabolic disease. While underlying mechanisms are multiple, the
root cause of all metabolic disease is a failure of adipose tissue nutrient buffering capacity, leading to
overflow of nutrients, metabolites, cytokines, and adipokines from adipose tissue to other tissues. The
clinical effects of overflow differ depending on the target tissue, but the fundamental cellular responses
to nutrient excess common to all tissues, adipose included, involve mechanisms by which cells control
nutrient flux and respond to nutrient excess. These cellular responses underlie the pathophysiology of
metabolic disease.
5 Metabolism, nutrient excess, and the root cause of metabolic disease: Energy homeostasis is the
dominant and overriding goal of all biologic systems. Metabolism (Gr. metabole, change) may be
defined as the sum total of all chemical reactions and physiologic processes that regulate cellular and
systemic energy homeostasis. At the cellular level, metabolic processes are fundamental to all metazoan
life and are highly conserved across phyla; examples include the citric acid cycle and mitochondrial
respiration, which utilize multiple enzymes, the structure and function of which are conserved from
yeast to humans. At the systemic level, metabolic processes are central to maintaining homeostasis and
interface with virtually with every organ system and every physiologic process. The basic substrates of
metabolism are the macro- and micronutrients that comprise the stuff of cells and tissues, the fatty
acids, amino acids, and carbohydrates and their derivatives that are the constituents of complex
macromolecules, and the micronutrients that contribute to the catalysis of reactions that synthesize and
degrade macronutrients and higher-order macromolecules. In one sense, all cells are simply
clearinghouses for nutrients. Cellular nutrient flux provides substrate for synthesis of macromolecules
via anabolic metabolic processes, which are in turn degraded via catabolic metabolic processes.
Maintaining the balance between anabolism and catabolism at cellular and systemic levels is of critical
importance. Cancer, for example, may be viewed as a metabolic imbalance that favors cellular
anabolism over catabolism. Cachexia, in contrast, may be considered as a metabolic disorder that favors
systemic catabolism over anabolism.
The nutrient flux with which cells are constantly faced determines the balance between anabolism and
catabolism and dictates organism-wide energy homeostasis. Nutrients are, by their very nature, high-
energy capacity molecules, much like oxygen, and like oxygen, are capable of participating in energy-
intensive and potentially damaging reactions. Fatty acid metabolites such as ceramides and
diacylglycerols, and glucose metabolites including advanced glycation end products and glucosamines,
trigger inflammation, oxidative stress, and insulin resistance at the cellular level.
Excess nutrients are therefore potentially damaging to cells, and cellular physiology has evolved
processes designed to control exposure, flux, and sequestering of these high-energy molecules. These
cellular processes were selected by evolution to manage transient nutrient excess, but are not well
adapted to manage chronic nutrient excess, a situation that cells only rarely encountered during
evolution. Maladaptive cellular responses to chronic nutrient excess underlie the pathogenesis of all
obesity-related disease and occur in all cells, explaining the involvement of virtually every organ system
in metabolic disease. These processes consist of a triumvirate of fundamental cellular stress responses:
endoplasmic reticulum (ER) stress, oxidative stress, and inflammation.
Cellular responses to excess nutrient flux: The ER is a complex organelle present in virtually all
eukaryotic cells that orchestrates synthesis, folding, and intracellular transport of macromolecules. The
rough ER, studded with ribosomes, is predominantly responsible for protein synthesis, while the smooth
ER is predominantly responsible for lipid and carbohydrate synthesis. The ER receives a constant influx
of nutrient substrates, which it sequesters and directs toward macromolecule synthesis or degradation,
thus carefully metering cellular nutrient exposure. In this capacity, the ER acts as a nutrient sensor,
responding to changes in cellular nutrient flux by directing cellular anabolism and catabolism
accordingly. The ER also responds to other cell stressors, including hypoxia, toxins, disturbances in
111
electrolyte or micronutrient balance, and a host of other stimuli that alter cell homeostasis. Excess
cellular nutrient flux, like other forms of stress, leads to a series of stepwise ER responses that are
collectively referred to as the ER stress response.
The initial ER stress response to modest increases in nutrient flux involves increased expression of
chaperone proteins involved in macromolecule synthesis to accommodate increased anabolism of excess
nutrients. If nutrient excess persists to exceed the capacity of cellular macromolecule synthesis and
nutrient sequestration, the ER stress response progresses to activate the unfolded protein response. The
unfolded protein response downregulates global protein expression while upregulating expression of
chaperone proteins in an adaptive response designed to maintain synthesis of essential cellular proteins.
If nutrient excess persists beyond the capacity of the ER to maintain proper protein synthesis, then the
unfolded protein response progresses to induce cell apoptosis. The unfolded protein response thus
protects cells from modest increases in nutrient flux and induces cell death in the face of extreme
nutrient excess.
The ER stress response is not the only cellular response to nutrient excess. Macromolecule synthesis
generates reactive oxygen species (e.g., superoxides, oxygen/hydroxyl-free radicals, hydrogen peroxide)
which, like nutrients, are highly energetic molecules capable of damaging cells. Cells have evolved
multiple mechanisms to sequester reactive oxygen species and manage oxidative stress, including
antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase, scavenging
molecules such as ascorbic acid, urate, and divalent ions, and the thioredoxin and glutaredoxin systems.
The ER and mitochondria are primary cellular sites of control of oxidative stress. When nutrient flux,
macromolecule synthesis, and reactive oxygen species production exceed cellular antioxidant capacity,
cells activate diverse oxidative stress responses, which increase expression of antioxidant proteins,
sequester reactive oxygen species, and increase mitochondrial uncoupling, which transiently reduces
cellular reactive oxygen species production. Oxidative stress responses overlap with ER stress responses,
and if oxidative stress persists, the unfolded protein response is activated and leads to apoptosis.
The third arm of the cellular stress response is inflammation. Increased nutrient flux generates an
inflammatory response designed to scavenge debris and byproducts from increased cell turnover and
macromolecule synthesis that result from ER and oxidative stress responses. Testament to the close
relationship between metabolism and inflammation, central inflammatory and metabolic mediators
demonstrate marked functional overlap. For example, TNF-α and leptin, in addition to their dominant
functions in regulating inflammation and satiety respectively, each plays important reciprocal roles in
regulating body weight and inflammation.14,15 TNF-α and leptin are but two examples of many satiety
and hunger factors and inflammatory cytokines that manifest dual immunoregulatory and energy
homeostasis functions. In addition, molecular byproducts of metabolism trigger inflammation. Free fatty
acids are ligands for Toll-like receptors, while advanced glycation end products trigger receptors of
advanced glycation end-products pathways which directly activate innate immune effector cells,
establishing a direct molecular link between metabolism and inflammation. Obesity is associated with a
state of chronic systemic inflammation that plays a central role in the pathogenesis of multiple
comorbid diseases. Serum cytokine levels are increased in obese animals and humans, and adipose tissue
manifests a pan-leukocyte infiltrate, findings that directly correlate with the magnitude of obesity and
severity of metabolic disease.
Increased ER stress, oxidative stress, and inflammation have been demonstrated in obese rodents and
humans. An important aspect of cellular stress responses is that each potentiates the others via overlap
in fundamental cell signaling pathways including PI3-Akt, MAPK, AMPK, mTOR, JAK-STAT, and NFκB.
These signaling pathways are triggered by multiple stimuli that are dysregulated in obesity, including
adipokines, cytokines, growth factors, and nutrients and metabolites. Furthermore these signaling
pathways participate in robust crosstalk at multiple levels, establishing a vicious cycle that perpetuates
cell stress in the face of chronic nutrient excess (Fig. 4-5). These processes are common to all cells and
affect all tissues in late-stage obesity, explaining the diverse manifestations of systemic metabolic
disease. But where do these processes begin, and what initiates them? To answer this question, we must
explore the early events in adipose tissue in evolving overweight and obesity – it is within adipose
tissue that metabolic disease originates.
Adipocyte hypertrophy, hypoxia, inflammation, and fibrosis: Adipocytes are exquisitely well designed to
manage high levels of nutrients. One of the first responses of adipocytes to chronic elevations in
nutrient flux in early overweight and obesity is hypertrophy. Free fatty acids are absorbed by
adipocytes through pinocytosis mediated by fatty acid-binding proteins, as well as being synthesized
from glucose and glutamine via de novo lipogenesis, and stored in lipid droplets via a highly regulated
112
process mediated by perilipin proteins. Virtually all cells are capable of storing lipid to some degree, but
adipocytes have an extremely high capacity for lipid storage and hypertrophy. Adipocytes are one of
only a few cell types that can enlarge to diameters greater than 100 microns, the diffusion distance of
oxygen. Adipocyte diameter in humans correlates directly with the magnitude of obesity and the
severity of metabolic disease; adipocytes in lean subjects are virtually all less than 100 microns in
diameter, while those in obese subjects are greater than 100 microns, in some cases exceeding 200
microns.16 Progressive adipocyte hypertrophy establishes a state of cellular hypoxia within adipose
tissue that has been verified in obese mice and humans. Decreased adipose tissue capillary density and
blood flow in obesity exacerbate hypoxia. This hypoxic state has broad effects on adipocyte metabolism,
inducing insulin resistance, ER stress, oxidative stress, and inflammation, and inhibiting lipogenesis.
Manipulation of hypoxic responses in adipocytes holds therapeutic promise. For example, targeting
hypoxia-inducible factor-1α, a dominant cellular hypoxia-response protein, in murine obesity
ameliorates metabolic disease.17
Hypoxia induces adipocyte apoptosis and necrosis which in turn recruits an inflammatory response
designed to scavenge dead and dying adipocytes. This inflammatory state is a dominant aspect of
adipose tissue dysfunction in obesity, and is directly linked to insulin resistance and dysregulation of
lipid metabolism at local (adipose tissue) and systemic levels. Central to adipose tissue inflammation is
a marked accumulation of adipose tissue macrophages (ATMs), the number of which directly correlates
with the degree of obesity in mice and humans. ATMs are important mediators of metabolic disease,
and are altered in phenotype, shifting from a scavenging M2 phenotype to an inflammatory
diabetogenic M1 phenotype.18 ATMs are a dominant source of inflammatory cytokines, including TNF-
α, IL-6, and IL-1, all of which induce insulin resistance and aberrations in glucose and lipid metabolism
in adipocytes via multiple mechanisms. In support of a central role for ATMs in the pathogenesis of
metabolic disease, mice transgenically engineered to lack macrophage homing molecules in adipose
tissue do not develop obesity-related ATM infiltrates and are protected from diabetes. Preliminary trials
of pharmacologic agents that interfere with macrophage homing to adipose tissue in humans show
promise as treatment for diabetes. Finally, adipose tissue inflammation in obesity involves more than
macrophages, and is associated with a pan-leukocyte infiltrate that includes T-cells, B-cells, NK cells,
NKT cells, and eosinophils. Therapy for metabolic disease based on nonmacrophage cellular immune
mediators is an area of active research.
Figure 4-5. Highly simplified schematic of major cell signaling pathways that regulate energy homeostasis and cell stress
responses. Primary stimuli for all cells include adipokines, insulin, IGF-1, nutrients and metabolites including free fatty acids, and
their derivatives such as ceramide (which activate Toll-like receptors, TLR), glucose, fructose, and advanced glycation end products
(which activate receptors for advanced glycation end products, RAGE), and cytokines. Primary intracellular signaling nexi include
mitogen-activated protein kinases (MAPK), PI3-Akt, JAK/STAT signaling mediators, AMP-activated protein kinase (AMPK),
mammalian target of rapamycin (mTOR), and NFκB, all of which are linked to ER stress and oxidative stress responses. These
113
pathways engage in highly redundant crosstalk via cross-reactivity of intracellular signaling mediators and induction of gene
transcription, and conspire to integrate multiple stimuli to regulate fundamental aspects of cell metabolism, survival, and death in
response to nutrient availability and cell stressors such as hypoxia.
6 As inflammation persists, adipose tissue undergoes fibrotic remodeling, with increased expression of
matrix metalloproteases and collagens and increased extracellular matrix turnover. Adipose tissue
fibrosis limits adipocyte hypertrophic and lipid storage capacity, accelerating adipocyte stress. Obese
collagen VI knockout mice demonstrate increased adipocyte hypertrophic capacity due to decreased
fibrosis and are protected from systemic metabolic disease.19 These observations speak to a critically
important role for adipose tissue as a buffer for excess nutrients, metabolites, and metabolic toxins. As
obesity progresses, adipose tissue buffering capacity is overwhelmed and cell stress responses, initially
confined to adipose tissue, overflow into circulation and cause systemic metabolic disease (Fig. 4-6).
Adipose tissue anatomy, adipose tissue overflow, and the pathogenesis of systemic metabolic disease: Patients
with rare congenital and acquired lipodystrophy syndromes characterized by a paucity of adipose tissue
suffer from metabolic disease just as in obesity, including insulin resistance, hyperlipidemia, and hepatic
steatosis, demonstrating that the absence of adipose tissue is as detrimental as its excess. In
lipodystrophy and obesity, adipose tissue nutrient buffering capacity is overwhelmed, and nutrients
overflow to other tissues not as well adapted as adipose tissue to manage nutrient excess, inducing
systemic metabolic disease.
Adipocytes are present throughout the mammalian body in discrete anatomic depots as well as within
every organ and every tissue. Adipose tissue is more than simply a storage depot for lipid; only half the
cells in adipose tissue are adipocytes, the remainder comprising the so-called stromovascular cell
fraction, which consists of immune leukocytes, fibroblasts, endothelial cells, adipocyte stem cells, and
other cell types. Adipose tissue is highly innervated with sympathetic and parasympathetic afferent and
efferent fibers, and has important immunoregulatory and endocrine functions. Adipose tissue
participates in robust communication with the CNS and all peripheral organs, orchestrating responses to
alterations in nutrient availability, systemic health and metabolism, ambient temperature, and a host of
other stimuli. Adipose tissue is a central regulator of systemic energy homeostasis.
Hibernating bears accumulate large amounts of adipose tissue without developing inflammation or
other cellular stress responses, while in some humans, excess subcutaneous adipose tissue appears to
protect against metabolic disease. These examples demonstrate that adipose tissue phenotype is as
important as quantity with respect to systemic metabolic state. Adipose tissue may be broadly divided
into white and brown phenotypes. White adipose tissue comprises the majority of adipose tissue in
humans, is strongly associated with metabolic disease, increases with increasing obesity, and is a
primary storage site for lipid. Brown adipose tissue, in contrast, comprises a minority of total adipose
tissue in humans, has beneficial effects on metabolism, decreases with increasing obesity and with age,
and manifests lower lipid storage capacity. Brown adipocytes engage in higher levels of fatty acid
oxidation and thermogenesis via expression of mitochondrial UCPs. White adipose tissue derives from
mesodermal stem cells that migrate to sites of canonical depots in humans in early embryonic
development and proliferate to form defined depots in late fetal and early neonatal periods. White
adipose tissue depots include visceral and subcutaneous, which may be further subdivided into omental,
retroperitoneal, and mesenteric visceral adipose tissue (VAT) compartments, and deep and superficial
subcutaneous adipose tissue compartments, each with distinct functional characteristics. Brown adipose
tissue develops in rodents during gestation from precursor cells that also give rise to myocytes and form
defined brown adipose tissue depots prior to birth. Brown adipose tissue in humans is less well
understood; while most voluminous in the neonatal period, positron emission tomography scanning
demonstrates cervical, supraclavicular, mediastinal, paraspinous, and perirenal brown adipose tissue
depots in adult humans as well.20
114
Figure 4-6. Nutrient excess and cell stress in adipocytes. Nutrient excess is an early signal that induces ER stress and hypertrophy in
adipocytes. ER stress is tightly linked to oxidative stress and inflammation, and each of these processes induces and potentiates the
others. As hypertrophy progresses, adipocyte diameter expands beyond the diffusion distance of oxygen, leading to cellular
hypoxia, which exacerbates cell stress responses, leading to adipocyte apoptosis and necrosis via the unfolded protein response and
other advanced cell stress responses. Adipocyte apoptosis and necrosis trigger recruitment of an advanced inflammatory response
designed to scavenge dead and dying adipocytes. This inflammatory response is associated with fibrotic tissue remodeling which
limits adipocyte hypertrophic and lipid buffering capacity of surviving adipocytes, leading to overflow of lipids, nutrients,
metabolites, and inflammatory products from adipose tissue into the systemic circulation.
Recent data suggest that the dichotomy between white adipose tissue and brown adipose tissue is
overly simplistic, and that adipocyte phenotype spans a spectrum. An intermediate phenotype, termed
“brite” (brown-in-white) or “beige adipocytes,” is found in white adipose tissue depots in rodents and
humans. These cells manifest brown adipocyte functions, and are induced to proliferate by cold stress
and β-adrenergic stimuli, suggesting phenotypic plasticity. An important area of research is directed
toward understanding the mechanisms that regulate adipocyte phenotype. The recently described
protein irisin is secreted by skeletal muscle in response to exercise, induces a brown phenotype in
adipocytes and improves systemic metabolism when overexpressed in mice.21 This finding underscores
the importance of interorgan communication in controlling adipose tissue biology and suggests the
potential for pharmacologic mediators to manipulate adipocyte phenotype with beneficial effects on
systemic metabolism, the so-called “browning” of adipose tissue.
Human adipose tissue accumulation is anatomically heterogeneous. Human obesity may be broadly
classified into android and gynecoid phenotypes, defined by excess VAT and subcutaneous adipose
tissue, respectively. Excess VAT is strongly associated with metabolic disease; excess subcutaneous
adipose tissue, in contrast, is less strongly associated with metabolic disease, and in some studies has
been shown to be protective, suggesting a greater lipid buffering capacity. Surgical lipectomy of VAT
but not subcutaneous adipose tissue ameliorates murine diabetes.22 In contrast to mice, similar studies
of visceral omentectomy in humans demonstrate conflicting results, likely due to more complex human
adipose tissue depot anatomy, but excess VAT as measured by waist circumference and imaging
techniques nonetheless correlates strongly with metabolic disease. The reasons for the disproportionate
effect of VAT on metabolic disease are unclear. While the abdominal location of VAT plays a role,
intrinsic differences between visceral and subcutaneous adipose tissues also exist, evidenced by
experiments in which transplantation of subcutaneous adipose tissue into a visceral location ameliorates
metabolic disease in mice.23 VAT manifests higher levels of inflammation, lipolysis, β-adrenergic
receptor expression, steroid sensitivity, insulin resistance, and adipocyte proliferation and
differentiation relative to subcutaneous adipose tissue.
SYSTEMIC METABOLIC DISEASE

Mediators of systemic metabolic disease: In addition to its distinct functional phenotype, VAT also
contributes to metabolic disease via its direct anatomic communication with the liver via the portal
venous system. Portal overflow of free fatty acids, excess nutrients and metabolites, and hormones and
cytokines from VAT to the liver is an early step in the progression to systemic metabolic disease. As it
progresses, peripheral overflow extends beyond the liver to involve all tissues. Adipose tissue overflow
affects not only skeletal muscle, vasculature, kidneys, and lungs, but also the CNS; inflammation and ER
stress have been documented in the hypothalamus in obesity, and mediate reciprocal effects on adipose
tissue and other organ systems via aberrations in CNS efferent outputs that exacerbate obesity and
metabolic disease. In essence, adipose tissue dysfunction “metastasizes” as its buffering capacity is
115
overwhelmed, inducing cell stress responses in all tissues that underlie the pathogenesis of metabolic
disease (Fig. 4-7).
Figure 4-7. Adipose tissue overflow, interorgan communication, and systemic metabolic disease. As adipose tissue buffering
capacity is overwhelmed, lipids, nutrients, cytokines, and adipokines overflow into the systemic circulation and cause systemic
metabolic disease via the same cellular effects that initially unfold in adipocytes. Early overflow occurs via the portal system,
which drains visceral adipose tissue venous effluent into the liver, which becomes the first site of systemic metabolic disease and
an important secondary site of nutrient buffering via the development of hepatic steatosis. Overflow progresses to involve all
peripheral tissues, inducing cell stress and disease in all organ systems. Overflow involves the central nervous system as well, as
inflammation and cell stress have been documented in the hypothalamus in obesity, which in turn is thought to disturb peripheral
metabolic function via alterations in CNS efferent signaling.
Nutrients and metabolites are central mediators of the systemic effects of adipose tissue overflow.
Free fatty acids mediate systemic lipotoxicity, a central mechanism of metabolic disease. Free fatty acids
trigger inflammation via binding to Toll-like receptors, and also act as ligands for multiple other
immunostimulatory and cell stress-inducing receptor families. Lipid metabolites induce cellular insulin
resistance, ER stress, and apoptosis. Metabolic products of glucose and fructose, including advanced
glycation end products and glucosamines, mediate similar effects. Cytokines and adipokines overflow
from adipose tissue as well. TNF-α, a dominant inflammatory cytokine expressed by ATM in obesity,
exerts proinflammatory and diabetogenic effects on tissues via diverse mechanisms. Leptin also
promotes inflammation and regulates cellular glucose homeostasis. Expression of adiponectin, which
attenuates inflammation and has beneficial effects of cellular metabolism, is decreased in obesity, as
adipose tissue’s cytokine and adipokine balance shifts toward a proinflammatory milieu. Metabolites,
adipokines, and cytokines establish in multiple tissues the same cellular stress responses that initially
unfold in adipose tissue, including ER stress, oxidative stress, and inflammation. Within target tissues,
as in adipose tissue, these processes potentiate one another and exacerbate cell stress, forming the basis
for systemic metabolic disease.
7 Portal overflow and liver disease: The liver is one of the first organs to be affected by failure of
adipose tissue buffering, as portal overflow induces hepatic steatosis. Hepatic steatosis is the result of an
imbalance in the delivery and export of hepatocyte lipid. Sources of hepatic lipid include fats absorbed
from the diet and delivered from the gut as chylomicrons, lipids synthesized by hepatocytes via de novo
lipogenesis, and free fatty acids delivered from VAT via the portal venous system and from
subcutaneous adipose tissue via the systemic venous system. Free fatty acids from adipose tissue are a
dominant source of hepatic lipid in obesity, constituting over 60% of lipid delivery to the liver.24 Lipids
are exported from the liver primarily in the form of very low-density lipoproteins (VLDL).
Abnormalities in each of these aspects of hepatic lipid delivery and efflux that contribute to steatosis
116
have been identified in obese animals and humans, including increased free fatty acid delivery to the
liver from increased adipose tissue stores, increased hepatocyte de novo lipogenesis, and decreased
VLDL secretion.
As lipid storage capacity is reached, hepatocytes experience ER stress, oxidative stress, and
inflammatory responses via similar mechanisms as in adipose tissue, causing steatohepatitis, a histologic
entity characterized by Mallory bodies, hepatocyte ballooning, and an inflammatory infiltrate consisting
of macrophages (Kupffer cells) and other leukocytes. As in adipose tissue, TNF-α plays a central role in
the hepatic inflammatory state, and neutralization of TNF-α ameliorates steatohepatitis in mice and is
under study as therapy in humans with promising results.25,26 IL-6 and other inflammatory cytokines
have also been implicated as mediators of steatohepatitis.
Steatosis is strongly associated with obesity and is present in over 90% of patients with a BMI >40.
Up to 30% of these patients will develop steatohepatitis and 10% to 30% of patients with steatohepatitis
will develop cirrhosis. Genetics contributes to these risks: ethnic predispositions to steatosis and
steatohepatitis exist, with Asians and Hispanics at higher risk than Caucasians or Blacks. Weight loss
secondary to diet or bariatric surgery reverses steatosis and halts progression of steatohepatitis in most
patients. Few pharmacologic options exist that specifically treat obesity-associated liver disease.
Diabetes: Insulin resistance is a central metabolic response of all cells to stress. ER stress, oxidative
stress, and inflammation each induce insulin resistance. Insulin resistance begins in adipose tissue. Free
fatty acids are central mediators of cellular insulin resistance. Insulin regulates not only glucose
homeostasis in adipocytes, but also lipid metabolism, inhibiting lipolysis and free fatty acid release.
Early nutrient excess, with resultant ER stress and oxidative stress, induces insulin resistance in
adipocytes, not only impairing adipocyte glucose uptake, but also attenuating insulin’s inhibitory effects
on lipolysis and thus increasing free fatty acid release by adipocytes. Free fatty acids in turn trigger
inflammation via activation of Toll-like receptors on resident adipose tissue inflammatory cells,
inducing expression of inflammatory cytokines, including TNF-α. TNF-α plays a central role in the
evolution of insulin resistance, regulating the expression and phosphorylation of multiple genes
involved in glucose homeostasis, including insulin receptor, insulin receptor substrates, the cell
signaling nexus protein Akt, and glucose transporter molecules. TNF-α also promotes lipolysis, further
exacerbating insulin resistance and free fatty acid release by adipocytes. While multiple other mediators
contribute, these interactions between free fatty acids and TNF provide a cogent example of the vicious
cycle established in adipose tissue that contributes to worsening insulin resistance.
As adipose tissue lipid buffering capacity is overwhelmed, free fatty acids overflow into the systemic
circulation, resulting in lipotoxicity, which underlies the pathogenesis of insulin resistance in all
peripheral tissues. Skeletal muscle, responsible for 60% to 80% of systemic glucose disposal, is a
dominant site of systemic insulin resistance. Similar to adipocytes and hepatocytes, skeletal muscle
myocytes accumulate lipid and exhibit ER stress, oxidative stress, and inflammation which contribute to
insulin resistance via mechanisms described above. Skeletal muscle, like adipose tissue, becomes
inflamed, with increased levels of macrophages and diabetogenic inflammatory cytokines. Increased
circulating free fatty acids also have important metabolic effects on the liver and skeletal muscle. As
lipid delivery to skeletal muscle and liver increases, energy production shifts from glucose utilization to
fatty acid oxidation. Increased free fatty acid beta-oxidation is associated with increased
gluconeogenesis in the liver and a reduction in glucose utilization in skeletal muscle, exacerbating
hyperglycemia. The initial response of pancreatic beta cells to the resultant peripheral insulin resistance
is a compensatory increase in insulin secretion, leading to hyperinsulinemia. As disease progresses,
lipotoxicity and cell stress responses affect pancreatic beta cells. Beta cell exhaustion ensues, insulin
secretion decreases, and insulin resistance progresses to frank diabetes.
Type 2 diabetes is strongly associated with obesity, with risk ratios increasing dramatically with
increasing BMI. Like obesity itself, genetics plays an important role: Asian, Black, and Hispanic
ethnicities are associated with increased risk and multiple SNPs that correlate with diabetes have been
identified. The specific mechanisms by which genetics contribute to increased susceptibility to cellular
insulin resistance and lipotoxicity are not yet well understood. Worldwide incidence is rapidly
increasing and diabetes represents a dominant emerging health crisis.
The obesity–cancer connection: Obesity is a strong risk factor for cancer. The incidences of almost all
types of cancer increase in a dose-dependent manner with increasing BMI, and at elevated BMI >40,
risk ratios range from 2 to greater than 6 depending on the type of cancer.27 The mechanisms
underlying the association between obesity and cancer are not well defined. At the cellular level, energy
homeostasis involves fundamental processes central to carcinogenesis, and signaling pathways activated
117
by chronic overnutrition promote cell proliferation. Suggesting the potential for cancer therapy based
on manipulation of metabolism, epidemiologic data suggest that long-term metformin use is associated
with decreased cancer incidence. Chronic inflammation, characteristic of obesity and a well-established
risk factor for cancer, activates NFκB and other signaling pathways that potentiate cell proliferation,
increase production of reactive oxygen species that may contribute to oncogenic mutation, and induce
expression of inflammatory cytokines that act as cell mitogens. Overnutrition in obesity predisposes to a
state of chronic anabolism and is associated with increased expression of multiple growth factors that
may promote cancer, including insulin, insulin-like growth factor-1, and leptin. Chronic inflammation on
a background of chronic anabolism creates an ideal milieu for carcinogenesis. Steroids represent another
putative molecular link between obesity and cancer. Steroid metabolism is aberrant in obesity and
adipose tissue is a source of estrogen which may promote estrogen-responsive cancers. Finally,
adipocytes have been implicated in carcinogenesis, with data demonstrating that peritumor adipose
tissue contributes to tumor progression. In addition, adipocyte precursors home from adipose tissue
depots to tumors and provide growth factors and metabolic energy substrates that promote tumor
growth. The mechanisms by which obesity causes cancer are multiple, and as details are elucidated,
metabolism-based therapy for cancer will emerge.
CONCLUSION
Obesity is associated with an increased risk of cardiovascular disease, including hypertension,
atherosclerosis, and hyperlipidemia, the result of cell stress responses that afflict vascular tissue.
Immune diseases including allergy, atopy, and autoimmune diseases, are increased in the obese, due in
part to the above described alterations in immune and inflammatory functions. While mechanical stress
due to excess weight is a contributing factor to sleep apnea, osteoarthritis, and gastroesophageal reflux
disease, fundamental cell stress mechanisms also contribute, as inflammation has been implicated in
these diseases as well. The pan-systemic nature of metabolic disease provides substantial opportunity for
developing therapy that will simultaneously treat multiple obesity-related pathologies.
References
1. Neel JV. Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? Am J Hum
Genet 1962;14(4):353–362.
2. Stewart WK, Fleming LW. Features of a successful therapeutic fast of 382 days’ duration. Postgrad
Med J 1973;49(569):203–209.
3. Bouchard C, Tremblay A, Despres JP, et al. The response to long-term overfeeding in identical
twins. N Engl J Med 1990;322:1477–1482.
4. Rosmond R. Association studies of genetic polymorphisms in central obesity: a critical review. Int J
Obes 2003;27:1141–1151.
5. Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype
hypothesis. Diabetologia 1992;35(7):595–601.
6. Dabelea D, Hanson RL, Lindsay RS, et al. Intrauterine exposure to diabetes conveys risks for type 2
diabetes and obesity: a study of discordant sibships. Diabetes 2000;49(12):2208–2211.
7. Bateson P, Barker D, Clutton-Brock T, et al. Developmental plasticity and human health. Nature
2004;430:419–421.
8. Hayes M, Chustek M, Heshka S, et al. Low physical activity levels of modern Homo sapiens among
free-ranging mammals. Int J Obes (Lond) 2005;29(1):151–156.
9. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human
homologue. Nature 1994;372(6505):425–432.
10. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body
weight. N Engl J Med 1995;332:621–628.
11. Levine JA, Eberhardt NL, Jensen MD. Role of nonexercise activity thermogenesis in resistance to
fat gain in humans. Science 1999;283(5399):212–214.
12. Spalding KL, Arner E, Westermark PO, et al. Dynamics of fat cell turnover in humans. Nature
2008;453(7196):783–787.
118
13. Knittle JL, Timmers K, Ginsberg-Fellner F, et al. The growth of adipose tissue in children and
adolescents. Cross-sectional and longitudinal studies of adipose cell number and size. J Clin Invest
1979;63:239–246.
14. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha:
direct role in obesity-linked insulin resistance. Science 1993;259(5091):87–91.
15. Lord G, Matarese G, Howard J, et al. Leptin modulates T-cell immune response and reverses
starvation-induced immunosuppression. Nature 1998;394:897–901.
16. O’Rourke RW, White AE, Metcalf MD, et al. Hypoxia-induced inflammatory cytokine secretion in
human adipose tissue stromovascular cells. Diabetologia 2011;54(6):1480–1490.
17. Shin MK, Drager LF, Yao Q, et al. Metabolic consequences of high-fat diet are attenuated by
suppression of HIF-1α. PLoS One 2012;7(10):e46562.
18. Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue
macrophage polarization. J Clin Invest 2007;117:89–93.
19. Khan T, Muise ES, Iyengar P, et al. Metabolic dysregulation and adipose tissue fibrosis: role of
collagen VI. Mol Cell Biol 2009;29(6):1575–1591.
20. Virtanen KA, Lidell ME, Orava J, et al. Functional brown adipose tissue in healthy adults. N Engl J
Med 2009;360:1518–1525.
21. Boström P, Wu J, Jedrychowski MP, et al. A PGC1-α-dependent myokine that drives brown-fat-like
development of white fat and thermogenesis. Nature 2012;481:463–468.
22. Shi H, Strader AD, Woods SC, et al. The effect of fat removal on glucose tolerance is depot specific
in male and female mice. Am J Physiol Endocrinol Metab 2007;293(4):E1012–E1020.
23. Tran TT, Kahn CR. Transplantation of adipose tissue and stem cells: role in metabolism and disease.
Nat Rev Endocrinol 2010;6:195–213.
24. Donnelly KL, Smith CI, Schwarzenberg SJ, et al. Sources of fatty acids stored in liver and secreted
via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005;115(5):1343–
1351.
25. Barbuio R, Milanski M, Bertolo MB, et al. Infliximab reverses steatosis and improves insulin signal
transduction in liver of rats fed a high-fat diet. J Endocrinol 2007;194:539–550.
26. Tilg H, Jalan R, Kaser A, et al. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in
severe alcoholic hepatitis. J Hepatol 2003;38:419–425.
27. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer
in a prospectively studied cohort of U.S. adults. N Engl J Med 2003;348(17):1625–1638.
119
Chapter 5
Wound Healing
Rajiv Chandawarkar and Michael J. Miller
Key Points
1 Nonhealing wounds affect about 3 to 6 million people in the United States, with persons 65 years and
older accounting for 85% of these events. The annual cost of this problem in the United States is
estimated to be as high as $25 billion for hospital admissions, antibiotics, and local wound care. The
development of new data regarding the normal and pathologic wound healing responses both at the
cellular levels and the biological markers associated with them will help us develop new strategies
to treat these difficult expensive clinical problems.
2 Normal wound healing is achieved through four highly integrated and overlapping biophysiological
phases: hemostasis, inflammation, proliferation, and tissue remodeling or resolution. Each phase initiates a
cascading set of processes critical to the final aim of a healed wound.
3 Wound healing is a complex biological process that consists of hemostasis, inflammation,
proliferation, and remodeling. Large numbers of cell types – including neutrophils, macrophages,
lymphocytes, keratinocytes, fibroblasts, and endothelial cells – are involved in this process. Multiple
factors can cause impaired wound healing by affecting one or more phases of the process and are
categorized into local and systemic factors.
4 Clinically the process of wound healing is important to understand from several perspectives. These
include: development of precise, least-traumatic surgical technique; the clear understanding of how
newer developments in the field of biofilm and anti-infective therapies affect wound management;
factors that lead to the formation of chronic versus acute wounds, and importantly, the comorbid
conditions that affect wound healing. The role of age, gender, nutrition, obesity, and diabetes are
critical factors to incorporate into the therapeutic repertoire.
The role of disease states including diabetes, and cancer-related treatments including radiation,
chemotherapy and ways to mitigate these factors are as important to assimilate.
1 A fundamental understanding of wound healing is essential to surgical practice. Years of research
have yielded extraordinary details of the wound healing process. The complexity can lead the practicing
clinician to the conclusion that this topic is perhaps best reserved for the wound specialist. It is critical,
however, for the practicing surgeon to have a fundamental understanding of wound healing. Besides the
controlled injury that occurs in elective surgery, all invasive surgical procedures cause soft tissue
trauma regardless of the circumstances. All aspects of surgical care from patient selection, surgical
instruments and technique, and postoperative management are intended to optimize tissue healing and
avoid complications. Highly specialized neurosurgical or cardiac procedures can be fraught with
complications if sound principles of soft tissue wound healing are overlooked. In addition to surgical
procedures, there is the growing problem of people suffering from chronic wounds. Nonhealing wounds
affect about 3 to 6 million people in the United States, with persons 65 years and older accounting for
85% of these events. The annual cost of this problem in the United States is estimated to be as high a
$25 billion for hospital admissions, antibiotics, and local wound care.1 Minimizing wound complications
is essential in the current health care environment with an emphasis on quality and safety with publicly
reported outcomes such as surgical site infection and readmission rates. For the benefit of the patient
and to meet increasingly stringent scrutiny of surgical outcomes by the public, it is incumbent on the
surgeon to be more than a technician. Specifically, the surgeon needs to understand how surgery alters
tissues and the physiology of healing in order to obtain the best outcomes for their patients. This
understanding is essential to allow the surgeon to constantly improve personal technique and quality
outcomes. The development of new data regarding the normal and pathologic wound healing responses
both at the cellular levels and the biological markers associated with them will help develop new
strategies.
120
NORMAL WOUND HEALING
The series of events associated with wound healing begins at the moment of injury. Although different
kinds of tissue (i.e., skin, fat, muscle, bone, nerve, parenchymal organs) have unique responses to
injury, each follows a similar process that involves four sequential overlapping periods known as the
hemostasis, inflammatory, proliferative, and remodeling phases of wound healing. The process is best
understood by considering a full-thickness injury of the skin, dermis, and subcutaneous tissue associated
with a simple surgical incision common to every surgical specialty.
2 Normal wound healing is achieved through four highly integrated and overlapping biophysiological
phases: hemostasis, inflammation, proliferation, and tissue remodeling or resolution.2 For a wound to heal
successfully, as shown in Figure 5-1, all four phases must occur in the proper sequence and time frame
(that takes almost 1 year to complete) and continue for a specific duration at an optimal intensity3
(Table 5-1).
Cellular components, the dominant processes as well as biochemical environments that elicit each of
the phases are markedly different in their functionality and work in concert to result in a normal healed
wound (Fig. 5-2). As shown in Figure 5-3, each phase initiates a cascading set of processes critical to the
final aim of a healed wound. In addition, the dominant cytokines for each phase are shown in Figure 5-
4.
Figure 5-1. Four phases of wound healing: plotted against “Time” on the X axis, the four phases shown in different colors occur
sequentially, and overlap. Overall the total time period for completion is 1 year.
Hemostasis
The first phase of hemostasis begins almost instantaneously after wounding. A scalpel drawn across
intact skin injures cells in the epidermis and dermis and separates components of the extracellular
matrix (ECM) that support the normal three-dimensional framework of the tissue and preserves the
barrier function. The zone of injury is limited to the dimensions of the blade when using a conventional
metal scalpel. With electrosurgery, the injury extends some distance into the surrounding tissues
depending on the power settings on the device. As the surgeon deepens the incision, the blood vessels in
the sub-dermal plexus and deeper in the subcutaneous planes, are cut, and bleeding occurs. The tissue
response is mediated by factors from three sources: (1) blood leaking into the wound, (2) proteins
stored in the ECM, and (3) locally resident surviving cells.
Table 5-1 Cellular and Biological Events that Frame the Normal Wound Healing
Process
121
Circulating factors that initiate the inflammatory phase of healing are platelets, plasma proteins, and
leukocytes. Platelets are unnucleated formed elements in the blood produced in the bone marrow by
megakaryocytes. The plasma membrane of each platelet contains specific receptors for collagen known
as the glycoprotein Ia/IIa complex. The platelet cytoplasm contains granules holding an array of factors
important for hemostasis and inflammation. When plasma membrane receptors come into contact with
collagen of the ECM (type I) and the basement membrane of the vascular endothelium (Type IV),
platelets bind and anchor to the site. Simultaneously, platelet activation occurs and the platelet changes
from a rounded amorphous shape to a flattened configuration and discharges the contents of stored
cytoplasmic granules in an event known as the platelet release reaction. These bioactive factors serve a
dual purpose in hemostasis and wound healing. Hemostasis is promoted by factors that cause
strengthened force of platelet binding, accelerated platelet aggregation, vasoconstriction, and activation
of the clotting cascade. Platelet anchoring is strengthened by von Willebrand factor (vWF) released by
damaged endothelium and activated platelets. Platelet binding is also characterized by rapid vascular
constriction and the formation of a stable fibrin clot. Platelets are the main cellular players of the first
phase (Fig. 5-5A and Fig. 5-5B). By their collective function, they prevent hemorrhage. Platelet-derived
functions that achieve this goal include: adhesion, aggregation, and formation of a procoagulant surface
that facilitates the generation of thrombin and results in a fibrin plug. In addition, platelets express and
release substances that promote tissue repair and influence processes such as angiogenesis,
inflammation, and the immune response. They contain large secretable pools of biologically active
proteins, including platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-B), and
vascular endothelial growth factor (VEGF) as well as cytokines while newly synthesized active
metabolites including proteins such as PF4 and CD40L are also released. Although anucleate, activated
platelets possess a spliceosome and can synthesize tissue factor and interleukin-1β. The binding of
secreted proteins within a developing fibrin mesh or to the ECM can create chemotactic gradients
favoring the recruitment of stem cells, stimulating cell migration and differentiation, and promoting
repair.4 The therapeutic use of platelets in a fibrin clot has a positive influence in clinical situations
requiring rapid healing. Dental implant surgery, orthopedic surgery, muscle and tendon repair, skin
ulcers, hole repair in eye surgery and cardiac surgery are situations where the use of autologous
platelets accelerates healing.
122
Figure 5-2. The dominant cells, physiologic process as well as the temporal distribution of the four phases of wound healing.
Figure 5-3. Flow chart of the phases and the cascading steps that result from each phase.
123
Figure 5-4. The patterns of cytokines and growth factors within each phase of wound healing.
Figure 5-5. A: Diagrammatic wound healing model. Platelets, the first cells to arrive at the wound are critical to create a clot and
establish hemostasis B: Phase 1 – Hemostasis.
The growing platelet plug inside the vessel is stabilized by fibrin polymerized from circulating
fibrinogen. The vascular response is mediated by local factors modulated by the systemic control of the
sympathetic nervous system. Vasoconstriction, mediated by catecholamines and prostaglandins
(thromboxane and PGF2a), normally is limited to the time required to achieve hemostasis. Vasodilation
and alteration in capillary permeability soon follow mediated by histamine, prostaglandins (PGE2 and
PGI2), and VEGF released from resident interstitial mast cells and damaged endothelium. This causes
increased blood flow and controlled delivery of fluid, leukocytes, macrophages, and relevant plasma
proteins to the wound environment. Platelets release two factors with particular importance for wound
healing: PDGF and TGF-β. Which in turn stimulate chemotaxis and proliferation of inflammatory cells.
Inflammatory Phase
The second phase of healing involves acute inflammation that begins at the moment of tissue disruption.
Inflammatory cells appearing during this phase of healing are polymorphonuclear leukocytes (PMNs)
and macrophages. PMNs are first to appear (Fig. 5-6). Their primary role is to clear devitalized tissue,
blood clot, foreign material, and bacteria from the wound. PMNs are part of natural host defenses that
destroy bacteria by phagocytosis and secreting oxygen free radicals. Migration of PMNs from the
intravascular compartment (the lumen) to the ECM and to the wound site is controlled by several
biochemical agents including selectins, cytokines, and integrins that act in series to activate, tether, and
facilitate extravascular escape (Fig. 5-7). PMNs work in concert with the immune system antibodies.
Their numbers and persistence depend on the initial wound conditions. A clean surgical wound
performed with atraumatic tissue handing will have low PMN activity, whereas a poorly performed
surgical incision or a traumatic wound may be characterized by a large amount of debris and require
124
prolonged participation of PMNs to set the stage for appearance of macrophages, the most important
cellular mediator of the inflammatory phase of wound healing.
Figure 5-6. Phase 2 – Inflammation.
Macrophages appear in large numbers within 48 hours of wounding and play a central role in the
inflammatory phase. They are derived from circulating monocytes or resident interstitial cells that
migrate into the wound from adjacent tissues. Macrophages are multifunctional (Fig. 5-8) and complete
the cleanup activities initiated by the PMNs by phagocytizing remaining wound debris. Most
importantly, they secrete a vast array of cytokines and growth factors, which function in a rapidly
amplifying process that affects all aspects of healing during the inflammatory phase. These factors
induce recruitment and activation of additional macrophages, angiogenesis, proliferation of fibroblasts,
and ECM production. Matrix production is accelerated as the inflammatory phase of healing transitions
into the next phase of healing, the proliferative phase.
Proliferative Phase
The defining characteristic of the proliferative phase of healing is ECM production (Fig. 5-9). The
phases of wound healing are not discreet. While the inflammatory phase is still most active, the
proliferative phase begins with formation of a provisional ECM composed of fibrin and fibronectin
precipitated from blood extravasated into the wound at the time of the initial injury. The provisional
matrix is a protein scaffold that stabilizes the wound edges and provides a framework for migration of
PMNs, macrophages, fibroblasts, and other cells into the wound from surrounding tissues. As the
inflammatory phase slows the proliferative phase begins and becomes dominant. Fibroblasts replace
macrophages as the most numerous cell type. Like macrophages, fibroblasts are multifunctional. They
are responsible for new tissue formation, collagen production, and the laying down of the ECM (Fig. 5-
9). Angiogenesis occurs simultaneously as new capillaries form and blood vessels penetrate the
provisional matrix sprouting from vessels of the surrounding uninjured tissues. The processes that
actually coordinate formation of ECM and new tissue with angiogenesis are not well defined. Signaling
pathways that stimulate new tissue formation involve the role of low oxygen tension that increases the
expression of “hypoxia-inducible factor” (HIF) by vascular endothelial cells. HIF in turn binds to specific
sequences of DNA that regulate the expression of VEGF thus stimulating angiogenesis. This also has a
negative feedback loop – increased formation of new blood vessels normalizes the oxygen tension. In
response, oxygen binds to HIF and blocks its activity resulting in decreased synthesis of VEGF.
Epidermal growth factor and TGFa produced by activated wound macrophages, platelets, and
keratinocytes play an important role at the creation of a robust scaffold.
125
Figure 5-7. The biochemical factors that elicit migration of cells from intravascular compartment into the wound site.
Figure 5-8. Macrophage functions.
Epidermal cells migrate over the scaffold and only after the epithelial bridge is completed, enzymes
are released to dissolve the attachment at the base of the overlying scab that falls off. In response to the
growing need for oxygen and nutrients at the site of healing, the wound microenvironment stimulates
the release of factors needed to bring in a new blood supply (low pH, reduced oxygen tension, and
increased lactate). This process – angiogenesis or neovascularization is stimulated by VEGF, basic
fibroblast growth factor (bFGF), and TGFb. These factors are secreted by several cell types including
vascular endothelial cells, epidermal cells, fibroblasts, and macrophages.
As the proliferative phase progresses the predominant cell in the wound site is the fibroblast. This
multifunctional cell of mesenchymal origin mainly produces and deposits the new matrix for structural
integrity at the level of the wound bed (Fig. 5-9B). ECM production is the defining feature of the
proliferative phase. The ECM is primarily collagen. At least 23 individual types of collagen have been
identified – type I is present mostly in scar tissues.5 Fibroblasts produce collagen via their attachment to
the cables of the provisional fibrin matrix.6 After transcription and processing of the collagen messenger
ribonucleic acid, it is attached to polyribosomes on the endoplasmic reticulum where the new collagen
chains are produced. During this process, there is an important step involving hydroxylation of proline
and lysine residues.7 The collagen molecule transforms itself into the classical triple helical structure
and thereafter its nascent chains are modified through glycosylation8; this procollagen molecule is
released into the extracellular space.9 The hydroxyproline in collagen gives the molecule its stable
helical conformation.10 Whereas fully hydroxylated collagen has a higher stability, unhydroxylated
forms are fragile, similar to collagen produced under anaerobic disease conditions or vitamin C-deficient
states (scurvy), wherein the collagen undergoes denaturation easily and can break.
126
Figure 5-9. A: Phase 3 – Proliferation. Vast array of cells are recruited into the wound bed and carry out diverse functions
including proliferation and deposition of ECM. B: Fibroblast functions.
Figure 5-10. Phase 4 – Remodeling and Maturation.
Finally, collagen released into the extracellular space undergoes further processing by cleavage of the
procollagen N- and C-terminal peptides. In the extracellular spaces, an important enzyme, lysyl oxidase,
acts on the collagen to form stable cross-links. As the collagen matures and becomes older, more and
more of these intramolecular and intermolecular cross-links are placed in the molecules. This important
cross-linking step gives collagen its strength and stability over time.11
Remodeling Phase
The remodeling phase is characterized by continued synthesis and degradation of the ECM components
trying to establish a new equilibrium – and the formation of an organized scar (Fig. 5-10). Collagen
degradation occurs12 via the action of specific collagenases that are secreted by various cells:
fibroblasts, neutrophils, and macrophages each of which can cleave the collagen molecule at differing
but specific locations on all three chains, and break it down to characteristic three-quarter and one-
quarter pieces. These collagen fragments undergo further denaturation and digestion by other proteases.
Several molecules including TGF play a major role in the remodeling phase. TGF-β-induced intracellular
signaling acts via a set of proteins called the SMAD proteins, which act as direct links between the cell
surface and the nucleus. The recent development of several SMAD pathway specific knockout mice and
transgenic animals has confirmed the pivotal nature of the SMAD pathway in fibrogenesis and
tumorigenesis. Still, several difficulties remain before the TGF-β/SMAD pathway can be efficiently
targeted in situations such as tissue fibrosis or impaired wound healing. In particular, the precise
spatiotemporal role of each TGF-β/SMAD pathway component during the development of excessive
127
ECM deposition leading to tissue fibrosis remains to be ascertained.
As the scar matures, late remodeling occurs (that takes up to 1 year); the scar contracts and thins out
(Fig. 5-11).
CLINICAL APPLICATIONS
Surgical Technique
The surgeon equipped with the knowledge of the fundamentals of wound healing is prepared to
insightfully minimize risks of wound healing complications while performing a surgical procedure from
start to finish. The stage is set for healing from the moment the incision is made. The skin and dermis
should be incised perpendicularly to the plane of the surface. Attention to this principle is particularly
important when making an incision on a curved surface. Electrosurgical currents should be used set on
the lowest power settings that accomplish hemostasis. The deep tissues should be handled as
atraumatically as possible. The incision is carried down through deeper layers ensuring that each new
incision is accurately placed in the same line as the previous one. This avoids a saw tooth surface with
devitalized sections. Proper tissue handling techniques in the subcutaneous fat and adjacent soft tissue
are based on well-established wound healing principles, which minimize the risk of infection, seroma,
delayed healing, unnecessary scarring, and other postoperative wound complications. For traumatic
wounds, the first step in treatment is to convert them into controlled surgical wounds by thoughtful
debridement and tissue repair. Treating traumatic wounds minimizing the risk of postoperative wound
complications requires mindfulness of wound healing principles in all of these clinical circumstances.
This is true regardless whether performing repair of a simple laceration or the most complex specialized
procedure. Controlling the degree of injury leads to improved outcomes with fewer complications
related to a failure in the wound healing process. An awareness of the wound healing process informs
proper surgical technique. A clear understanding of wound healing allows the surgeon to advance in
technical skill and achieve continuously improving outcomes throughout a professional career.
Figure 5-11. Contraction of scar – This process occurs over the course of 1 year.
128
Figure 5-12. Effects of biofilm on wound healing.
Elective surgery creates controlled tissue injury. Minimizing tissue injury forms the basis of proper
surgical technique. Trauma inures tissues in an uncontrolled fashion. Wounds can occur under special
conditions such as pressure, physiologic impairment (e.g., diabetes) that create traumatic tissue damage
in an uncontrolled injury. Finally, there are wounds that occur under specialized circumstances such as
radiotherapy in cancer treatment.
Biofilm
Biofilm comprises a colony of microorganisms enveloped with a matrix of extracellular polymers.
Estimated biofilm-associated infections costs >$1 billion annually. Both chronic and acute dermal
wounds are susceptible to the formation and propagation of biofilm. Covered in other chapters of this
book, biofilm is relevant to wound healing due to the several inhibitory effects on healing processes
(Fig. 5-12).
Table 5-2 Comparison of Acute and Chronic Wounds
Chronic Versus Acute wounds

Wounds heal within a reasonable time of 4 to 6 week. Those that do not are termed chronic. As shown
in Table 5-2, a variety of factors and disease conditions impair wound healing and result in chronic
nonhealing wounds. Reasons that lead to chronicity instead of normal healing, are complex – but the
salient points are defined in Figure 5-13. The most important concept is a persistent proinflammatory
condition that paradoxically leads to increased degradation of matrix proteins, and an unstable wound
that is recalcitrant to healing.
Comorbid Conditions that Influence Wound Healing

3 Wound healing is a complex biological process that consists of hemostasis, inflammation,
proliferation, and remodeling. Large numbers of cell types – including neutrophils, macrophages,
lymphocytes, keratinocytes, fibroblasts, and endothelial cells – are involved in this process. Multiple
factors can cause impaired wound healing by affecting one or more phases of the process and are
categorized into local and systemic factors (Table 5-3). The influences of these factors are not mutually
129
exclusive.13 Single or multiple factors may play a role in any one or more individual phases,
contributing to the overall outcome of the healing process (Fig. 5-14).
Advanced Age and Gender

The elderly population (people over 60 years of age) is growing faster than any other age group (World
Health Organization [WHO, www.who.int/topics/ageing]), and increased age is a major risk factor for
impaired wound healing. Many clinical and animal studies at the cellular and molecular level have
examined age-related changes and delays in wound healing. It is commonly recognized that, in healthy
older adults, the effect of aging causes a temporal delay in wound healing, but not an actual impairment
in terms of the quality of healing.13 Delayed wound healing in the aged is associated with an altered
inflammatory response, such as delayed T-cell infiltration into the wound area with alterations in
chemokine production and reduced macrophage phagocytic capacity.14 Overall, there are global
differences in wound healing between young and aged individuals. A review of the age-related changes
in healing capacity demonstrates that every phase of healing undergoes characteristic age-related
changes, including enhanced platelet aggregation, increased secretion of inflammatory mediators,
delayed infiltration of macrophages and lymphocytes, impaired macrophage function, decreased
secretion of growth factors, delayed re-epithelialization, delayed angiogenesis and collagen deposition,
reduced collagen turnover and remodeling, and decreased wound strength.
Table 5-3 Factors that Affect Wound Healing
Figure 5-13. Comparison of cellular mechanisms in normal and poor wound healing.
Sex hormones play a role in age-related wound healing deficits. Compared with aged females, aged
males have been shown to have delayed healing of acute wounds. A partial explanation for this is that
the female estrogens (estrone and 17β-estradiol), male androgens (testosterone and 5α-
dihydrotestosterone, DHT), and their steroid precursor dehydroepiandrosterone (DHEA) appear to have
significant effects on the wound healing process.15 It was recently found that the differences in gene
expression between elderly male and young human wounds are almost exclusively estrogen regulated.16
Estrogen affects wound healing by regulating a variety of genes associated with regeneration, matrix
production, protease inhibition, epidermal function, and genes primarily associated with
inflammation.17 Studies indicate that estrogen can improve the age-related impairment in healing in
both men and women, while androgens regulate cutaneous wound healing negatively.
130
Figure 5-14. Mechanisms that elicit the effects of comorbid conditions on wound healing.
Several treatments to reduce the age-related impairment of healing have been studied. Interestingly,
exercise has been reported to improve cutaneous wound healing in older adults as well as aged mice,
and the improvement is associated with decreased levels of proinflammatory cytokines in the wound
tissue. Improved healing response may also be due to an exercise-induced anti-inflammatory response in
the wound.18
Nutrition
Malnutrition or specific nutrient deficiencies can have a profound impact on wound healing after trauma
and surgery. Patients with chronic or nonhealing wounds and experiencing nutrition deficiency often
require special nutrients. Energy, carbohydrates, proteins, fat, vitamins, and mineral metabolism all can
affect the healing process.19
Carbohydrates, Proteins, and Amino Acids. Together with fats, carbohydrates are the primary source
of energy in the wound healing process. Glucose is the major source of fuel used to create the cellular
ATP that provides energy for angiogenesis and deposition of the new tissues.20 The use of glucose as a
source for ATP synthesis is essential in preventing the depletion of other amino acid and protein
substrates.
Protein is one of the most important nutrient factors affecting wound healing. A deficiency of protein
can impair capillary formation, fibroblast proliferation, proteoglycan synthesis, collagen synthesis, and
wound remodeling. A deficiency of protein also affects the immune system, with resultant decreased
leukocyte phagocytosis and increased susceptibility to infection. Collagen is the major protein
component of connective tissue and is composed primarily of glycine, proline, and hydroxyproline.
Collagen synthesis requires hydroxylation of lysine and proline, and cofactors such as ferrous iron and
vitamin C. Impaired wound healing results from deficiencies in any of these cofactors.21
Arginine is a semiessential amino acid that is required during periods of maximal growth, severe
stress, and injury. Arginine has many effects in the body, including modulation of immune function,
wound healing, hormone secretion, vascular tone, and endothelial function. Arginine is also a precursor
to proline, and, as such, sufficient arginine levels are needed to support collagen deposition,
angiogenesis, and wound contraction. Arginine improves immune function, and stimulates wound
healing in healthy and ill individuals.22 Under psychological stress situations, the metabolic demand for
arginine increases, and its supplementation has been shown to be an effective adjuvant therapy in
wound healing.
Glutamine is the most abundant amino acid in plasma and is a major source of metabolic energy for
rapidly proliferating cells such as fibroblasts, lymphocytes, epithelial cells, and macrophages. Glutamine
improves nitrogen balance and diminishes immunosuppression and plays a crucial role in stimulating the
early inflammatory phase of wound healing. Major surgery, trauma, and sepsis require supplementation
of glutamine. Oral glutamine supplementation has been shown to improve wound breaking strength and
131
to increase levels of mature collagen.23
Fatty Acids
Lipids are used as nutritional support for surgical or critically ill patients to help meet energy demands
and provide essential building blocks for wound healing and tissue repair. Polyunsaturated fatty acids
(PUFAs), consist mainly of two families, n-6 (omega-6, found in soybean oil) and n-3 (omega-3, found
in fish oil). Although fish oil has been widely touted, effects of omega-3 fatty acids on wound healing
are not conclusive. They have been reported to affect proinflammatory cytokine production, cell
metabolism, gene expression, and angiogenesis in wound sites.24
Vitamins, Micronutrients, and Trace Elements

Vitamins C (L-ascorbic acid), A (retinol), and E (tocopherol) show potent antioxidant and anti-
inflammatory effects. Vitamin C has many roles in wound healing, and a deficiency in this vitamin has
multiple effects on tissue repair. Vitamin C deficiencies result in impaired healing, and have been linked
to decreased collagen synthesis and fibroblast proliferation, decreased angiogenesis, and increased
capillary fragility. Also, vitamin C deficiency leads to an impaired immune response and increased
susceptibility to wound infection. Similarly, vitamin A deficiency leads to impaired wound healing. The
biological properties of vitamin A include antioxidant activity, increased fibroblast proliferation,
modulation of cellular differentiation and proliferation, increased collagen and hyaluronate synthesis,
and decreased MMP-mediated ECM degradation.25
Vitamin E, an antioxidant, maintains and stabilizes cellular membrane integrity by providing
protection against destruction by oxidation. Vitamin E also has anti-inflammatory properties and has
been suggested to have a role in decreasing excess scar formation in chronic wounds. Animal
experiments have indicated that vitamin E supplementation is beneficial to wound healing, and topical
vitamin E has been widely promoted as an antiscarring agent. However, clinical studies have not yet
proved a role for topical vitamin E treatment in improving healing outcomes.26
Several micronutrients have been shown to be important for optimal repair. Magnesium functions as a
cofactor for many enzymes involved in protein and collagen synthesis, while copper is a required
cofactor for cytochrome oxidase, for cytosolic antioxidant superoxide dismutase, and for the optimal
cross-linking of collagen. Zinc is a cofactor for both RNA and DNA polymerase, and a zinc deficiency
causes a significant impairment in wound healing. Iron is required for the hydroxylation of proline and
lysine, and, as a result, severe iron deficiency can result in impaired collagen production.27 As indicated
above, the nutritional needs of the wound are complex, suggesting that composite nutrition support
would benefit both acute and chronic wound healing. A recent clinical research study examined the
effects of a high-energy, protein-enriched supplement containing arginine, vitamin C, vitamin E, and
zinc on chronic pressure ulcers and indicated that this high-energy and nutrition-enriched supplement
improved overall healing of the pressure ulcer.28 In summary, proteins, carbohydrates, arginine,
glutamine, PUFAs, vitamin A, vitamin C, vitamin E, magnesium, copper, zinc, and iron play a significant
role in wound healing, and their deficiencies affect wound healing. Additional studies will be needed to
fully understand how nutrition affects the healing response.
Obesity
The prevalence of obesity continues to increase among adults, children, and adolescents in the United
States, with more than 30% of adults and 15% of children and adolescents classified as obese in a recent
survey.29 Obesity is well known to increase the risk of many diseases and health conditions, which
include coronary heart disease, type 2 diabetes, cancer, hypertension, dyslipidemia, stroke, sleep apnea,
respiratory problems, and impaired wound healing. Obese individuals frequently face wound
complications, including skin wound infection, dehiscence, hematoma and seroma formation, pressure
ulcers, and venous ulcers.30 An increased frequency of wound complications has been reported for obese
individuals undergoing both bariatric and nonbariatric operations.31 In particular, a higher rate of
surgical site infection occurs in obese patients. Many of these complications may be the result of a
relative hypoperfusion and ischemia that occurs in subcutaneous adipose tissue. This situation may be
caused by a decreased delivery of antibiotics as well. In surgical wounds, the increased tension on the
wound edges that is frequently seen in obese patients also contributes to wound dehiscence. Wound
tension increases tissue pressure, reducing microperfusion and the availability of oxygen to the
wound.32
132
Figure 5-15. Cellular mechanisms that impair healing of the diabetic wound.
The increase in pressure ulcers or pressure-related injuries in obese individuals is also influenced by
hypovascularity, since poor perfusion makes tissue more susceptible to this type of injury. In addition,
the difficulty or inability of obese individuals to reposition themselves further increases the risk of
pressure-related injuries. Moreover, skin folds harbor microorganisms that thrive in moist areas and
contribute to infection and tissue breakdown. The friction caused by skin-on-skin contact invites
ulceration. Together, these factors predispose obese individuals to the development of impaired wound
healing.
In addition to local conditions, systemic factors also play an important role in impaired wound
healing and wound complications in obese patients. Obesity can be connected to stress, anxiety, and
depression, all situations that can cause an impaired immune response.
The function of adipose tissue used to be considered as primarily caloric storage. However, more
recent findings have documented that adipose tissue secretes a large variety of bioactive substances that
are collectively named adipokines. Both adipocytes as well as resident macrophages in adipose tissue
are known to produce bioactive molecules including cytokines, chemokines, and hormone-like factors
such as leptin, adiponectin, and resistin. Adipokines have a profound impact on the immune and
inflammatory response.33 The negative influence of adipokines on the systemic immune response seems
likely to influence the healing process, although direct proof for this is lacking. Impaired peripheral
blood mononuclear cell function, decreased lymphocyte proliferation, and altered peripheral cytokine
levels have been reported in obesity. Importantly, many of the obesity-related changes in peripheral
immune function are improved by weight loss.34
Diabetes Mellitus
Diabetes affects hundreds of millions of people worldwide. Diabetic individuals exhibit a documented
impairment in the healing of acute wounds. Moreover, this population is prone to develop chronic
nonhealing diabetic foot ulcers (DFUs), which are estimated to occur in 15% of all persons with
diabetes. DFUs are a serious complication of diabetes, and precede 84% of all diabetes-related lower leg
amputations.35 The impaired healing of both DFUs and acute cutaneous wounds in persons with diabetes
involves multiple complex pathophysiological mechanisms (Fig. 5-15). DFUs, like venous stasis disease
and pressure-related chronic nonhealing wounds, are always accompanied by hypoxia.36 A situation of
prolonged hypoxia, which may be derived from both insufficient perfusion and insufficient
angiogenesis, is detrimental for wound healing. Hypoxia can amplify the early inflammatory response,
thereby prolonging injury by increasing the levels of oxygen radicals.37 Hyperglycemia can also add to
the oxidative stress when the production of reactive oxygen species exceeds the antioxidant capacity.38
The formation of advanced glycation end products under hyperglycemia and the interaction with their
receptors are associated with impaired wound healing in diabetic mice as well.39 High levels of
metalloproteases (MMP) are a feature of DFUs, and the MMP levels in chronic wound fluid are almost
60 times higher than those in acute wounds. This increased protease activity supports tissue destruction
and inhibits normal repair processes.40
Several dysregulated cellular functions are involved in diabetic wounds, such as defective T-cell
immunity, defects in leukocyte chemotaxis, phagocytosis, and bactericidal capacity, and dysfunction of
fibroblasts and epidermal cells. These defects are responsible for inadequate bacterial clearance and
delayed or impaired repair in individuals with diabetes.41
As mentioned above, hypoxia contributes to the compromised healing of DFUs, and diabetic wounds
exhibit inadequate angiogenesis. Several studies that have investigated the mechanisms behind the
decreased restoration of vasculature in diabetic wounds have implied that endothelial progenitor cell
133
mobilization and homing are impaired, and that the level of VEGF, the primary proangiogenic factor in
wounds, is decreased in the diabetic state.42 Stem-cell–based therapies aimed at inducing endothelial
progenitor cells or bone marrow–derived multipotent stem cells have shown a promising outcome in
diabetic nonhealing wounds, both in animals and in clinical trials.43 In animal studies, therapeutic
restoration of VEGF has been shown to improve repair outcomes significantly.44
The neuropathy that occurs in diabetic individuals probably also contributes to impaired wound
healing. Neuropeptides such as nerve growth factor, substance P, and calcitonin gene-related peptide are
relevant to wound healing, because they promote cell chemotaxis, induce growth factor production, and
stimulate the proliferation of cells. A decrease in neuropeptides has been associated with DFU
formation. In addition, sensory nerves play a role in modulating immune defense mechanisms, with
denervated skin exhibiting reduced leukocyte infiltration.45
In summary, the impaired healing that occurs in individuals with diabetes involves hypoxia,
dysfunction in fibroblasts and epidermal cells, impaired angiogenesis and neovascularization, high levels
of MMP, damage from reactive oxygen species and advanced glycation end products, decreased host
immune resistance, and neuropathy.
Medications and Dietary Supplements

Glucocorticoid Steroids. Systemic glucocorticoids, which are frequently used as anti-inflammatory
agents, are well known to inhibit wound repair via global anti-inflammatory effects and suppression of
cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic steroids
cause wounds to heal with incomplete granulation tissue and reduced wound contraction.46
Glucocorticoids also inhibit production of HIF-1, a key transcriptional factor in healing wounds.47
Beyond effects on repair itself, systemic corticosteroids may increase the risk of wound infection. While
systemic corticosteroids inhibit wound repair, topical application produces quite different effects.
Topical low-dosage corticosteroid treatment of chronic wounds has been found to accelerate wound
healing, reduce pain and exudate, and suppress hypergranulation tissue formation in 79% of cases.
While these positive effects are striking, careful monitoring is necessary to avoid a potential increased
risk of infection with prolonged use.48
Nonsteroidal Anti-Inflammatory Drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as

ibuprofen are widely used for the treatment of inflammation and rheumatoid arthritis and for pain
management. Low-dosage aspirin, due to its antiplatelet function, is commonly used as a preventive
therapeutic for cardiovascular disease, but not as an anti-inflammatory drug.49 There are few data to
suggest that short-term NSAIDs have a negative impact on healing. However, the question of whether
long-term NSAIDs interfere with wound healing remains open. In animal models, systemic use of
ibuprofen has demonstrated an antiproliferative effect on wound healing, resulting in decreased
numbers of fibroblasts, weakened breaking strength, reduced wound contraction, delayed
epithelialization,50 and impaired angiogenesis. The effects of low-dose aspirin on healing are not
completely clear. Clinical recommendations suggest that, to avoid antiplatelet effects, individuals should
discontinue NSAIDs for a time period equal to 4 to 5 times the half-life of drugs before surgery. Thus,
the majority of surgical patients do not have significant NSAID activity at the time of wound repair. The
exception may be those cardiac patients who must be maintained on low-dose aspirin due to severe risk
of cardiovascular events. In terms of the topical application of NSAIDs on the surfaces of chronic
wounds, the local use of ibuprofen foam provides moist wound healing, reduces persistent and
temporary wound pain, and benefits chronic venous leg ulcer healing.
Peripheral Vascular Disease

Total disease prevalence based on objective testing has been evaluated in several epidemiologic studies
and is in the range of 3% to 10%, increasing to 15% to 20% in persons over 70 years.51 Peripheral
vascular disease (PVD) is an independent risk factor for subsequent ulceration and limb loss in diabetes.
It is present in 50% of patients with diabetic foot ulcer (DFU), a proportion that may be increasing.
Those with DFU and peripheral arterial disease (PAD) are less likely to heal and more likely to require
amputation compared to patients without PAD. It is therefore essential that PVD is identified in all
patients with diabetes.
Patients with PVD commonly suffer from chronic toe and foot sores, cramping leg muscles when
walking or numbness, weakness or heaviness in the muscles. Other PVD symptoms include:
Numbness in the extremities
Weakness and atrophy of calf muscles
134
A feeling of coldness in legs or feet
Changes in the color of the feet: feet will turn pale when elevated and turn dusky red when in the
dependent position
Hair loss over the dorsum of the feet, thickening toenails
Painful ulcers and/or gangrene in tissue, typically in the toes
Pathophysiology: The etiology of ulceration in diabetic patients with PVD is multifactorial distal
polyneuropathy (motor, sensory, and autonomic), abnormal foot anatomy, functional changes in the
microcirculation in the presence of PVD, lead to abnormal loading or trauma of the poorly perfused
painless neuropathic foot. Infection in the foot exponentially increases the demand for oxygen, which in
PVD is unmet. Healing is impaired also due to impaired humoral immunity and abnormal inflammatory
responses.52
Traditional wound care algorithms include aggressive detection of PAD and treatment with
revascularization for all patients with PVD and lower extremity wounds – in order to prevent limb
amputation. The Transatlantic Inter-Society Consensus (TASCII) criteria for critical limb ischemia is a
commonly used method for revascularization. When the TcPO2 is >30 mm Hg, the ankle-brachial index
(ABI) and the TASC II definition of critical limb ischemia predict wound healing and should be key
factors in considering conservative therapy. New strategies are being developed to diagnose PVD in
patients with diabetes, referring those presenting with a new foot ulcer to a multidisciplinary team, so
that appropriate interventions help preserve the limb.
Stress
Stress has a great impact on human health and social behavior. Many diseases – such as cardiovascular
disease, cancer, compromised wound healing, and diabetes – are associated with stress. Numerous
studies have confirmed that stress-induced disruption of neuroendocrine immune equilibrium is
consequential to health.53 The pathophysiology of stress results in the deregulation of the immune
system, mediated primarily through the hypothalamic–pituitary–adrenal and sympathetic–adrenal
medullary axes or sympathetic nervous system.54
Studies in both humans and animals have demonstrated that psychological stress causes a substantial
delay in wound healing.55 Caregivers of persons with Alzheimer’s and students undergoing academic
stress during examinations demonstrated delayed wound healing.56 The hypothalamic – pituitary–
adrenal and the sympathetic–adrenal medullary axes regulate the release of pituitary and adrenal
hormones. These hormones include the adrenocorticotrophic hormones, cortisol and prolactin, and
catecholamines (epinephrine and norepinephrine). Stress upregulates glucocorticoids and reduces the
levels of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α at the wound site. Stress also reduces
the expression of IL-1α and IL-8 at wound sites – both chemoattractants that are necessary for the initial
inflammatory phase of wound healing.57 Furthermore, glucocorticoids influence immune cells by
suppressing differentiation and proliferation, regulating gene transcription, and reducing expression of
cell adhesion molecules that are involved in immune cell trafficking.58 Cortisol functions as an anti-
inflammatory agent and modulates the Th1-mediated immune responses that are essential for the initial
phase of healing. Thus, psychological stress impairs normal cell-mediated immunity at the wound site,
causing a significant delay in the healing process.59
Stressors can lead to negative emotional states, such as anxiety and depression, which may in turn
have an impact on physiologic processes and/or behavioral patterns that influence health outcomes. In
addition to the direct influences of anxiety and depression on endocrine and immune function, stressed
individuals are more likely to have unhealthy habits, which include poor sleep patterns, inadequate
nutrition, less exercise, and a greater propensity for abuse of alcohol, cigarettes, and other drugs. All of
these factors may come into play in negatively modulating the healing response.
Cigarette Smoking
It is well known that smoking increases the risk of heart and vascular disease, stroke, chronic lung
disease, and many kinds of cancers. Similarly, the negative effects of smoking on wound healing
outcomes have been known for a long time.60 Postoperatively, patients who smoke show a delay in
wound healing and an increase in a variety of complications such as infection, wound rupture,
anastomotic leakage, wound and flap necrosis, epidermolysis, and a decrease in the tensile strength of
wounds.61 In the realm of oral surgery, impaired healing in smokers has been noticed both in routine
oral surgery and in the placement of dental implants.62 Cosmetic outcomes also appear to be worse in
smokers, and plastic and reconstructive surgeons are often reluctant to perform cosmetic surgeries on
135
individuals who refuse to quit smoking.63 Approximately 4000 substances in tobacco smoke have been
identified, and some have been shown to have a negative impact on healing.64 Most studies have
focused on the effects of nicotine, carbon monoxide, and hydrogen cyanide from smoke. Nicotine
interferes with oxygen supply by inducing tissue ischemia, since nicotine can cause decreased tissue
blood flow via vasoconstrictive effects.65 Nicotine stimulates sympathetic nervous activity, resulting in
the release of epinephrine, which causes peripheral vasoconstriction and decreased tissue blood
perfusion. Nicotine also increases blood viscosity caused by decreasing fibrinolytic activity and
augmentation of platelet adhesiveness. In addition to the effects of nicotine, carbon monoxide in
cigarette smoke also causes tissue hypoxia. Carbon monoxide binds to hemoglobin with an affinity 200
times greater than that of oxygen, resulting in a decreased fraction of oxygenated hemoglobin in the
bloodstream. Hydrogen cyanide, another well-studied component of cigarette smoke, impairs cellular
oxygen metabolism, leading to compromised oxygen consumption in the tissues. Beyond these direct
tissue effects, smoking increases the individual’s risk for atherosclerosis and chronic obstructive
pulmonary disease, two conditions that might also lower tissue oxygen tension.66
Several cell types and processes that are important to healing have been shown to be adversely
affected by tobacco smoke. In the inflammatory phase, smoking causes impaired white blood cell
migration, resulting in lower numbers of monocytes and macrophages in the wound site, and reduces
neutrophil bactericidal activity. Lymphocyte function, cytotoxicity of natural killer cells, and production
of IL-1 are all depressed, and macrophage sensing of gram-negative bacteria is inhibited.67 These effects
result in poor wound healing and an increased risk of opportunistic wound infection.
During the proliferative phase of wound healing, exposure to smoke yields decreased fibroblast
migration and proliferation, reduced wound contraction, hindered epithelial regeneration, decreased
ECM production, and upset in the balance of proteases.68
Pharmacologically, the influence of smoking on wound healing is complicated, and neither nicotine
alone nor any other single component can explain all of the effects of smoking on wounds. What is
certain is that smoking cessation leads to improved repair and reduces wound infection.69 For surgery
patients who find it difficult to forego smoking, the use of a transdermal patch during the preoperative
period might be beneficial. A study has shown that the use of a transdermal nicotine patch as a nicotine
replacement for smoking cessation therapy can increase type I collagen synthesis in wounds.70 Despite
the overall negative effects of smoking, some recent studies have suggested that low doses of nicotine
enhance angiogenesis and actually improve healing.71
Alcohol and Substance Abuse

Clinical evidence and animal experiments have shown that exposure to alcohol impairs wound healing
and increases the incidence of infection.72 The effect of alcohol on repair is quite clinically relevant,
since over half of all emergency room trauma cases involve either acute or chronic alcohol exposure.
Alcohol exposure diminishes host resistance, and ethanol intoxication at the time of injury is a risk
factor for increased susceptibility to infection in the wound.73 Studies have demonstrated profound
effects of alcohol on host-defense mechanisms, although the precise effects are dependent upon the
pattern of alcohol exposure (i.e., chronic vs. acute alcohol exposure, amount consumed, duration of
consumption, time from alcohol exposure, and alcohol withdrawal). A recent review on alcohol-induced
alterations on host defense after traumatic injury suggested that, in general, short-term acute alcohol
exposure results in suppressed pro-inflammatory cytokine release in response to an inflammatory
challenge. The higher rate of postinjury infection correlates with decreased neutrophil recruitment and
phagocytic function in acute alcohol exposure.74
Beyond the increased incidence of infection, exposure to ethanol also seems to influence the
proliferative phase of healing. In murine models, exposure to a single dose of alcohol that caused a
blood alcohol level of 100 mg/dL (just above the legal limit in most states in the United States)
perturbed re-epithelialization, angiogenesis, collagen production, and wound closure.75 The most
significant impairment seems to be in wound angiogenesis, which is reduced by up to 61% following a
single ethanol exposure. This decrease in angiogenic capacity involves both decreased expression of
VEGF receptors and reduced nuclear expression of HIF-1alpha in endothelial cells.76 The ethanol-
mediated decrease in wound vascularity causes increased wound hypoxia and oxidative stress.77
Connective tissue restoration is also influenced by acute ethanol exposure, and results in decreased
collagen production and alterations in the protease balance at the wound site. In summary, acute
ethanol exposure can lead to impaired wound healing by impairing the early inflammatory response,
inhibiting wound closure, angiogenesis, and collagen production, and altering the protease balance at
136
the wound site.
As mentioned previously, the host response to chronic alcohol exposure appears to be different from
that of acute alcohol exposure. Analysis of clinical data indicates that chronic alcohol exposure causes
impaired wound healing and enhanced host susceptibility to infections, but the detailed mechanisms that
explain this effect need more investigation.
Cancer, Chemotherapy, and Radiation

Chemotherapeutic Drugs. Most chemotherapeutic drugs are designed to inhibit cellular metabolism,
rapid cell division, and angiogenesis and thus inhibit many of the pathways that are critical to
appropriate wound repair. These medications inhibit DNA, RNA, or protein synthesis, resulting in
decreased fibroplasia and neovascularization of wounds.78 Chemotherapeutic drugs delay cell migration
into the wound, decrease early wound matrix formation, lower collagen production, impair proliferation
of fibroblasts, and inhibit contraction of wounds.79 In addition, these agents weaken the immune
functions of the patients, and thereby impede the inflammatory phase of healing and increase the risk of
wound infection. Chemotherapy induces neutropenia, anemia, and thrombocytopenia, thus leaving
wounds vulnerable to infection, causing less oxygen delivery to the wound, and also making patients
vulnerable to excessive bleeding at the wound site.
Impaired wound healing due to chemotherapeutic drugs such as Adriamycin is most common when
the drugs are administered preoperatively or within 3 weeks postoperatively.80 Additionally, low
postoperative albumin levels, low postoperative hemoglobin, advanced stage of disease, and
electrosurgery use have all been reported as risk factors for the development of wound complications.81
A newer generation of tumor chemotherapeutics include angiogenesis inhibitors, such as
bevacizumab, which is an antibody fragment that neutralizes VEGF. These therapies work in conjunction
with traditional chemotherapeutics to limit the blood supply to tumors, reducing their ability to grow.
Wound healing complications, including an increase in wound dehiscence, have been described in
patients on angiogenesis inhibitors.82 A caveat is that most patients on angiogenesis inhibitors are also
on traditional chemotherapeutics, making it difficult to sort out whether angiogenesis inhibitors alone
would perturb repair.83 Nevertheless, current recommendations include discontinuation of angiogenesis
inhibitors well in advance of any surgical procedures.
Radiation
Radiation is one of the most commonly used therapies for the treatment of multiple types of human
cancer. It results in a wide range of acute and chronic toxicities, with poor health outcomes, and often
become dose-limiting for patients and impairing their quality of life (QoL) and recovery in both the
short and the long term.
4 Injury resulting from radiation and chemotherapy is initiated through two major paths: radiolytic
hydrolysis and stimulation of the innate immune response. Of the two, oxidative stress is the best
studied with respect to cancer treatment-associated tissue injury. After an initial exposure to radiation,
there is immediate damage to the keratinocyte cells of the skin, which is accompanied by a
simultaneous increase in free radicals, DNA damage, and inflammation. Radiation- or chemotherapy-
induced oxidative stress leads to the production of oxygen free radicals; specifically the reactive oxygen
species superoxides, hydrogen peroxides, and hydroxyl radicals that cause oxidative damage to the
tissue. Inflammatory cells are recruited to the injured area, a process orchestrated by vasodilation and
vascular permeability. On the cellular level, fibrosis involves the coordination of a variety of cell types
largely mediated through the fibroblast. The infiltrating immune cells secrete cytokines that drive the
differentiation of fibroblasts and other self-renewing cells into myofibroblasts which deposit collagens
and other ECM proteins at and around the site of tissue damage.84
References
1. Staylor A. Wound care devices: growth amid uncertainty. Med Tech Insight 2009;11(1):32–47.
2. Gosain A, DiPietro LA. Aging and wound healing. World J Surg 2004;28(3): 321–326.
3. Niinikoski J, Bakker D, Cronjé F, et al. ECHM-ETRS joint conference on oxygen and tissue repair,
Ravenna, Italy, October 27–28, 2006: recommendations by the international jury. Int J Low Extrem
Wounds 2007;6(3):139–142.
4. Nurden AT, Nurden P, Sanchez M, et al. Platelets and wound healing. Front Biosci 2008;13:3532–
137
3548.
5. Prockop DJ, Kivirikko KI. Collagens: molecular biology, diseases, and potentials for therapy. Annu
Rev Biochem 1995;64:403–434.
6. Clark RA. Fibrin and wound healing. Ann N Y Acad Sci 2001;936:355–367.
7. Peterkofsky B. Ascorbate requirement for hydroxylation and secretion of procollagen: relationship
to inhibition of collagen synthesis in scurvy. Am J Clin Nutr 1991;54:1135S–1140S.
8. Blumenkrantz N, Assad R, Peterkofsky B. Characterization of collagen hydroxylysyl
glycosyltransferases as mainly intramembranous microsomal enzymes. J Biol Chem 1984;259:854–
859.
9. Prockop DJ, Sieron AL, Li SW. Procollagen N-proteinase and procollagen C-proteinase. Two unusual
metalloproteinases that are essential for procollagen processing probably have important roles in
development and cell signaling. Matrix Biol 1998;16:399–408.
10. Zanaboni G, Rossi A, Onana AM, et al. Stability and networks of hydrogen bonds of the collagen
triple helical structure: influence of pH and chaotropic nature of three anions. Matrix Biol
2000;19:511–520.
11. Hornstra IK, Birge S, Starcher B, et al. Lysyl oxidase is required for vascular and diaphragmatic
development in mice. J Biol Chem 2003;278:14387–14393.
12. Parks WC. Matrix metalloproteinases in repair. Wound Repair Regen 1999; 7:423–432.
13. Keylock KT, Vieira VJ, Wallig MA, et al. Exercise accelerates cutaneous wound healing and
decreases wound inflammation in aged mice. Am J Physiol Regul Integr Comp Physiol
2008;294(1):R179–R184.
14. Swift ME, Burns AL, Gray KL, et al. Age-related alterations in the inflammatory response to dermal
injury. J Invest Dermatol 2001;117(5):1027–1035.
15. Gilliver SC, Ashworth JJ, Ashcroft GS. The hormonal regulation of cutaneous wound healing. Clin
Dermatol 2007;25(1):56–62.
16. Hardman MJ, Ashcroft GS. Estrogen, not intrinsic aging, is the major regulator of delayed human
wound healing in the elderly. Genome Biol 2008;9(5):R80.
17. Hardman MJ, Emmerson E, Campbell L, et al. Selective estrogen receptor modulators accelerate
cutaneous wound healing in ovariectomized female mice. Endocrinology 2008;149(2):551–557.
18. Emery CF, Kiecolt-Glaser JK, Glaser R, et al. Exercise accelerates wound healing among healthy
older adults: a preliminary investigation. J Gerontol A Biol Sci Med Sci 2005;60(11):1432–1436.
19. Arnold M, Barbul A. Nutrition and wound healing. Plast Reconstr Surg 2006; 117(7 Suppl):42S–58S.
20. Shepherd AA. Nutrition for optimum wound healing. Nurs Stand 2003; 18(6):55–58.
21. Campos AC, Groth AK, Branco AB. Assessment and nutritional aspects of wound healing. Curr Opin
Clin Nutr Metab Care 2008;11(3):281–288.
22. Tong BC, Barbul A. Cellular and physiological effects of arginine. Mini Rev Med Chem
2004;4(8):823–832.
23. da Costa MA, Campos AC, Coelho JC, et al. Oral glutamine and the healing of colonic anastomoses
in rats. JPEN J Parenter Enteral Nutr 2003;27(3):182–185; discussion 185–186.
24. McDaniel JC, Belury M, Ahijevych K, et al. Omega-3 fatty acids effect on wound healing. Wound
Repair Regen 2008;16(3):337–345.
25. Burgess C. Topical vitamins. J Drugs Dermatol 2008;7(7 Suppl):s2–s6.
26. Khoosal D, Goldman RD. Vitamin E for treating children’s scars. Does it help reduce scarring? Can
Fam Physician 2006;52:855–856.
27. Arnold M, Barbul A. Nutrition and wound healing. Plast Reconstr Surg 2006;117(7Suppl):42S–58S.
28. Heyman H, Van De Looverbosch DE, Meijer EP, et al. Benefits of an oral nutritional supplement on
pressure ulcer healing in long-term care residents. J Wound Care 2008;17(11):476–478, 480.
29. Centers for Disease Control and Prevention, CDC. Available from:
http://www.cdc.gov/obesity/data/index.html. Accessed April 21, 2016.
30. Wilson JA, Clark JJ. Obesity: impediment to postsurgical wound healing. Adv Skin Wound Care
2004;17(8):426–435.
31. Momeni M, Hafezi F, Rahbar H, et al. Effects of silicone gel on burn scars. Burns 2009;35(1):70–74.
32. Anaya DA, Dellinger EP. The obese surgical patient: a susceptible host for infection. Surg Infect
138
(Larchmt) 2006;7(5):473–480.
33. Calabro P, Yeh ET. Obesity, inflammation, and vascular disease: the role of the adipose tissue as an
endocrine organ. Subcell Biochem 2007;42:63–91.
34. de Mello VD, Kolehmainen M, Schwab U. Effect of weight loss on cytokine messenger RNA
expression in peripheral blood mononuclear cells of obese subjects with the metabolic syndrome.
Metabolism 2008;57(2):192–199.
35. Brem H, Tomic-Canic M. Cellular and molecular basis of wound healing in diabetes. J Clin Invest
2007;117(5):1219–1222.
36. Tandara AA, Mustoe TA. Oxygen in wound healing–more than a nutrient. World J Surg
2004;28(3):294–300.
37. Woo K, Ayello EA, Sibbald RG. The edge effect: current therapeutic options to advance the wound
edge. Adv Skin Wound Care 2007;20(2):99–117; quiz 118–119.
38. Vincent MA, Clerk LH, Lindner JR, et al. Microvascular recruitment is an early insulin effect that
regulates skeletal muscle glucose uptake in vivo. Diabetes 2004;53(6):1418–1423.
39. Prompers L, Schaper N, Apelqvist J, et al. Prediction of outcome in individuals with diabetic foot
ulcers: focus on the differences between individuals with and without peripheral arterial disease.
The EURODIALE Study. Diabetologia 2008;51(5):747–755.
40. Woo K, Sibbald G, Fogh K, et al. Assessment and management of persistent (chronic) and total
wound pain. Int Wound J 2008;5(2):205–215.
41. Loots MA, Lamme EN, Zeegelaar J, et al. Differences in cellular infiltrate and extracellular matrix
of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 1998;111(5):850–857.
42. Quattrini C, Jeziorska M, Boulton AJ, et al. Reduced vascular endothelial growth factor expression
and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care 2008;31(1):140–
145.
43. Liu ZJ, Velazquez OC. Hyperoxia, endothelial progenitor cell mobilization, and diabetic wound
healing. Antioxid Redox Signal 2008;10(11):1869–1882.
44. Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates
diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone
marrow-derived cells. Am J Pathol 2004;164(6):1935–1947.
45. Galkowska H, Wojewodzka U, Olszewski WL. Chemokines, cytokines, and growth factors in
keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound
Repair Regen 2006;14(5):558–565.
46. Franz MG, Steed DL, Robson MC. Optimizing healing of the acute wound by minimizing
complications. Curr Probl Surg 2007;44(11):691–763.
47. Wagner AE, Huck G, Stiehl DP, et al. Dexamethasone impairs hypoxia-inducible factor-1 function.
Biochem Biophys Res Commun 2008;372(2):336–340.
48. Hofman D, Moore K, Cooper R, et al. Use of topical corticosteroids on chronic leg ulcers. J Wound
Care 2007;16(5):227–230.
49. Biesenbach G, Biesenbach P, Bodlaj G, et al. Impact of smoking on progression of vascular diseases
and patient survival in type-1 diabetic patients after simultaneous kidney-pancreas transplantation
in a single centre. Transpl Int 2008;21(4):357–363.
50. Krischak GD, Augat P, Claes L, et al. The effects of non-steroidal anti-inflammatory drug
application on incisional wound healing in rats. J Wound Care 2007;16(2):76–78.
51. Selvin E, Erlinger TP. Prevalence of and risk factors for peripheral arterial disease in the United
States: results from the National Health and Nutrition Examination Survey, 1999–2000. Circulation
2004;110(6):738–743.
52. Martin JM, Zenilman JM, Lazarus GS. Molecular microbiology: new dimensions for cutaneous
biology and wound healing. J Invest Dermatol 2010; 130:38–48.
53. Kiecolt-Glaser JK, Page GG, Marucha PT, et al. Psychological influences on surgical recovery.
Perspectives from psychoneuroimmunology. Am Psychol 1998;53(11):1209–1218.
54. Boyapati L, Wang HL. The role of stress in periodontal disease and wound healing. Periodontol 2000
2007;44:195–210.
55. Holmes CJ, Plichta JK, Gamelli RL, et al. Dynamic Role of Host Stress Responses in Modulating the
Cutaneous Microbiome: Implications for Wound Healing and Infection. Adv Wound Care (New
139
Rochelle) 2015; 4(1):24–37.
56. Glaser R, Kiecolt-Glaser JK. Stress-induced immune dysfunction: implications for health. Nat Rev
Immunol 2005;5(3):243–251.
57. Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing,
infectious disease and cancer. J Neuroimmune Pharmacol 2006;1(4):421–427.
58. Peyroux J, Sternberg M. Advanced glycation endproducts (AGEs): pharmacological inhibition in
diabetes. Pathol Biol (Paris) 2006;54(7):405–419.
59. Godbout JP, Glaser R. Stress-induced immune dysregulation: implications for wound healing,
infectious disease and cancer. J Neuroimmune Pharmacol 2006;1(4):421–427.
60. Siana JE, Rex S, Gottrup F. The effect of cigarette smoking on wound healing. Scand J Plast Reconstr
Surg Hand Surg 1989;23(3):207–209.
61. Ahn C, Mulligan P, Salcido RS. Smoking-the bane of wound healing: biomedical interventions and
social influences. Adv Skin Wound Care 2008; 21(5):227-236; quiz 237–238.
62. Levin L, Schwartz-Arad D. The effect of cigarette smoking on dental implants and related surgery.
Implant Dent 2005;14(4):357–361.
63. Siana JE, Rex S, Gottrup F. The effect of cigarette smoking on wound healing. Scand J Plast Reconstr
Surg Hand Surg 1989;23(3):207–209.
64. Scolaro JA, Schenker ML, Yannascoli S, et al. Cigarette smoking increases complications following
fracture: a systematic review. J Bone Joint Surg Am 2014;96(8):674–681.
65. S⊘rensen LT, J⊘rgensen S, Petersen LJ, et al. Acute effects of nicotine and smoking on blood flow,
tissue oxygen, and aerobe metabolism of the skin and subcutis. J Surg Res 2009;152(2):224–230.
66. Siasos G, Tsigkou V, Kokkou E, et al. Smoking and atherosclerosis: mechanisms of disease and new
therapeutic approaches. Curr Med Chem 2014;21(34):3936–3948.
67. McMaster SK, Paul-Clark MJ, Walters M, et al. Cigarette smoke inhibits macrophage sensing of
Gram-negative bacteria and lipopolysaccharide: relative roles of nicotine and oxidant stress. Br J
Pharmacol 2008;153(3):536–443.
68. S⊘rensen LT, Zillmer R, Agren M, et al. Effect of smoking, abstention, and nicotine patch on
epidermal healing and collagenase in skin transudate. Wound Repair Regen 2009;17(3):347–353.
69. S⊘rensen LT. Wound healing and infection in surgery: the pathophysiological impact of smoking,
smoking cessation, and nicotine replacement therapy: a systematic review. Ann Surg
2012;255(6):1069–1079.
70. S⊘rensen LT, Jorgensen LN, Zillmer R, et al. Transdermal nicotine patch enhances type I collagen
synthesis in abstinent smokers. Wound Repair Regen 2006;14(3):247–251.
71. Morimoto N, Takemoto S, Kawazoe T, et al. Nicotine at a low concentration promotes wound
healing. J Surg Res 2008;145(2):199–204.
72. Jung MK, Callaci JJ, Lauing KL, et al. Alcohol exposure and mechanisms of tissue injury and repair.
Alcohol Clin Exp Res 2011;35(3):392–399.
73. Choudhry MA, Li X, Chaudry IH. A role for corticosterone in impaired intestinal immunity and
barrier function in a rodent model of acute alcohol intoxication and burn injury. J Neuroimmune
Pharmacol 2006;1(4):428–434.
74. Curtis BJ, Hlavin S, Brubaker AL, et al. Episodic binge ethanol exposure impairs murine
macrophage infiltration and delays wound closure by promoting defects in early innate immune
responses. Alcohol Clin Exp Res 2014;38(5):1347–1355.
75. Aberg KM, Radek KA, Choi EH, et al. Psychological stress downregulates epidermal antimicrobial
peptide expression and increases severity of cutaneous infections in mice. J Clin Invest
2007;117(11):3339–3349.
76. Fitzgerald DJ, Radek KA, Chaar M, et al. Effects of acute ethanol exposure on the early
inflammatory response after excisional injury. Alcohol Clin Exp Res 2007;31(2):317–323.
77. Radek KA, Kovacs EJ, Gallo RL, et al. Acute ethanol exposure disrupts VEGF receptor cell signaling
in endothelial cells. Am J Physiol Heart Circ Physiol 2008;295(1):H174–H184.
78. Zimmerman-Pope N, Waldron DR, Barber DL, et al. Effect of fenoldopam on renal function after
nephrotomy in normal dogs. Vet Surg 2003;32(6):566–573.
79. Franz MG, Steed DL, Robson MC. Optimizing healing of the acute wound by minimizing
140
complications. Curr Probl Surg 2007;44(11):691–763.
80. Lawrence WT, Talbot TL, Norton JA. Preoperative or postoperative doxorubicin hydrochloride
(adriamycin): which is better for wound healing? Surgery 1986;100(1):9–13.
81. Kolb BA, Buller RE, Connor JP, et al. Effects of early postoperative chemotherapy on wound
healing. Obstet Gynecol 1992;79(6):988–992.
82. Bessissow T, Lemmens B, Ferrante M, et al. Prognostic value of serologic and histologic markers on
clinical relapse in ulcerative colitis patients with mucosal healing. Am J Gastroenterol
2012;107(11):1684–1692.
83. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in
metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91(3):173–180.
84. Mancini, M, Sonis ST. Mechanisms of cellular fibrosis associated with cancer regimen-related
toxicities. Front Pharmacol 2014;5:51.
141
Chapter 6
Hemostasis
Peter K. Henke and Thomas W. Wakefield
Key Points
1 At the same time that thrombin forms, natural anticoagulant mechanisms oppose further thrombin
formation and help to localize thrombin activity to areas of vascular injury. Just as thrombin
generation is key to coagulation, antithrombin is the central anticoagulant protein.
2 The endothelial cell acts as a nonthrombogenic surface, and inflammation tips the balance to
procoagulant state.
3 Thrombosis and inflammation are closely linked, and may perpetuate each other. Leukocytes and
chemokines are involved with normal DVT resolution. These essential inflammatory mechanisms
may drive vein wall injury.
4 Both acquired and inherited factors contribute to pathologic thrombosis; often occurring together.
5 Heparin-induced thrombocytopenia (HIT) occurs in 0.6% to 30% of patients in whom heparin is
given; severe thrombocytopenia associated with thrombosis (HITTS) is much less frequent. Cessation
of heparin is critical.
6 Factor VIII and IX deficiency states are involved in hemophilia A and B and von Willebrand disease.
BASIC CONSIDERATIONS
Coagulation is an essential homeostatic mechanism for survival, and involves tightly controlled
processes to maintain vascular integrity including thrombosis localization, amplification, and
neutralization. These coordinated steps occur at the vessel, cellular and subcellular levels. Thrombosis,
directly or indirectly, is the underlying leading cause of death in the world, and is an essential part of
surgery.
Platelets form the initial hemostatic plug after vascular injury, and are locally activated and
aggregation induced (Fig. 6-1). Platelet aggregation is mediated by receptors that are part of the
mammalian integrin family. This family includes the β1 family, mediating platelet interaction with cells,
collagen, fibronectin, and laminin; the β2 family (LeuCAM), present on leukocytes mediating
interactions between leukocytes and other cells important in inflammation; and the β3 family
(cytoadhesion), including the megakaryocyte-specific glycoprotein (Gp) IIb/IIIa receptor and the
vitronectin (Vn) receptor present on platelets and other cells.1 Platelet aggregation is mediated by
GpIIb/IIIa, which binds fibrinogen, von Willebrand factor (vWF), fibronectin, Vn, and thrombospondin
to activated platelets. These high-density receptors are hidden on inactivated platelets and become
exposed on the surface of activated platelets.
Two platelet activation routes are thought to occur physiologically.2 Without direct vessel damage,
platelet activation may occur via tissue factor (TF) de-encryption and activation by protein disulfide
isomerase (PDI), with factor VIIa generation and activation of platelets. Alternatively, subendothelial
collagen may directly bind to GpVI and vWF, leading to platelet capture and activation. Of note, PDI
inhibition can directly block experimental thrombus formation.3
Once stimulated, activated platelets contract, with externalization of negatively charged procoagulant
phospholipids, including phosphatidylserine and phosphatidylinositol (termed platelet factor 3). This
allows the coagulation proteins to assemble on the surface membrane of platelets, accelerating the
coagulation reaction.4 During platelet activation, granules release their contents of calcium, serotonin,
and membranes are exposed that are rich in receptors for factors Va and VIIIa,5,6 as well as fibrinogen,
vWF, and ADP, a potent activator of other platelets. vWF is responsible for platelet adhesion through
binding to GpIb,7 whereas fibrinogen forms bridges between activated platelets by binding to GpIIb/IIIa
on adjacent stimulated platelets.8 Platelets also release polyphosphates that activate factor XII and the
142
intrinsic pathway.9
While long thought to be a bystander in venous thrombosis (VT) as compared to the arterial system,
the role of the platelet is now thought to play a critical role, as well as directing later inflammatory cell
actions.10,11 First, recent clinical trials suggest antiplatelet therapy may reduce recurrent VTE.12 Second,
in stasis and nonstasis experimental murine VT, genetic deletion of vWF was associated with
significantly reduced VT size and not restored with recombinant factor rVIII.13 Intravital microscopy
also showed direct association of leukocytes and platelets in a growing acute thrombus. Consistently,
platelets via GpIb2, may promote VT by colocalizing leukocytes and coagulation factors at the site of
injury or stasis in the vein.14
Once the platelet plug has formed, the stage is set for coagulation protein assembly (Fig. 6-2).
Initiating agents for coagulation include subendothelial collagen and TF, usually from vascular injury.2
There is also growing evidence that blood-borne TF associated with leukocytes, or circulating in soluble
form, is also involved with venous thrombogenesis.15,16 Leukocyte adhesion to platelets may trigger
leukocyte activation, causing recruitment of blood-borne TF onto the surface of leukocytes associated
with thrombus, or recruitment of TF-positive leukocytes onto the growing thrombus.17 TF, both blood
borne and local, activates the extrinsic pathway of coagulation by complexing with activated factor VII
(VIIa), activating factors IX and X to factors IXa and Xa.16,18 Factor Xa, activated factor V (Va), ionized
calcium, and factor II (prothrombin) form on the platelet phospholipid surface to initiate the
prothrombinase complex, which catalyzes the formation of thrombin faster than can be achieved with
factor Xa alone.
Thrombin is central to coagulation and acts to cleave fibrinopeptide A (FPA) from the α chain of
fibrinogen and fibrinopeptide B (FPB) from the β chain. This leads to the release of fibrinopeptides and
the formation of new fibrin monomers, which then cross-link, resulting in fibrin polymerization.
Thrombin also activates factor XIII, which catalyzes the cross-linking of fibrin to make the clot firm,
activates platelets, and activates factors V and VIII, two nonenzymatic cofactors, to Va and VIIIa. This is
important because only activated factors Va and VIIIa are involved in coagulation. Factor XIIIa also
cross-links other plasma proteins, such as fibronectin and α2-antitrypsin, resulting in their incorporation
into clot.
Figure 6-1. Primary hemostasis is achieved initially with a platelet aggregation as illustrated. Note that platelet adhesion, shape
change, granule release, followed by recruitment and the hemostatic plug at the area of subendothelial collagen (binds to GpVI)
exposure are the initial events for thrombus formation. Platelets can also be activated by PDI with de-encryption of TF.
The intrinsic pathway of blood coagulation requires activation of factor XI to XIa. This may occur by
both the contact activation system through activation of factor XII, plasma prekallikrein, and high–
molecular-weight kininogen and, more important, through thrombin with negatively charged surfaces.19
Factor XIa activates factor XI autocatalytically and also catalyzes the conversion of factor IX to IXa.
After activation, factor VIIIa dissociates from vWF and assembles with factors IXa and X. Factor IXa,
factor X, ionized calcium, and thrombin-activated factor VIII (VIIIa) then assemble on the platelet
surface in a complex called the Xase complex to catalyze the activation of factor X to Xa. Factor Xa then
shunts into the prothrombinase complex for further amplification of thrombin formation.
The importance of a mechanism of factor XI activation independent of the contact activation system is
apparent because patients deficient in those factors of the contact activation system, including factor XI,
bleed, whereas patients deficient in factor XII, prekallikrein, and high–molecular-weight kininogen do
not usually bleed.20 The contact activation system is the most important coagulation process involved in
extracorporeal bypass circuits, including cardiopulmonary bypass and extracorporeal membrane
oxygenation.
143
Figure 6-2. The classical pathway showing the interface between the intrinsic pathway, extrinsic pathway, and the common
pathway is illustrated with the ultimate production of thrombin. This catalyzes fibrin from fibrinogen, and then cross-linking the
fibrin to form a stable clot.
NATURAL ANTICOAGULANT MECHANISMS

1 At the same time that thrombin forms, natural anticoagulant mechanisms oppose further thrombin
formation and help to localize thrombin activity to areas of vascular injury. Just as thrombin generation
is key to coagulation, antithrombin (AT) is the central anticoagulant protein (Fig. 6-3). This
glycoprotein of 70-kD molecular weight binds to thrombin, preventing the removal of FPA and FPB
from fibrinogen, prevents the activation of factors V and VIII, and inhibits the activation and
aggregation of platelets. In addition, AT directly inhibits factors IXa, Xa, and XIa.
A second natural anticoagulant is activated protein C (APC), which inactivates factors Va21,22 and
VIIIa, thus reducing the Xase and prothrombinase complex acceleration of the rate of thrombin
formation. In the circulation, protein C is activated on endothelial cell surfaces by thrombin complexed
with one of its receptors, thrombomodulin (TM).23–25 The formation of this thrombin–TM complex
accelerates the activation of protein C compared with thrombin alone. Thrombin, at the same time, by
binding to TM, loses its platelet-activating activity as well as its enzymatic activity for fibrinogen and
factor V. Protein S is a cofactor for APC.
Another innate anticoagulant is tissue factor pathway inhibitor (TFPI). The protein binds to TF–VIIa
complex, inhibiting the activation of factor X to Xa and the formation of the prothrombinase complex.26
A fourth natural anticoagulant is heparin cofactor II.27 Its concentration in plasma is estimated to be
significantly less than that of AT, and its action is implicated primarily in the regulation of thrombin
formation in extravascular tissues. Finally, thrombin is inactivated when it becomes incorporated into
the clot.
FIBRINOLYSIS
In addition to natural anticoagulants such as protein C and S, physiologic clot formation is balanced by a
contained process of clot lysis, which prevents thrombus formation from proceeding outside of the
injured area (Fig. 6-4). The central fibrinolytic enzyme is plasmin, a serine protease generated by the
144
proteolytic cleavage of the proenzyme, plasminogen. Its main substrates include fibrin, fibrinogen, and
other coagulation factors. Plasminogen, tissue plasminogen activator (tPA), and α2-antiplasmin (α2-AP)
become incorporated into the fibrin clot as it forms. Plasminogen activators are serine proteases that
activate plasminogen, by cleavage of a single arginine–valine peptide bond, to the enzyme plasmin.
Plasminogen activation provides localized proteolytic activity.28–30 In fact, thrombin promotes tPA
release from endothelial cells as well as the production of plasminogen activator inhibitor (PAI-1) from
endothelial cells.31,32
Figure 6-3. Antithrombin is a primary anticoagulant. Note antithrombin complexes with IIa to inhibit fibrin polymerization, as
well as factor Xa, and an inactivating factor Va and VIIIa.
Figure 6-4. Hemostasis with thrombus production is a tight and intricate process that is locally confined. Balancing thrombus
production is tissue plasmin activator and urokinase plasminogen activator which activates plasmin and causes thrombolysis. These
are balanced by plasminogen activator inhibitor-1 and alpha-2-antiplasmin. Free plasmin is complexed rapidly. Fibrin degradation
products, such as D-dimer are produced.
The major endogenous plasminogen activators include tPA and urokinase, and intrinsic factors, such
as factor XII, prekallikrein, and high–molecular-weight kininogen. These later factors of the contact
system are more important in clot lysis than thrombus formation. These enzymes may also liberate
bradykinin from high–molecular-weight kininogen, resulting in an increase in vascular permeability,
145
prostacyclin (PGI2) liberation, and tPA secretion. Finally, APC has been found to proteolytically
inactivate the inhibitor to tPA, thus promoting tPA activity and fibrinolysis.33
Fibrin, when digested by plasmin, yields one molecule of fragment E and two molecules of fragment
D. In physiologic clot formation, fragment D is released in dimeric form (D-dimer),20,34 and is a marker
for fibrinolysis of formed clot. An elevated D-dimer level after treatment of DVT is one biomarker that
has been found to accurately predict an ongoing risk of recurrent VTE.35
Two primary inhibitors of plasmin are important. First, α2-AP is released by endothelial cells and
complexes with plasmin. In physiologic fibrinolysis, α2-AP is bound to fibrin and excess plasmin is
readily inactivated. In plasma, PAI-1 is the primary inhibitor of plasminogen activators. It is secreted in
an active form from liver and endothelial cells and stabilized by binding to Vn. PAI-1 levels are elevated
by hyperlipidemia, and PAI-1 elevation appears to synergize with factor V Leiden genetic
abnormalities.36
In summary, coagulation is an ongoing process of thrombus formation, inhibition of thrombus
formation, and thrombus dissolution. The central mediators are TF, platelets, thrombin, and plasmin.
Abnormalities in coagulation occur when one process – thrombus formation, thrombus inhibition, or
fibrinolysis – overcomes the others and dominates the delicate balance.
ENDOTHELIUM AND HEMOSTASIS

2 Through its ability to express procoagulants and anticoagulant factors, vasoconstrictors and
vasodilators, as well as key cell adhesion molecules and cytokines, the endothelial cell is a key regulator
of hemostasis (Fig. 6-5).37 Vascular endothelium maintains a vasodilatory and local fibrinolytic state in
which coagulation, platelet adhesion and activation, and leukocyte activation are suppressed.
Vasodilatory endothelial products include adenosine, nitric oxide (NO), and PGI2. A nonthrombogenic
endothelial surface is maintained by four main mechanisms including; endothelial production of TM and
subsequent activation of protein C, endothelial expression of surface heparan- and dermatan sulfate,
constitutive expression of TFPI by endothelium (which is markedly accelerated in response to heparin),
and local production of tPA and urokinase plasminogen activator (uPA).37,38 Finally, the elaboration of
NO and interleukin (IL)-10 by endothelium inhibits leukocyte adhesion and activation.
During states of endothelial disturbances such as injury, a prothrombotic and proinflammatory state
of vasoconstriction is driven by the endothelial surface. Endothelial release of platelet-activating factor
(PAF) and endothelin-1 promotes vasoconstriction.38 Endothelial cells increase production of vWF, TF,
PAI-1, and factor V to augment thrombosis with exposure to prothrombotic stimuli. Finally, in response
to endothelial injury, endothelial cells are activated, resulting in increased surface expression of cell
adhesion molecules, promoting leukocyte adhesion and activation.
THROMBOSIS, INFLAMMATION, AND RESOLUTION

3 After VT, an acute to chronic inflammatory response occurs in the vein wall and thrombus progressing
from thrombus amplification, to organization, and vein recanalization (often at the expense of vein wall
fibrosis and vein valvular damage). Initially, there is an increase in neutrophils (PMN) in the vein wall
followed by monocytes/macrophages. Cytokines, chemokines, and inflammatory factors (e.g., tumor
necrosis factor [TNF]) facilitate inflammation. The ultimate response of the vein wall depends on
proinflammatory and anti-inflammatory mediator balance at the interface between the leukocyte,
activated platelet, and endothelium.39
Cell Adhesion Molecules

Selectins (P- and E-selectin) have been found to be intimately involved in this process (Fig. 6-6).40
Selectins are the first upregulated glycoproteins on activated platelets (alpha granules) and endothelial
cells (Weibel–Palade bodies). They mediate the adhesion of leukocytes, platelets, and even cancer cells
in inflammation and thrombosis. The P-selectin receptor is P-selectin glycoprotein ligand-1 (PSGL-1). P-
selectin:PSGL-1 interactions trigger the release of procoagulant microparticles (MPs), that support fibrin
formation, thrombus growth, and increase monocyte TF expression.
MPs <1 micron fragments may be central for P-selectin’s effect. It is believed that with initial
thrombosis, P-selectin upregulation leads to MP formation. These procoagulant MPs, which may express
146
TF, are then recruited into the area of developing thrombosis, amplifying the process. Consistently, P-
selectin gene deficiency, results in less MP formation, and less thrombosis.41 In an experimental study,
the generation of procoagulant activity was shown to be dependent on P-selectin:PSGL-1 interactions
related to MP formation.42 The procoagulant nature of these MP was demonstrated by their ability to
normalize bleeding in factor VIII–deficient mice.
Figure 6-5. The endothelium is a primary interface allowing both anticoagulant functions in the resting state, with prostacyclin,
NO, plasminogen activators, and thrombomodulin. Procoagulant proteins are expressed on activated endothelium including
selectins, procoagulant proteins, such as the von Willebrand factor, TF, as well as PAI-1.
E-selectin, upregulated after P-selectin, is an important regulator of thrombus formation and fibrin
content in a mouse VT model.43,44 Endotoxin-induced TF-mediated coagulation is enhanced in humans
carrying the S128R E-selectin allele,45 and patients homozygous for the S128R E-selectin allele have an
increased risk for VTE recurrence, highlighting the importance of E-selectin in DVT.46 E-selectin has
been shown to be efficient at raising the affinity and avidity of 2 (CD18) integrins which support
neutrophil trafficking to sites of acute inflammation and recruit platelets and red blood cells.47
PSGL-1 has greatest affinity for P-selectin, and lesser affinity for E-selectin and L-selectin. The role of
P-selectin in VT has been suggested by the study of a mouse with high fourfold higher circulating levels
of P-selectin than wild type.48 These mice are hypercoagulable based on clotting tests, and a receptor
antagonist against the P-selectin receptor (rPSGL-Ig) reverses the hypercoagulability. Consistently, wild-
type mice administered soluble P-selectin (sP-sel) become hypercoagulable. In models of VT, P-selectin
inhibition given prophylactically decreases thrombosis in a dose-dependent fashion, and can treat
established VT as effectively as heparin without anticoagulation.49,50
147
Figure 6-6. The interaction between stasis injury and procoagulant syndromes are represented by Virchow triad. Endothelial and
vascular injuries cause leukocytes and platelets to express P- and E-selectin and the PSGL-1 receptor. Microparticles are released
which express TF. This stimulates the coagulation pathway, fibrin production, and thrombus amplification.
sP-sel is released from activated platelets and endothelial cells and levels rise significantly during
pathologic conditions.51–53 sP-sel has been studied as a biomarker for DVT,51,54–56 combining Sp-sel with
Wells score (clinical pretest probability of DVT) establishes the diagnosis of DVT. A sP-sel (≥90 ng/mL)
combined with Wells score (≥2), showed a better PPV (91%) than D-dimer (≥500 ng/mL) combined
with Wells score (≥2), which was 69%.57
Other factors of importance to venous thrombogenesis include vWF, a factor that stabilizes
procoagulant factor VIII to promote the initiation and formation of stable thrombus at the site of
vascular inflammation and TF. Using a ferric chloride model of vein wall injury, it has been shown that
occlusive thrombus formation is dependent on vWF.58 Regarding TF, mouse models using gene-
targeting and bone marrow transplantation technologies found that TF in the vessel wall is more
imporant than TF from leukocytes for thrombus formation when there is no flow in the experimental
model.59 TF has been linked to circulating procoagulant MPs, particularly in cancer patients, cancer is
associated with high levels of DVT, and TF activity is increased in cells treated with chemotherapeutic
agents.60 In addition, cancer patients with VTE were found to have elevated levels of microparticle TF
compared to cancer patients without VTE.61,62
Leukocytes and Thrombosis

Inflammatory cells are important to the process of thrombus recanalization and organization (Fig. 6-
7).40,63 Thrombus resolution resembles wound healing, and involves both profibrotic growth factors,
collagen deposition, matrix metalloproteinase (MMP) expression, and activation.64,65 As the thrombus
resolves, a number of proinflammatory factors are released into the local environment, including
interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).66 The cellular sources of these
different mediators are probably leukocytes and smooth muscle–like cells within the resolving thrombus
and adjacent vein wall. The fact that leukocytes invade the thrombus in a specific sequence suggests
their importance in the normal thrombus resolution.66
The first cell type in the thrombus is the PMN. Although PMNs may cause vein wall injury, they are
essential for early thrombus resolution by promoting both fibrinolysis as well as collagenolysis.67,68 In a
rat model of stasis VT, neutropenia was associated with larger thrombi at 2 and 7 days, and was
correlated with increased thrombus fibrosis and significantly lower thrombus levels of both uPA and
MMP-9.69 Conversely, in a nonstasis VT model, PMNs may promote thrombosis.14 It is likely the timing
of PMN influx and the amount of perithrombus blood flow that determines prothrombotic or
prothrombolytic activities. Through processes that also involve the initial activation of leukocytes and
platelets, PMNs form neutrophil endothelial traps (NETs), which are extracellular fragments of DNA
containing histones and antimicrobial proteins.14,70 NETs provide a scaffold for thrombus formation and
are prothrombotic.71
In order to investigate if plasma DNA is a surrogate for NETs in patients with DVT, and to determine
correlations with other biomarkers of DVT studied in our laboratory, patients presenting to our
diagnostic vascular laboratory were investigated.72 Patients were divided into positive for DVT by
ultrasound, leg pain but negative for DVT by ultrasound, and control volunteers. Circulating DNA was
significantly elevated in DVT patients, compared with controls. Of interest was a significant positive
correlation of circulating DNA with C-reactive protein, D-dimer, vWF, and the Wells score (all p
<0.01).
The monocyte/macrophage is likely the most important cell for later DVT resolution.73 Monocyte
influx into the thrombus peaks at day 8 after thrombogenesis, and correlates with elevated MCP-1
levels, which has been associated with DVT resolution.74 Targeted deletion of CC receptor-2 (CCR-2 KO)
in the mouse model of stasis thrombosis was associated with late impairment of thrombus resolution,
probably via impaired MMP-2 and MMP-9 activities.75 Indeed, precedent exists in humans that the
monocytic activation state may predict long-term DVT resolution.76
Thrombi have been found to contain increasing amounts of both tPA and uPA activities as they
resolve, and this activity is expressed by invading monocytes.77,78 In a recent study, mice genetically
deleted for uPA had impaired thrombus resolution with reduced monocyte infiltration at the margins of
the thrombus, with few neovascular channels present.79 Mice gene deleted for tPA, however, were not
similarly affected, suggesting that uPA, not tPA, is responsible for this activity.
148
Figure 6-7. The proposed resolution mechanism involves both early thrombolysis with a large distending clot and then, over time,
a fibrotic thrombus that resembles scar tissue as produced. Note proinflammatory factors, as well as neutrophils (releasing NETs),
platelets, and MMP are present early with subsequent vein wall injury related to collagenolysis and elastinolysis. Later, vascular
smooth muscle cell proliferation appears to occur, with thrombus resolution with increased profibrotic growth factor such as IL-13
and TGF-β. This promotes collagen accumulation. Both PAI-1 and CCR7 are protective against fibrosis.
The local venous environment is by definition hypoxic, hypoxia-inducible factor-1 alpha (HIF-1α). A
major angiogenic growth factor is HIF-1α. Experimental data in a stasis model of VT suggest that
thrombosis stimulates increased vein wall HIF-1α, and that by exogenous stimulation of HIF-1α
expression, thrombus recanalization was increased and associated with accelerated VT resolution.80
Thus, thrombus resolution is in part dependent on neovascularization. The effect of mechanical stretch,
such as by a VT, may also stimulate HIF-1α as well as MMP-2 and MMP-9, both leading to reduced vein
contractility.81
Recent data linking inflammation to fibrosis demonstrate that inhibition of the inflammatory response
can decrease vein wall fibrosis. In a rat model of stasis DVT, treated with either low–molecular-weight
heparin (LMWH) or an oral inhibitor to P-selectin 2 days after establishment of thrombosis, inhibition
of P-selectin significantly decreased vein wall injury (independent of thrombus size).82 The mechanism
accounting for this protective effect is not yet known, but probably does not involve leukocyte
blockade, because no differences in influx of monocytes into the vein wall were observed.
Loss of venous endothelium likely also contributes to the vein wall fibrosis, as well as the
predisposition to recurrent thrombosis. An experimental model of DVT showed lower expression of
homeostatic endothelial genes such as NO and TM than in controls, which correlated with loss of vWF
positive cell luminal staining.83 Other investigators have found that prolonged venous stasis is
associated with decreased plasminogen activators, probably related to loss of endothelium.84
Associated with the early biomechanical injury from DVT is an elevation of profibrotic mediators,
including transforming growth factor-beta (TGF-b), interleukin-13 (IL-13), IL-6, and monocyte
chemotactic protein-1 (MCP-1).82,85,86 These mediators are present within the vein wall and thrombus
and may drive the fibrotic response. Although exogenous MCP-1 may hasten DVT resolution, it
promotes organ fibrosis in vivo. The profibrotic growth factor TGF-b is also present in the thrombus and
is activated with normal thrombolysis.87 TGF-b may be a key mechanism promoting vein wall fibrosis.
Late fibrosis has been observed in our mouse model of DVT, which demonstrated a significant
increase in vein wall collagen after stasis thrombogenesis.88–90 Based on experimental studies,
elastinolysis and collagenolysis seem to occur early, as measured by an increase in vein wall stiffness,
persisting through 14 days, and are accompanied by elevated MMP-2 and MMP-9 activities.85,89
Correlating with this increase in fibrosis is altered procollagen I and III gene expression, as well as an
increase in MMP-2 and MMP-9 gene expression and activity. Genetic deletion of MMP-2 or MMP-2/9 is
associated with decreased midterm vein wall fibrosis, possibly by modulating vein wall elastin/collagen
metabolism as well as monocyte influx.64,65 It has been demonstrated that decreasing inflammation with
a selectin inhibitor or with neutralizing IL-6 can also decrease vein wall fibrosis.43,91,92 Moreover, the
thrombus size itself does not drive the vein wall injury response; rather the mechanism of thrombosis
seems more important.85,93 Lastly, PAI-1 overexpression is associated with decreased vein wall fibrosis,
in part by decreased MMP-2/9 activity.90
ARTERIAL VERSUS VENOUS THROMBOSIS

149
Thrombosis in the arterial system occurs somewhat differently than in the venous system (Fig. 6-8). The
elements required for the initiation of DVT were described by Virchow as stasis, endothelial injury, and
hypercoagulability of the blood. In the arterial circulation, endothelial vascular injury (whether acute or
chronic) is key to thrombosis. This is most clearly demonstrated by the typical atherosclerotic plaque. In
advanced lesions, the lipid core of the plaque is rich in inflammatory cells, cholesterol crystals, and TF
(generated by activated macrophages within the plaque).94 Plaque ulceration exposes highly
thrombogenic lipid to the bloodstream, activating coagulation, platelet aggregation, and leading to the
deposition of clot.95 Platelet deposition occurs at the apex of stenosis, the point of maximal shear force.
The blood flow velocity itself regulates how quickly both thrombi form and dissolve.96
A platelet-rich thrombus is observed in arterial thrombus while in contrast, venous blood stasis and
changes in its composition (leading to hypercoagulability) incite the formation of thrombus from local
procoagulant events, including small endothelial disruptions at venous confluences, saccules, and valve
pockets.11 Hypercoagulable states have classically been highly associated with VTE, but do play a role
in cardiovascular disease as well.97,98 Moreover, HMG-CoA reductase inhibitors (statin) not only
decrease atherothrombotic events, but also incident VTE,99 suggesting some common pathogenic
pathways.
PROCOAGULANT STATES
Acquired Procoagulant States
4 Most thrombotic clinical episodes have an identifiable cause, although environment risks and genetic
predispositions to thrombosis may account for many of the VTE that manifest clinically.11 Risk factors
for arterial thrombosis are primarily related to atherosclerosis, and are detailed elsewhere.
The most common risk factors for VTE are prior DVT, malignancy, immobility, intravenous catheters,
increased age, major surgery, trauma, infections such as pneumonia and urinary tract infection, and
certain chemotherapies (Table 6-1).100–102 Certain medications such as oral contraceptives and hormonal
replacement therapies also increase the risk of VTE.
Of primary importance to surgeons is how best to estimate perioperative VTE risk, and apply
appropriate prophylaxis. This can be done with a screening form, such as that devised by Caprini et
al.103 and Pannucci et al.104 Essentially, this is a focused assessment of VTE risks related to current
illnesses and history that may not be fully covered in the routine history and physical. The
recommendations are also well detailed in the routinely updated American College of Chest Physicians
VTE evidence-based guidelines.105 The higher the risk, the more intensive the prophylaxis, is the
paradigm. For example, an outpatient hernia patient may require no prophylaxis outside of early
ambulation where as a hip replacement in an obese patient would be best treated with anticoagulation
as well as sequential compression devices for the lower extremities. However, all patients should be
assessed for VTE risk.
Malignancy
Cancer represents an independent risk factor for the development of VTE, with a sixfold increased risk
in cancer patients. Importantly, cancer patients undergoing surgical procedures have twice the risk of
development of postoperative DVT.106 Highest rates of VTE are seen in pancreas, stomach, and lung
cancer. The malignancy itself activates a procoagulant phenotype by expression of TF by malignant
cells, release of TF-bearing MPs, and increased activation of neutrophil extracellular traps – the
downstream effects of which have been outlined above.107
Despite considerable evidence supporting the use of prophylactic anticoagulation in cancer patients,
many do not receive optimal pharmacoprophylaxis for DVT while inpatient.108 An extended duration of
therapy – 28 days – was found to be associated with a decreased incidence of DVT at the end of the
study period; consequently, current guidelines recommend extended thromboprophylaxis in cancer
patients after an operative intervention.108
150
Figure 6-8. Depicted in A is the typical atherosclerotic thrombotic nidus, which includes rupture of a plaque, composed of smooth
muscle, foam cells, and leukocytes. Platelets are the primary intermediary in arterial thrombosis, as well as TF. In figure B,
increased coagulability, as well as vessel wall changes with procoagulant TF expression promotes thrombosis.
Inflammatory Bowel Disease

Since the first half of the last century, a link between inflammatory bowel disease (IBD) and VTE has
been recognized. While there does appear some correlation between thrombosis and the inflammatory
nature of the disease, the link between the inflammatory and coagulation cascades does not tell the
whole story. There are several possible mechanisms for this increased tendency toward thromboembolic
events under active investigation, including spontaneous platelet activation through the CD40–CD40L
pathway.109
A recent retrospective cohort study of the National Surgical Quality Improvement Program database
demonstrated that the presence of IBD is an independent risk factor for postoperative VTE with an odds
ratio of 2.110 Interestingly, there appears to be an increased tendency to form clot in unusual locations,
such as cerebral and hepatic veins. Currently, guidelines recommend only standard pharmacologic
thromboprophylaxis for patients with IBD.
Trauma
As with other acquired prothrombotic states, the systemic inflammatory milieu is associated with VTE in
trauma patients. Activation of inflammatory pathways through TNF-α with increased circulating TF and
procoagulant MP induces a prothrombotic state.111 Incidence of VTE in trauma patients is around 2%,
and this may be higher in patients with other risk factors, such as old age, obesity, and prolonged
immobility after bone fractures.112,113 LMWH with application of pneumatic compression devices has
been shown to be the preferred thromboprophylaxis in trauma patients, and this is reflected in
anticoagulation guidelines.105 However, optimal dosing regiments are not well defined.
Table 6-1 Acquired Hypercoagulable States
151
Lupus Anticoagulant/Antiphospholipid Syndrome (Antiphospholipid Antibody)
Antiphospholipid antibody syndrome is a particularly virulent hypercoagulable state that results in both
arterial thrombosis and VT and consists of an elevated antiphospholipid antibody titer in association
with thrombosis, recurrent fetal loss, thrombocytopenia, and livedo reticularis. Strokes, myocardial
infarction, visceral infarction, and extremity gangrene may also occur. Although the lupus anticoagulant
has been noted often in patients with systemic lupus erythematosus (SLE), it does occur in patients
without SLE. It may also be induced in patients by medications, cancer, and certain infections.114
A number of possible thrombotic mechanisms have been suggested, including inhibition of PGI2
synthesis or release from endothelial cells,115 inhibition of APC by thrombin/TM,116 elevated PAI-1
levels,117 platelet activation,118 endothelial cell activation,119 and interference with the endothelial cell–
associated annexin V anticoagulant activity.120 Increased TF expression on monocytes and low free
protein S plasma levels have also been found with the antiphospholipid syndrome and a history of
thrombosis.121,122
At least one-third of patients with lupus anticoagulants have a history of one or more thrombotic
events, 70% or more being VTE.123 Graft thrombosis has been observed in 27% to 50% of patients
positive for antiphospholipid antibody.124,125
For the diagnosis of antiphospholipid syndrome, both clinical and laboratory criteria are necessary.
For the clinical criteria, ≥1 must be present:
1. ≥1 clinical episode of, objectively confirmed, arterial, venous, or small vessel thrombosis.
2. Pregnancy morbidity: ≥1 unexplained fetal death @ ≥10 weeks EGA; ≥1 premature birth (≤34th
week of gestation) due to eclampsia, severe preeclampsia, or placental insufficiency; ≥3 unexplained
consecutive spontaneous abortions @ <10 weeks EGA.126
For the laboratory criteria, ≥1 must be present:
1. LA (+) ≥2 occasions, at least 12 weeks apart, according to ISTH guidelines (prolonged PL-based
clotting assay, lack of correction with 1:1 mix, and correction with excess PL).
2. ACLA and/or anti-β2 glycoprotein-I antibody (medium or high immunoglobulin G (IgG) and/or IgM
isotype titer ≥2 occasions, at least 12 weeks apart using standardized ELISA assays).
The prolongation in the aPTT is strictly a laboratory phenomenon. The dilute Russell viper venom
time confirms the presence of a lupus anticoagulant.
There is imperfect agreement between diagnostic tests for this abnormality. Approximately 80% of
patients with a prolonged aPTT will have a positive antiphospholipid antibody, but only 10% to 50% of
patients with a positive antiphospholipid antibody will have a prolonged aPTT.127
Heparin followed by warfarin has been recommended for the treatment of the antiphospholipid
syndrome.114,123 For recurrent fetal loss, heparin or LMWH use through pregnancy is recommended. In
patients with lupus anticoagulants, heparin is monitored by antifactor Xa levels.
Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

5 Heparin-induced thrombocytopenia (HIT) occurs in 0.6% to 30% of patients in whom heparin is given,
although severe thrombocytopenia associated with thrombosis (HITTS) is seen much less
frequently.128,129 Approximately one half of HIT patients have thrombosis that is noted clinically or by
duplex imaging. In an analysis of 11 prospective studies, the incidence was reported to be 3%, with
152
thrombosis in 0.9%.130 Although earlier morbidity and mortality rates of 61% and 23% had been
reported,116 with early diagnosis and appropriate treatment, these rates have declined to 6% and 0%,
respectively.131 HIT is caused by a heparin-dependent IgG antibody that, when bound to platelet factor
4 (PF4), induces platelet aggregation in part by inducing MP formation.132,133 The antibody may not be
heparin specific, as the degree of sulfonation of the heparin-like compound has been suggested to be
critical for this aggregation.134
Both porcine and bovine UFH as well as LMWH have been associated with HIT.135 The syndrome
usually begins 3 to 14 days after heparin is begun. Both arterial and venous thromboses have been
reported, and even small exposures to heparin (heparin coating on catheters) can cause the
syndrome.128,136 VTE associated with HIT is <1% for LMWH, while it is approximately 12% to 13% for
UFH with a higher risk for mortality.137
The diagnosis should be suspected when a patient experiences a 50% or greater decline in platelet
count, when there is a fall in platelet count below 100,000/mL during heparin therapy, or in any patient
who experiences thrombosis during heparin administration.138 The syndrome may be difficult to
diagnose as many hospitalized patients have multiple reasons for low platelet counts, and vigilance is
important. A platelet count should be checked about every 2 days when on heparin therapy.
The laboratory diagnosis of HIT/HITTS is made by a number of assays. The serotonin release assay
was the “gold standard” in the past. An ELISA test detecting the antiheparin antibody in the patient’s
plasma directed against the heparin–PF4 complex is now commonly used.128 This assay is less specific
but more sensitive and is easier to perform and interpret than the serotonin assay. However,
inappropriate testing is common when HIT is suspected. The 4Ts score is a validated measure of pretest
probability with a high negative predictive value that, used appropriately, can limit expensive over-
testing and unnecessarily subjecting patients to cessation of heparin and alternative
anticoagulation.139,140
When the diagnosis is made (clinically), cessation of heparin is mandatory. This includes removing
heparin from intravenous catheters and flushes.136 Warfarin should not be administered until an
adequate alternative anticoagulant has been started to prevent thrombotic complications. A number of
anticoagulants are now available to substitute for patients with this diagnosis. The direct thrombin
inhibitor, argatroban, is FDA approved for this indication and shows no cross-reactivity to heparin
antibodies.138,141 When using argatroban, it is important to keep in mind that the INR is artificially
elevated with this agent. Fondaparinux has also been used for this indication.142
Hypercoagulability Testing: Clinical signs of possible thrombophilia include thrombosis at a young
age (<40), unprovoked thrombosis, recurrent thrombosis, thrombosis at unusual locations such as the
mesentery, CNS venous sinus, and portal vein, a family history of thrombosis, particularly unprovoked,
severe, and in those <50 years of age.143 Testing for hereditary defects in patients with thrombosis
with no family history has pros and cons. On the pro side, testing may: improve understanding of
pathogenesis of thrombosis, identify and counsel affected family members, and obviate expensive
diagnostic testing (e.g., CT scans) looking for a malignancy. On the con side, testing may identify
patients with defects whose management would change, with the potential for overaggressive
management, insurance implications for the patient arise, and the testing is rather costly.
In order to determine the efficacy of hypercoagulable testing, a multicenter international
observational registry on clinical characteristics, treatment patterns, and outcome in consecutive
patients with symptomatic, objectively confirmed acute VTE, was done. In this study, 22,847 patients
were enrolled and 4,503 tested for thrombophilia. Of the total patient population, 8.4% had with factor
V Leiden, 6.8% had PTG20210A, and 3% had activated protein C resistance (APC-R). The authors
concluded that for the low incidence and in accordance with the recommendations made by other
authors and international bodies, “the undertaking of thrombophilia testing on patients with a first
episode of VTE is not advisable.”144
A hypercoagulable screen should include routine coagulation tests such as the aPTT and platelet
count, AT activity and antigen assay, protein C antigen and activity levels, protein S antigen level, and
mixing studies to identify a lupus anticoagulant (if indicated); APC-R assay and factor V Leiden gene
analysis; prothrombin G20210A genetic analysis; homocysteine level; an antiphospholipid antibody
screen that includes anticardiolipin antibody; fibrinogen level; FVIII, FIX, and FXI levels and a
functional plasminogen assay.
Inherited Procoagulant States

Defects with High Risk for Thrombosis
153
Antithrombin Deficiency. AT is a serine protease inhibitor (SERPIN) of thrombin, kallikrein, and
factors Xa, IXa, VIIa, XIIa, and XIa (Table 6-2). It is synthesized in the liver and has a half-life of 2.8
days. AT deficiency, accounts for approximately 0.5% to 3% of episodes of VTE, the prevalence in the
population is 0.2%, and it carries a 20× increased risk for VTE when heterozygous145–147 and may occur
at unusual sites such as mesenteric or cerebral veins. Arterial and graft thromboses have also been
described in AT deficiency.148,149 It is inherited in an autosomal dominant fashion most cases become
apparent by 50 years of age.150 Homozygous patients usually die in utero, whereas heterozygous
patients usually demonstrate AT levels <70% of normal. Acquired AT deficiency results from liver
disease, malignancy, sepsis, disseminated intravascular coagulation (DIC), malnutrition, and renal
disease.148 AT deficiency is divided into type I deficiency (quantitative) and type II deficiency
(qualitative).
Table 6-2 Severity and Frequency of VTE due to Hypercoagulable States
The diagnosis of AT deficiency is suspected in a patient who cannot be adequately anticoagulated with
heparin or who develops thrombosis while on heparin and is made by measuring AT antigen and
activity levels. However, patients should not have been exposed to heparin or related compounds for at
least 2 weeks as heparin decreases AT levels 30%.151 Conversely, warfarin increases AT levels.
For a patient with AT deficiency, anticoagulation with heparin requires the administration of fresh
frozen plasma (FFP) to provide AT, 2 units every 8 hours, decreasing to 1 unit every 12 hours, followed
by oral anticoagulation. A reasonable alternative includes anticoagulation with direct thrombin
inhibitors such as argatroban or bivalirudin.105 Aggressive prophylaxis against VTE is recommended
during the perioperative period, and usually lifelong anticoagulation therapy is required after a first
episode of significant VTE.
Protein C and S Deficiencies. Protein C and its cofactor protein S are both vitamin K–dependent
factors synthesized in the liver with half-lives of 4 to 6 hours and 12 to 14 hours, respectively. The
majority of cases of protein C or protein S deficiency are inherited as autosomal dominant. Patients
present with VTE, often between the ages of 15 and 30 years.152,153 Heterozygous protein C deficiency
is present in 1 in 200 to 500 individuals in the general population and in approximately 3% of
individuals with VTE.146 In a study of 10,000 healthy blood donors, protein C deficiency was noted in
1.45 per 1,000.154 Protein deficiency is divided into a type I deficiency (quantitative) and a type II
deficiency (qualitative).
Levels of protein C in those heterozygous deficient may overlap with lower limit normal levels. In
addition to VTE, cases of arterial thrombosis have also been reported.155 If present as a homozygous
state at birth, infants usually die from unrestricted clotting and fibrinolysis, a condition of extreme DIC
termed purpura fulminans. Patients heterozygous for protein C deficiency usually have antigenic protein
C levels less than 60% of normal.156,157 Acquired protein C deficiency occurs with liver failure, DIC, and
nephrotic syndrome.
Protein S is a cofactor to protein C in inactivating FVa and FVIIIa, and is regulated by complement
C4b-binding protein. Inheritance of protein S deficiency is in an autosomal dominant pattern.157,158
154
Approximately 40% of protein S circulates in a free active form, with the remainder bound to C4b-
binding protein. Free protein S is functionally active as an anticoagulant. Protein S levels increase with
age, and females have lower levels than males. The deficiency of protein S results in a clinical state
identical to protein C deficiency with a VTE rate 5% to 7%, an estimated 8.5× higher risk for the
development of VTE.159 The frequency of protein S deficiency ranges from 3% to 6% for those with
VTE. Levels of protein S are reduced in liver disease, nephrotic syndrome, inflammation, OCP use, in
pregnancy, and during breastfeeding. Nephrotic syndrome leads to a reduction in free protein S,160
whereas inflammatory states such as SLE can result in an elevation of C4b-binding protein, reducing
free protein S.
The diagnosis of protein C or S deficiency is made by measuring plasma protein C and S levels.34,161
For protein C, both antigen and activity are measured, whereas for protein S, only antigen is measured.
A condition also exists in which there is an abnormality in the function of protein C itself, resulting in a
decrease in protein C activity without a decline in antigenic protein C.153
Treatment consists of anticoagulation, initially with heparin, usually followed by lifelong oral
anticoagulation after a first thrombotic event. However, not all patients with low levels develop VTE.
Many heterozygous family members of homozygous protein C–deficient infants also are unaffected.33
Thus, the institution of anticoagulation therapy in patients should occur only following an episode of
thrombosis. However, aggressive anticoagulant prophylaxis during perioperative periods or high-risk
environmental situations is necessary for asymptomatic heterozygote carriers.
With the initiation of oral anticoagulation, blood may become transiently hypercoagulable as the
vitamin K–dependent factors with short half-lives are inhibited (factor VII, protein C) before the other
vitamin K–dependent factors (factors II, IX, and X).162 In someone already partially deficient in protein
C or S, the levels of these anticoagulant factors will diminish even further with the initiation of
warfarin. This results in temporary hypercoagulability, resulting in thrombosis in the microcirculation
and warfarin-induced skin necrosis.163 This leads to full-thickness skin loss, especially over fatty areas
such as the breasts, buttocks, and abdomen. This complication can be prevented by initiating warfarin
therapy under the protection of systemic heparin anticoagulation or a direct thrombin inhibitor.
Defects with Lower Risk for Thrombosis

Resistance to APC (Factor V Leiden). Resistance to APC has been reported to be present in 20% to
60% of cases of idiopathic VTE and is the most common underlying abnormality associated with VTE.
This disorder is present in 1% to 2% of the general population.164–166 In a study of 4,047 Americans, the
carrier frequency of this mutation was 5.3% for Whites, 2.2% for Hispanic Americans, 1.25% for Native
Americans, 1.2% for African Americans, and 0.45% for Asian Americans, with no gender differences.164
It confers a relatively low risk for thrombosis, however, and is more common in whites than in
nonwhite Americans.164
As a result of the substitution of a single amino acid, glutamine for arginine, at position 506 in the
protein for factor V, caused by a nucleotide substitution of guanine for adenine at 1,691 in factor V
gene, hypercoagulability is conferred by resistance to inactivation of factor Va by APC.167–169
Additionally, less VIIIa is interfered with, compounding the hypercoagulability. Factor V Leiden
accounts for 90% of APC-R.
Thrombotic manifestations are noted in those individuals both homozygous and heterozygous for this
mutation. The relative risk for VTE in patients heterozygous for factor V Leiden is 7-fold, whereas the
relative risk is 80-fold for those homozygous for factor V Leiden.165,168 In contrast to factor deficiency
states, persons homozygous for this mutation usually do not die in infancy. Additionally, thrombosis is
potentiated in the presence of additional acquired risk factors.168,170
Combined defects with other hypercoagulable states, such as protein C and S deficiency or
prothrombin G20210A, are not uncommon and increase the thrombotic risk.171,172 In addition to cases
of VTE, recurrent VTE is also more common in patients with this entity, with a relative risk 1.4-
fold.166,173 Although VTE predominates in patients with this syndrome, arterial thrombosis has also been
reported.174
The diagnosis of APC-R is made by a clot-based functional assay with the addition of APC (modified
aPTT). Additionally, genetic analysis should be performed to confirm heterozygosity versus
homozygosity, as treatment decisions may be different between the two states.
Treatment options for APC-R after VTE include anticoagulation, initially heparin or LMWH, followed
by oral anticoagulation. The long-term use of warfarin is controversial. No data exist to suggest that
long-term warfarin should be given after a first episode of VTE in a patient heterozygous for the
155
mutation. The fact that APC-R is a relatively low risk for recurrent thrombosis (1.4-fold) suggests that
not all patients after their first episode of VTE need long-term anticoagulant treatment. Patients must be
evaluated in light of their overall risk for bleeding versus thrombosis.152
Prothrombin G20210A Polymorphism. Prothrombin (factor II), a vitamin K–dependent factor

synthesized in the liver, becomes thrombin when activated. A genetic polymorphism in the distal 3′
untranslated region of the gene for prothrombin, a transition from guanine to adenine at the 20210
nucleotide of the prothrombin gene, has been described in patients with VTE.175 This results in a normal
prothrombin but at increased levels.153,170,176 This polymorphism, confers an increased risk for VTE by
2.8-fold, and is associated with 4% to 6% of patients with VTE.152,177–180 Of patients with spontaneous
DVT, the incidence is 7% to 16%.181,182 This is the second most common cause for hypercoagulability in
Caucasians and its prevalence is 1% to 2% of Caucasians. The thrombosis risk is increased in pregnant
women,183 in women with early myocardial infarctions,179 and in synergy with factor V Leiden.170 Most
patients are heterozygous for this mutation, and whites are more often affected than those of Asian or
African descent.179 Genetic analysis is the marker for this abnormality.184
Patients who present with VTE should be treated according to current standards and akin to the
treatment for heterozygous factor V Leiden. Individuals with prothrombin G20210A who have recurrent
episodes of VTE should undergo lifelong anticoagulation, as should those patients with both
prothrombin G20210A and factor V Leiden.170
Hyperhomocysteinemia. Hyperhomocysteinemia has been a known risk factor for atherosclerosis and
vascular disease for more than 25 years, though a direct cause and effect relationship has not been
established.185–187 However, a recent meta-analysis suggests the risk of VTE to be 2.5-fold with elevated
homocysteine levels.187–192
Two enzyme deficiencies, N5, N10, methylenetetrahydrofolate reductase (MTHFR) or cystathionine
beta synthase, are responsible for elevated homocysteine levels.193 Although mutations in these
enzymes are not infrequent, the common polymorphism in MTHFR alone is not a factor in either the
elevation of plasma homocysteine or thrombosis.194 Acquired causes include advanced age, smoking,
coffee consumption, low dietary folate, and low vitamin B6 and B12 intake. Higher levels are also
associated with diabetes mellitus, cancer, hypothyroidism, lupus IBD, and medications such as
metformin, methotrexate, anticonvulsants, theophylline, and levodopa.195,196
Hyperhomocysteinemia has a frequency of 10% in patients with a first episode of VTE, and is a risk
factor for VTE in those younger than 40 years,189 in women,185 and for recurrent VTE in patients
between 20 and 70 years of age.186 The combination of hyperhomocysteinemia and factor V Leiden
results in an increased risk of venous and arterial thromboses.197 Elevated plasma homocysteine results
in abnormal endothelial function.198–202 Fasting homocysteine levels are determined from serum,
usually on two occasions. The test may also be performed after a methionine oral loading
regimen.203,204
Homocysteine elevation is treated with folate supplements. Although the association between
hyperhomocysteinemia and VTE has been established, treatment to lower homocysteine levels and the
long-term effects of such treatment on procoagulant activity have yet to be validated.185
Other Disorders Associated with Thrombosis

Defective Fibrinolysis/Dysfibrinogenemia/Lipoprotein(a). Abnormal plasminogens
(dysplasminogenemias), although rare (<1%), have been described in cases of spontaneous arterial or
VTE.205 Both type I quantitative and type II qualitative deficiency states have been described. Other
defects in fibrinolysis may affect up to 10% of the normal population.206 Abnormal fibrinogens may
account for 1% to 3% of patients with VT and those presenting with digital ischemia.207 Numerous
molecular defects have been classified. Defective thrombin binding or resistance to plasmin-mediated
breakdown has been described.208 Although not clearly documented, defects in plasminogen activators,
tPA, or uPA may incite thrombotic events.209 Moreover, elevated PAI-1 has been associated with DVT
and myocardial infarction.205 Although the relationship between VTE and abnormal fibrinolysis is
debated, it is clear that in the postoperative period there is a connection between fibrinolysis and
VTE.205,210,211 Additionally, PAI-1 is upregulated by thrombin, endotoxin, and IL-1, explaining the
elevated circulating levels of PAI-1 during infections.212
Lipoprotein(a), associated with LDL, has both atherogenic and prothrombotic properties.213–215 It
prevents plasminogen from binding to cells or fibrin and inhibits fibrinolysis.216 Elevated levels of
lipoprotein(a) have been associated with VTE in childhood; it is a weak thrombotic risk factor in
156
adults.217–219 When an individual with thrombosis presents with one of the previously mentioned
abnormalities, standard anticoagulation is necessary.220,221
Abnormal Platelet Aggregation. It has been recognized for some time that there are patients who
have thrombosis and may have hyperactive/hyperresponsive platelets but this entity is poorly defined.
Diabetes mellitus, which is known to be associated with hyperactive platelets and hyperlipidemic states,
may be a contributing factor. Hyperactive platelets have been noted during graft thrombosis in
peripheral vascular reconstructions.117 Although platelet aggregation assays may be helpful in making
the diagnosis, these assays are not commonly performed or standardized and, thus, the incidence and
importance of platelets to thrombosis are not well known. Bleeding time measurements are not specific,
and not recommended for making this diagnosis. This condition has been called “sticky platelet
syndrome” and both arterial and venous events have been reported.151
Standard anticoagulant treatment is recommended for this condition. Aspirin and the thienopyridine
derivatives such as clopidogrel may be useful, but their utility is unknown.222
Elevated Procoagulant Factors: VIII, IX, and XI

Elevated prothrombotic factors have only recently been associated with primary and recurrent
VTE.152,223 A dose–response effect has been observed; and elevated factor VIII has been best
studied.223–225 Factor VIII:C above the 90th percentile is associated with a 5-fold increased risk of
VTE.225,226 Factor VIII:C elevation is also affected by blood type and race. The risk is 6.7× after
adjusting for age, sex, factor V Leiden, prothrombin G20210A, and duration of Coumadin therapy.227 In
African American women, a statistically higher level of factor VIII has been found than in the white and
Asian populations.228 Elevation of factor XI above the 90th percentile is associated with a 2-fold
increase in VTE, independent of other hypercoagulability factors.229 Similar increases in VTE risk have
been observed with elevated factor IX.230 Acquired and environmental factors precipitate VTE in
patients with elevation of these factors, as opposed to inherited deficiencies of AT, protein C, and
protein S that confer higher VTE risk.231
The diagnosis is made by the direct measurement of these factors with activity assays. However, since
the carrier protein for factor VIII is vWF which is an acute-phase reactant, measurement of factor VIII
levels should be combined with an acute-phase reactant such as CRP or ESR. If VTE occurs with one of
these factor elevated, standard anticoagulant management should be undertaken.221
Disseminated Intravascular Coagulation

DIC is a primary form of acute thrombosis. Causes of DIC include sepsis, trauma, pancreatitis, obstetric
complications such as abruptio placentae or amniotic embolism, transplant rejection, malignant tumors,
certain snake bites, hematologic malignancies, and hepatic failure. Coagulation in DIC is activated by
the release of TF into the circulation causing unregulated activation of the coagulation cascade, leading
to massive thrombin production and fibrin generation. Fibrinolysis then becomes activated as well,
leading to bleeding in the later, hemorrhagic stages of the syndrome because of the consumption of
clotting factors, depletion of fibrinogen, and unchecked plasmin activity. The diagnosis of DIC is a
clinical one, which requires consideration of the gestalt of the patient. Laboratory values in DIC reveal a
downtrend in platelet count – even within the normal range, decreased fibrinogen level, prolonged PT,
and concomitant elevation in fibrin split products and the presence of a positive D-dimer test. The
treatment of DIC requires treatment of the underlying condition. The need for platelet or plasma
transfusion is based on the presence of hemorrhage, rather than on particular laboratory values.232
BLEEDING DISORDERS
Although the surgeon deals more often with procoagulant states than bleeding disorders, it is important
to recognize these disorders when they occur.
Coagulation Factor Deficiency

Coagulation factor deficiency states are important causes of bleeding and the most common are factor
VIII and IX deficiency states, termed hemophilia A and B, and type I von Willebrand disease (vWD).
6 Hemophilia A is inherited as a sex-linked recessive deficiency of factor VIII, with fewer cases
secondary to spontaneous mutation. The incidence of this abnormality is approximately 1 in 5,000
births.233 Clinical findings range from bleeding into joints and muscles, epistaxis, hematuria, and
157
bleeding after minor trauma, to prolonged postoperative bleeding, retroperitoneal bleeding, and
intramural bowel hemorrhage. Laboratory screening tests usually reveal a prolongation of the aPTT
along with decreased factor VIII levels; other test results are normal. The minimum level of factor VIII
required for hemostasis is 30%, and spontaneous bleeding is uncommon with factor VIII levels greater
than 5% to 10% of normal. Levels less than 2% constitute severe, 2% to 5% moderate, and greater than
5% mild deficiency.234 Although the half-life of factor VIII is 2.9 days in normal subjects, the half-life of
factor VIII concentrates is only 9 to 18 hours.233 Levels between 80% and 100% of normal should be
attained for surgical bleeding or life-threatening hemorrhage. Acquired deficiency has been reported to
occur with the development of antibodies to factor VIII after therapy. Inhibitor antibodies develop in
approximately 10% to 15% of patients with hemophilia A, although the incidence of antibody formation
may be much higher in previously untreated patients and in those with severe hemophilia A.
Recombinant factor VIII preparation has been developed and tested in children and infants. Despite
the development of low levels of inhibitors in 20% of children at a mean 9 days after first
administration, these inhibitors either disappeared or remained at low levels.235
Factor IX deficiency (Christmas factor), known as hemophilia B, is transmitted as an X-linked
recessive trait. It may also be acquired because of enhanced factor IX clearance in states such as the
nephrotic syndrome, abnormal protein production in vitamin-K deficiency, and acquired specific
inhibitors to factor IX in various autoimmune diseases, such as SLE. It is clinically indistinguishable
from hemophilia A, and laboratory screening tests reveal a prolonged aPTT, with other test results
normal, although a greater proportion of patients have only mild or moderate deficiency.236 Severe
deficiency (approximately 30% of cases) is defined as a level of activity less than 4% of normal,
whereas moderate deficiency is reported with activity levels between 20% and 40%.234 Treatment
consists of plasma or factor IX concentrates and vitamin-K. It has been recommended that levels greater
than 30% be achieved for hemostasis.
vWF causes platelet adhesion to collagen, initiating platelet plug formation. It also forms a complex
with factor VIII in the blood. Produced in endothelial cells and megakaryocytes (compared with the
liver for factor VIII), it has a circulating half-life of 6 to 20 hours. vWD, a deficiency of vWF, is the
most common of the inherited coagulation disorder. A number of different subtypes have been
identified for its deficiency state, and the syndrome is transmitted as both autosomal dominant
(heterozygous) and autosomal recessive (homozygous) forms. Variants include types I and III
(quantitative decreases in normal-appearing vWF) and type II (qualitative abnormalities in structure and
function of vWF).237 vWF deficiency is probably as common as hemophilia A, although the true
incidence may surpass what is generally appreciated because many mild cases probably remain
undiagnosed.
The classic syndrome is caused by a reduction of factor VIII activity (although not as great as in
hemophilia A) and vWF (vWF–factor VIII complex). Clinical manifestations include easy bruisability,
mild to moderate epistaxis, gingival bleeding, menorrhagia, rare joint or muscle bleeding, prolonged
bleeding following surgery, and subcutaneous bleeding. Spontaneous bleeding is not as common as in
hemophilia A.
Abnormal laboratory tests include a prolonged bleeding time; a decreased level of factor VIII activity;
decreased immunoreactive levels of the vWF; and abnormal platelet aggregation response to ristocetin.
The most reliable source of vWF is cryoprecipitate, although many concentrates of factor VIII have vWF
present and show promise. Desmopressin acetate (DDAVP) is available for the treatment of mild cases
of type I vWD and type 2a and 2b, serum levels of 25% to 50% are needed for hemostasis. In other type
II states and type III vWD, factor VIII concentrates are necessary. Recombinant factor VIII/vWF
concentrates that avoid the infectious risks of transfusion are available.
Rare Factor Deficiencies

Other specific factor deficiencies are much less common and receive only a brief mention here. These
include factors II, XI, V, VII, and X. These can be measured by serum assays, although this is not
routinely available in many hospitals. The treatments are primarily FFP concentrates to give back the
clotting factors.
Deficiencies of fibrinogen can also lead to bleeding disorders. This is the only factor deficiency state
in which the TCT is prolonged. It is generally believed that a fibrinogen level of 100 mg/mL should be
achieved to stop bleeding related to fibrinogen abnormalities. Fibrinogen deficiency may also occur
from consumption during DIC and from primary fibrinolytic states.
Platelet Disorders
158
Platelet disorders are another important cause of bleeding. Inherited defects of platelet receptors
include defects of GpIIb/IIIa (Glanzmann’s thrombasthenia), characterized by impaired platelet binding
to vWF, fibrinogen, and fibronectin. In patients with defects in GpIb (Bernard–Soulier syndrome), the
absolute number of platelets is decreased, the platelets are larger, and platelet aggregation and adhesion
are abnormal. Acquired deficits occur in uremia, both GpIb and GpIIb/IIIa receptors are defective,
resulting in impaired adhesion and aggregation. Acquired deficits also occur in patients who previously
received platelet transfusions and then acquire immune-mediated antiplatelet antibodies.
Abnormalities in Fibrinolysis
Abnormalities in fibrinolysis may play a role in abnormal bleeding disorders. Genetic or acquired
deficiencies in α2-AP may be associated with bleeding, whereas deficiencies in factor XIII (fibrin
stabilizing factor) may lead to highly lysable clot. α2-AP deficiency is treated with ε-aminocaproic acid
or tranexamic acid. Homozygous patients with factor XIII deficiency and less than 1% of normal plasma
activity often show bleeding from the umbilical cord at birth, bleeding after trauma or surgery, and
delayed bleeding 24 to 36 hours later. Screening test results include a shortened euglobulin lysis time. A
specific assay for factor XIII activity exists. Treatment consists of FFP, cryoprecipitate, and factor XIII
concentrates.
References
1. Coller BS. Platelets and thrombolytic therapy. N Eng J Med 1990;322:33–42.
2. Furie B, Furie BC. Mechanisms of thrombus formation. N Eng J Med 2008;359:938–949.
3. Jasuja R, Passam FH, Kennedy DR, et al. Protein disulfide isomerase inhibitors constitute a new
class of antithrombotic agents. J Clin Invest 2012;122:2104–2113.
4. Monroe DM, Hoffman M. What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol
2006;26:41–48.
5. Sims PJ, Faioni EM, Wiedmer T, et al. Complement proteins c5b-9 cause release of membrane
vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor
Va and express prothrombinase activity. J Biol Chem 1988;263:18205–18212.
6. Gilbert GE, Sims PJ, Wiedmer T, et al. Platelet-derived microparticles express high affinity
receptors for factor VIII. J Biol Chem 1991;266:17261–17268.
7. Hickey MJ, Williams SA, Roth GJ. Human platelet glycoprotein IX: an adhesive prototype of
leucine-rich glycoproteins with flank-center-flank structures. Proc Nat Acad Sci U S A 1989;86:6773–
6777.
8. Bennett JS, Vilaire G, Cines DB. Identification of the fibrinogen receptor on human platelets by
photoaffinity labeling. J Biol Chem 1982;257:8049–8054.
9. Muller F, Mutch NJ, Schenk WA, et al. Platelet polyphosphates are proinflammatory and
procoagulant mediators in vivo. Cell 2009;139:1143–1156.
10. Morrell CN, Aggrey AA, Chapman LM, et al. Emerging roles for platelets as immune and
inflammatory cells. Blood 2014;123:2759–2767.
11. Reitsma PH, Versteeg HH, Middeldorp S. Mechanistic view of risk factors for venous
thromboembolism. Arterioscler Thromb Vasc Biol 2012;32:563–568.
12. Brighton TA, Eikelboom JW, Mann K, et al. Low-dose aspirin for preventing recurrent venous
thromboembolism. N Eng J Med 2012;367:1979–1987.
13. Brill A, Fuchs TA, Chauhan AK, et al. von willebrand factor-mediated platelet adhesion is critical for
deep vein thrombosis in mouse models. Blood 2011;117:1400–1407.
14. von Bruhl ML, Stark K, Steinhart A, et al. Monocytes, neutrophils, and platelets cooperate to
initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012;209:819–835.
15. Mackman N. New insights into the mechanisms of venous thrombosis. J Clin Invest 2012;122:2331–
2336.
16. Mackman N, Tilley RE, Key NS. Role of the extrinsic pathway of blood coagulation in hemostasis
and thrombosis. Arterioscler Thromb Vasc Biol 2007;27:1687–1693.
17. Himber J, Wohlgensinger C, Roux S, et al. Inhibition of tissue factor limits the growth of venous
thrombus in the rabbit. J Thromb Haemost 2003;1:889–895.
159
18. Jesty J, Beltrami E. Positive feedbacks of coagulation: their role in threshold regulation. Arterioscler
Thromb Vasc Biol 2005;25:2463–2469.
19. Naito K, Fujikawa K. Activation of human blood coagulation factor XI independent of factor XII.
Factor XI is activated by thrombin and factor XIa in the presence of negatively charged surfaces. J
Biol Chem 1991;266:7353–7358.
20. Davie EW, Fujikawa K, Kisiel W. The coagulation cascade: initiation, maintenance, and regulation.
Biochemistry 1991;30:10363–10370.
21. Kisiel W, Canfield WM, Ericsson LH, et al. Anticoagulant properties of bovine plasma protein C
following activation by thrombin. Biochemistry 1977;16:5824–5831.
22. Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin-
dependent anticoagulant enzyme. Blood 1982;59:1067–1072.
23. Esmon CT, Owen WG. Identification of an endothelial cell cofactor for thrombin-catalyzed
activation of protein C. Proc Natl Acad Sci U S A 1981;78:2249–2252.
24. Owen WG, Esmon CT. Functional properties of an endothelial cell cofactor for thrombin-catalyzed
activation of protein C. J Biol Chem 1981;256:5532–5535.
25. Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed
activation of protein C. J Biol Chem 1982;257:859–864.
26. Wood JP, Ellery PE, Maroney SA, et al. Biology of tissue factor pathway inhibitor. Blood
2014;123:2934–2943.
27. Tollefsen DM. Heparin cofactor II modulates the response to vascular injury. Arterioscler Thromb
Vasc Biol 2007;27:454–460.
28. Dano K, Andreasen PA, Grondahl-Hansen J, et al. Plasminogen activators, tissue degradation, and
cancer. Adv Cancer Res 1985;44:139–266.
29. Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest
1991;88:1067–1072.
30. Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Eng J
Med 2000;342:1792–1801.
31. Gelehrter TD, Sznycer-Laszuk R. Thrombin induction of plasminogen activator-inhibitor in cultured
human endothelial cells. J Clin Invest 1986;77:165–169.
32. Dichek D, Quertermous T. Thrombin regulation of mRNA levels of tissue plasminogen activator and
plasminogen activator inhibitor-1 in cultured human umbilical vein endothelial cells. Blood
1989;74:222–228.
33. Esmon CT. The regulation of natural anticoagulant pathways. Science 1987; 235:1348–1352.
34. Hassouna HI. Laboratory evaluation of hemostatic disorders. Hematol Oncol Clin North Am
1993;7:1161–1249.
35. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation
therapy. N Eng J Med 2006;355:1780–1789.
36. Schulman S, Wiman B. The significance of hypofibrinolysis for the risk of recurrence of venous
thromboembolism. Duration of anticoagulation (DURAC) trial study group. Thromb Haemost
1996;75:607–611.
37. Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ
Res 2007;100:158–173.
38. Gross PL, Aird WC. The endothelium and thrombosis. Semin Thromb Hemost 2000;26:463–478.
39. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008; 111:5271–5281.
40. Wakefield TW, Myers DD, Henke PK. Mechanisms of venous thrombosis and resolution. Arterioscler
Thromb Vasc Biol 2008;28:387–391.
41. Myers DD, Hawley AE, Farris DM, et al. P-selectin and leukocyte microparticles are associated with
venous thrombogenesis. J Vasc Surg 2003;38:1075–1089.
42. Hrachovinova I, Cambien B, Hafezi-Moghadam A, et al. Interaction of P-selectin and PSGL-1
generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med
2003;9:1020–1025.
43. Myers D Jr, Farris D, Hawley A, et al. Selectins influence thrombosis in a mouse model of
experimental deep venous thrombosis. J Surg Res 2002;108:212–221.
160
44. Sullivan VV, Hawley AE, Farris DM, et al. Decrease in fibrin content of venous thrombi in selectin-
deficient mice. J Surg Res 2003;109:1–7.
45. Jilma B, Marsik C, Kovar F, et al. The single nucleotide polymorphism Ser128Arg in the E-selectin
gene is associated with enhanced coagulation during human endotoxemia. Blood 2005;105:2380–
2383.
46. Jilma B, Kovar FM, Hron G, et al. Homozygosity in the single nucleotide polymorphism Ser128Arg
in the E-selectin gene associated with recurrent venous thromboembolism. Arch Intern Med
2006;166:1655–1659.
47. Chase S, Magnani J, Simon S. E-selectin ligands as mechanosensitive receptors on neutrophils in
health and disease. Ann Biomed Eng 2012;40:849–859.
48. Andre P, Hartwell D, Hrachovinova I, et al. Pro-coagulant state resulting from high levels of
soluble P-selectin in blood. Proc Natl Acad Sci U S A 2000; 97:13835–13840.
49. Myers DD Jr, Schaub R, Wrobleski SK, et al. P-selectin antagonism causes dose-dependent venous
thrombosis inhibition. Thromb Haemost 2001;85:423–429.
50. Myers D, Wrobleski S, Londy F, et al. New and effective treatment of experimentally induced
venous thrombosis with anti-inflammatory rPSGL-Ig. Thromb Haemost 2002;87:374–382.
51. Rectenwald JE, Myers DD Jr, Hawley AE, et al. D-dimer, P-selectin, and microparticles: novel
markers to predict deep venous thrombosis. A pilot study. Thromb Haemost 2005;94:1312–1317.
52. Wagner DD, Burger PC. Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol
2003;23:2131–2137.
53. Ridker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events.
Circulation 2001;103:491–495.
54. Smith A, Quarmby JW, Collins M, et al. Changes in the levels of soluble adhesion molecules and
coagulation factors in patients with deep vein thrombosis. Thromb Haemost 1999;82:1593–1599.
55. Ay C, Jungbauer LV, Sailer T, et al. High concentrations of soluble P-selectin are associated with
risk of venous thromboembolism and the P-selectin Thr715 variant. Clin Chem 2007;53:1235–1243.
56. Ramacciotti E, Blackburn S, Hawley AE, et al. Evaluation of soluble P-selectin as a marker for the
diagnosis of deep venous thrombosis. Clin Appl Thromb Hemost 2011;17(4):425–431.
57. Vandy FC, Stabler C, Eliassen AM, et al. Soluble P-selectin for the diagnosis of lower extremity
deep venous thrombosis. J Vasc Surg Venous Lymphat Disord 2013;1:117–125.
58. Chauhan AK, Kisucka J, Lamb CB, et al. von Willebrand factor and factor VIII are independently
required to form stable occlusive thrombi in injured veins. Blood 2007;109:2424–2429.
59. Day SM, Reeve JL, Pedersen B, et al. Macrovascular thrombosis is driven by tissue factor derived
primarily from the blood vessel wall. Blood 2005;105:192–198.
60. Swystun LL, Shin LY, Beaudin S, et al. Chemotherapeutic agents doxorubicin and epirubicin induce
a procoagulant phenotype on endothelial cells and blood monocytes. J Thromb Haemost 2009;7:619–
626.
61. Tesselaar ME, Romijn FP, van der Linden IK, et al. Microparticle-associated tissue factor activity in
cancer patients with and without thrombosis. J Thromb Haemost 2009;7:1421–1423.
62. Manly DA, Wang J, Glover SL, et al. Increased microparticle tissue factor activity in cancer patients
with venous thromboembolism. Thromb Res 2010;125:511–512.
63. Ripplinger CM, Kessinger CW, Li C, et al. Inflammation modulates murine venous thrombosis
resolution in vivo: assessment by multimodal fluorescence molecular imaging. Arterioscler Thromb
Vasc Biol 2012;32:2616–2624.
64. Deatrick KB, Luke CE, Elfline MA, et al. The effect of matrix metalloproteinase 2 and matrix
metalloproteinase 2/9 deletion in experimental post-thrombotic vein wall remodeling. J Vasc Surg
2013;58:1375–1384.e2.
65. Deatrick KB, Obi A, Luke CE, et al. Matrix metalloproteinase-9 deletion is associated with
decreased mid-term vein wall fibrosis in experimental stasis DVT. Thromb Res 2013;132:360–366.
66. Wakefield TW, Strieter RM, Wilke CA, et al. Venous thrombosis-associated inflammation and
attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb
Vasc Biol 1995;15:258–268.
67. Varma MR, Varga AJ, Knipp BS, et al. Neutropenia impairs venous thrombosis resolution in the rat.
J Vasc Surg 2003;38:1090–1098.
161
68. Stewart GJ. Neutrophils and deep venous thrombosis. Haemostasis 1993; 23(suppl 1):127–140.
69. Varma MR, Moaveni DM, Dewyer NA, et al. Deep vein thrombosis resolution is not accelerated
with increased neovascularization. J Vasc Surg 2004;40:536–542.
70. Fuchs TA, Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl
Acad Sci 2010;107:15880–15885.
71. Massberg S, Grahl L, von Bruehl ML, et al. Reciprocal coupling of coagulation and innate immunity
via neutrophil serine proteases. Nat Med 2010;16:887–896.
72. Diaz JA, Fuchs TA, Jackson TO, et al.; for the Michigan Research Venous Group. Plasma DNA is
elevated in patients with deep vein thrombosis. Journal of vascular surgery. J Vasc Surg Venous
Lymphat Disord 2013;1(4). doi: 10.1016/j.jvsv.2012.12.002.
73. Saha P, Humphries J, Modarai B, et al. Leukocytes and the natural history of deep vein thrombosis:
current concepts and future directions. Arterioscler Thromb Vasc Biol 2011;31:506–512.
74. Humphries J, McGuinness CL, Smith A, et al. Monocyte chemotactic protein-1 (MCP-1) accelerates
the organization and resolution of venous thrombi. J Vasc Surg 1999;30:894–899.
75. Henke PK, Pearce CG, Moaveni DM, et al. Targeted deletion of CCR2 impairs deep vein thrombosis
resolution in a mouse model. J Immunol 2006;177:3388–3397.
76. Deatrick KB, Wakefield TW, Henke PK. Chronic venous insufficiency: current management of
varicose vein disease. Am Surg 2010;76:125–132.
77. Northeast AD, Soo KS, Bobrow LG, et al. The tissue plasminogen activator and urokinase response
in vivo during natural resolution of venous thrombus. J Vasc Surg 1995;22:573–579.
78. Soo KS, Northeast AD, Happerfield LC, et al. Tissue plasminogen activator production by monocytes
in venous thrombolysis. J Pathol 1996;178:190–194.
79. Singh I, Burnand KG, Collins M, et al. Failure of thrombus to resolve in urokinase-type plasminogen
activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation
2003;107:869–875.
80. Evans CE, Humphries J, Waltham M, et al. Upregulation of hypoxia-inducible factor 1 alpha in local
vein wall is associated with enhanced venous thrombus resolution. Thromb Res 2011;128:346–351.
81. Lim CS, Qiao X, Reslan OM, et al. Prolonged mechanical stretch is associated with upregulation of
hypoxia-inducible factors and reduced contraction in rat inferior vena cava. J Vasc Surg
2011;53:764–773.
82. Myers DD Jr, Henke PK, Bedard PW, et al. Treatment with an oral small molecule inhibitor of P
selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc
Surg 2006;44:625–632.
83. Moaveni DK, Lynch EM, Luke C, et al. Vein wall re-endothelialization after deep vein thrombosis is
improved with low-molecular-weight heparin. J Vasc Surg 2008;47:616–624.
84. Stenberg B, Bylock A, Risberg B. Effect of venous stasis on vessel wall fibrinolysis. Thromb Haemost
1984;51:240–242.
85. Henke PK, Varma MR, Moaveni DK, et al. Fibrotic injury after experimental deep vein thrombosis
is determined by the mechanism of thrombogenesis. Thromb Haemost 2007;98:1045–1055.
86. Wojcik BM, Wrobleski SK, Hawley AE, et al. Interleukin-6: a potential target for post-thrombotic
syndrome. Ann Vasc Surg 2011;25:229–239.
87. Grainger DJ, Wakefield L, Bethell HW, et al. Release and activation of platelet latent TGF-beta in
blood clots during dissolution with plasmin. Nat Med 1995;1:932–937.
88. Diaz JA, Ballard-Lipka NE, Farris DM, et al. Impaired fibrinolytic system in ApoE gene-deleted mice
with hyperlipidemia augments deep vein thrombosis. J Vasc Surg 2012;55(3):815–822.
89. Deatrick KB, Eliason JL, Lynch EM, et al. Vein wall remodeling after deep vein thrombosis involves
matrix metalloproteinases and late fibrosis in a mouse model. J Vasc Surg 2005;42:140–148.
90. Obi AT, Diaz JA, Ballard-Lipka NL, et al. Plasminogen activator-1 overexpression decreases
experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism. J
Thromb Haemost 2014;12:1353–1363.
91. Myers DD Jr, Henke PK, Bedard PW, et al. Treatment with an oral small molecule inhibitor of P
selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc
Surg 2006;44:625–632.
162
92. Wojcik BM, Wrobleski SK, Hawley AE, et al. Interleukin-6: a potential target for post-thrombotic
syndrome. Ann Vasc Surg 2011;25:229–239.
93. Baldwin JF, Sood V, Elfline MA, et al. The role of urokinase plasminogen activator and plasmin
activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis. J Vasc Surg
2012;56:1089–1097.
94. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008;451:914–918.
95. Ross R. Atherosclerosis–an inflammatory disease. N Eng J Med 1999;340:115–126.
96. Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol
2006;26:1729–1737.
97. Dentali F, Squizzato A, Ageno W. The metabolic syndrome as a risk factor for venous and arterial
thrombosis. Semin Thromb Hemost 2009;35:451–457.
98. Chan MY, Andreotti F, Becker RC. Hypercoagulable states in cardiovascular disease. Circulation
2008;118:2286–2297.
99. Glynn RJ, Danielson E, Fonseca FA, et al. A randomized trial of rosuvastatin in the prevention of
venous thromboembolism. N Eng J Med 2009;360(18):1851–1861.
100. Gangireddy C, Rectenwald JR, Upchurch GR, et al. Risk factors and clinical impact of postoperative
symptomatic venous thromboembolism. J Vasc Surg 2007;45:335–341; discussion 341–332.
101. Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc
Biol 2008;28:370–372.
102. Heit JA, Silverstein MD, Mohr DN, et al. The epidemiology of venous thromboembolism in the
community. Thromb Haemost 2001;86:452–463.
103. Caprini JA, Arcelus JI, Reyna JJ. Effective risk stratification of surgical and nonsurgical patients for
venous thromboembolic disease. Semin Hematol 2001;38:12–19.
104. Pannucci CJ, Laird S, Dimick JB, et al. A validated risk model to predict 90-day VTE events in post-
surgical patients. Chest 2013;145(3):567–573.
105. Gould MK, Garcia DA, Wren SM, et al.; American College of Chest Physicians. Prevention of VTE in
nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012;141:e227S–e277S.
106. van den Berg YW, Osanto S, Reitsma PH, et al. The relationship between tissue factor and cancer
progression: insights from bench and bedside. Blood 2012;119:924–932.
107. Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009;27:4834–
4838.
108. Khorana AA. The NCCN clinical practice guidelines on venous thromboembolic disease: strategies
for improving VTE prophylaxis in hospitalized cancer patients. Oncologist 2007;12:1361–1370.
109. Twig G, Zandman-Goddard G, Szyper-Kravitz M, et al. Systemic thromboembolism in inflammatory
bowel disease: mechanisms and clinical applications. Ann N Y Acad Sci 2005;1051:166–173.
110. Merrill A, Millham F. Increased risk of postoperative deep vein thrombosis and pulmonary
embolism in patients with inflammatory bowel disease: a study of national surgical quality
improvement program patients. Arch Surg 2012;147:120–124.
111. Selby R, Geerts W, Ofosu FA, et al. Hypercoagulability after trauma: hemostatic changes and
relationship to venous thromboembolism. Thromb Res 2009;124:281–287.
112. Shackford SR, Davis JW, Hollingsworth-Fridlund P, et al. Venous thromboembolism in patients
with major trauma. Am J Surg 1990;159:365–369.
113. Paffrath T, Wafaisade A, Lefering R, et al.; Trauma Registry of DGU. Venous thromboembolism
after severe trauma: incidence, risk factors and outcome. Injury 2010;41:97–101.
114. Khamashta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the
antiphospholipid-antibody syndrome. N Eng J Med 1995;332:993–997.
115. Carreras LO, Defreyn G, Machin SJ, et al. Arterial thrombosis, intrauterine death and “lupus”
antiocoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet
1981;1:244–246.
116. Comp PC, DeBault LE, Esmon NL, et al. Human thrombomodulin is inhibited by IgG from two
patients with non-specific anticoagulants (abstract). Blood 1983;62:244–246.
163
117. Eldrup-Jorgensen J, Flanigan DP, Brace L, et al. Hypercoagulable states and lower limb ischemia in
young adults. J Vasc Surg 1989;9:334–341.
118. Vermylen J, Blockmans D, Spitz B, et al. Thrombosis and immune disorders. Clin Haematol
1986;15:393–412.
119. Ferro D, Pittoni V, Quintarelli C, et al. Coexistence of anti-phospholipid antibodies and endothelial
perturbation in systemic lupus erythematosus patients with ongoing prothrombotic state. Circulation
1997;95:1425–1432.
120. Rand JH, Wu XX, Andree HA, et al. Pregnancy loss in the antiphospholipid-antibody syndrome–a
possible thrombogenic mechanism. N Eng J Med 1997;337:154–160.
121. Reverter JC, Tassies D, Font J, et al. Hypercoagulable state in patients with antiphospholipid
syndrome is related to high induced tissue factor expression on monocytes and to low free protein
S. Arterioscler Thromb Vasc Biol 1996;16:1319–1326.
122. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. Eng J Med
2013;368:1033–1044.
123. Greenfield LJ. Lupus-like anticoagulants and thrombosis. J Vasc Surg 1988; 7:818–819.
124. Ahn SS, Kalunian K, Rosove M, et al. Postoperative thrombotic complications in patients with lupus
anticoagulant: increased risk after vascular procedures. J Vasc Surg 1988;7:749–756.
125. Nielsen TG, Nordestgaard BG, von Jessen F, et al. Antibodies to cardiolipin may increase the risk of
failure of peripheral vein bypasses. Eur J Vasc Endovasc Surg 1997;14:177–184.
126. Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the
classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4:295–
306.
127. Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies in predicting adverse pregnancy
outcome. A prospective study. Ann Intern Med 1994;120:470–475.
128. Alving BM. How I treat heparin-induced thrombocytopenia and thrombosis. Blood 2003;101:31–37.
129. Ansell JE, Price JM, Shah S, et al. Heparin-induced thrombocytopenia. What is its real frequency?
Chest 1985;88:878–882.
130. Cancio LC, Cohen DJ. Heparin-induced thrombocytopenia and thrombosis. J Am Coll Surg
1998;186:76–91.
131. Almeida JI, Coats R, Liem TK, et al. Reduced morbidity and mortality rates of the heparin-induced
thrombocytopenia syndrome. J Vasc Surg 1998; 27:309–314; discussion 315–316.
132. Kelton JG, Smith JW, Warkentin TE, et al. Immunoglobulin G from patients with heparin-induced
thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood 1994;83:3232–3239.
133. Walenga JM, Jeske WP, Messmore HL. Mechanisms of venous and arterial thrombosis in heparin-
induced thrombocytopenia. J Thromb Thrombolysis 2000;10(suppl 1):13–20.
134. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is
not heparin specific. Thromb Haemost 1992; 67:545–549.
135. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated
with low-molecular-weight heparin or unfractionated heparin. N Eng J Med 1995;332:1330–1335.
136. Laster J, Silver D. Heparin-coated catheters and heparin-induced thrombocytopenia. J Vasc Surg
1988;7:667–672.
137. Levine RL, McCollum D, Hursting MJ. How frequently is venous thromboembolism in heparin-
treated patients associated with heparin-induced thrombocytopenia? Chest J 2006;130:681–687.
138. Warkentin TE. Heparin-induced thrombocytopenia. Dis Mon 2005;51:141–149.
139. Cuker A, Gimotty PA, Crowther MA, et al. Predictive value of the 4Ts scoring system for heparin-
induced thrombocytopenia: a systematic review and meta-analysis. Blood 2012;120:4160–4167.
140. Pouplard C, Gueret P, Fouassier M, et al. Prospective evaluation of the ‘4Ts’ score and particle gel
immunoassay specific to heparin/PF4 for the diagnosis of heparin-induced thrombocytopenia. J
Thromb Haemost 2007;5:1373–1379.
141. Warkentin TE. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost
1999;82:439–447.
142. Anderson JA, Weitz JI. Hypercoagulable states. Crit Care Clin 2011;27:933–952; vii.
143. Nakashima MO, Rogers HJ. Hypercoagulable states: an algorithmic approach to laboratory testing
164
and update on monitoring of direct oral anticoagulants. Blood Res 2014;49:85–94.
144. Gabriel F, Portolés O, Labiós M, et al.; RIETE Investigators. Usefulness of thrombophilia testing in
venous thromboembolic disease: findings from the RIETE registry. Clin Appl Thromb Hemost
2013;19:42–47.
145. Schafer AI, Levine MN, Konkle BA, et al. Thrombotic disorders: diagnosis and treatment.
Hematology Am Soc Hematol Educ Program 2003:520–539.
146. Mateo J, Oliver A, Borrell M, et al. Laboratory evaluation and clinical characteristics of 2,132
consecutive unselected patients with venous thromboembolism–results of the Spanish Multicentric
Study on Thrombophilia (EMET-study). Thromb Haemost 1997;77:444–451.
147. Rosendaal FR. Risk factors for venous thrombotic disease. Thromb Haemost 1999;82:610–619.
148. Flinn WR, McDaniel MD, Yao JS, et al. Antithrombin III deficiency as a reflection of dynamic
protein metabolism in patients undergoing vascular reconstruction. J Vasc Surg 1984;1:888–895.
149. Towne JB, Bernhard VM, Hussey C, et al. Antithrombin deficiency–a cause of unexplained
thrombosis in vascular surgery. Surgery 1981;89:735–742.
150. Pabinger I, Schneider B. Thrombotic risk of women with hereditary antithrombin III-, protein C-
and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural
Inhibitors. Thromb Haemost 1994;71:548–552.
151. Thomas RH. Hypercoagulability syndromes. Arch Intern Med 2001;161:2433–2439.
152. Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Eng J Med 2001;344:1222–
1231.
153. Bick RL. Prothrombin G20210A mutation, antithrombin, heparin cofactor II, protein C, and protein
S defects. Hematol Oncol Clin North Am 2003; 17:9–36.
154. Tait RC, Walker ID, Reitsma PH, et al. Prevalence of protein C deficiency in the healthy
population. Thromb Haemost 1995;73:87–93.
155. Donaldson MC, Belkin M, Whittemore AD, et al. Impact of activated protein C resistance on general
vascular surgical patients. J Vasc Surg 1997;25:1054–1060.
156. de Moerloose P, Bounameaux HR, Mannucci PM. Screening test for thrombophilic patients: which
tests, for which patient, by whom, when, and why? Semin Thromb Hemost 1998;24:321–327.
157. Franco RF, Reitsma PH. Genetic risk factors of venous thrombosis. Hum Genet 2001;109:369–384.
158. Gladson CL, Scharrer I, Hach V, et al. The frequency of type I heterozygous protein S and protein C
deficiency in 141 unrelated young patients with venous thrombosis. Thromb Haemost 1988;59:18–
22.
159. Martinelli I, Mannucci PM, De Stefano V, et al. Different risks of thrombosis in four coagulation
defects associated with inherited thrombophilia: a study of 150 families. Blood 1998;92:2353–2358.
160. Siddiqi FA, Tepler J, Fantini GA. Acquired protein S and antithrombin III deficiency caused by
nephrotic syndrome: an unusual cause of graft thrombosis. J Vasc Surg 1997;25:576–580.
161. Jennings I, Cooper P. Screening for thrombophilia: a laboratory perspective. Br J Biomed Sci
2003;60:39–51.
162. Dahlback B. Blood coagulation. Lancet 2000;355:1627–1632.
163. Cole MS, Minifee PK, Wolma FJ. Coumarin necrosis–a review of the literature. Surgery
1988;103:271–277.
164. Ridker PM, Miletich JP, Hennekens CH, et al. Ethnic distribution of factor V Leiden in 4047 men
and women. Implications for venous thromboembolism screening. JAMA 1997;277:1305–1307.
165. Rosendaal FR, Koster T, Vandenbroucke JP, et al. High risk of thrombosis in patients homozygous
for factor V Leiden (activated protein C resistance). Blood 1995;85:1504–1508.
166. Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Eng
J Med 1994;330:517–522.
167. Kalafatis M, Mann KG. Factor VLeiden and thrombophilia. Arterioscler Thromb Vasc Biol
1997;17:620–627.
168. Mann KG, Kalafatis M. Factor V: a combination of Dr Jekyll and Mr Hyde. Blood 2003;101:20–30.
169. Simioni P, Prandoni P, Lensing AW, et al. The risk of recurrent venous thromboembolism in
patients with an Arg506–>Gln mutation in the gene for factor V (factor V Leiden). N Eng J Med
1997;336:399–403.
165
170. De Stefano V, Martinelli I, Mannucci PM, et al. The risk of recurrent deep venous thrombosis
among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N
Eng J Med 1999;341:801–806.
171. Koeleman BP, Reitsma PH, Allaart CF, et al. Activated protein C resistance as an additional risk
factor for thrombosis in protein C-deficient families. Blood 1994;84:1031–1035.
172. Koeleman BP, van Rumpt D, Hamulyák K, et al. Factor V Leiden: an additional risk factor for
thrombosis in protein S deficient families? Thromb Haemost 1995;74:580–583.
173. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the
prevention of recurrent venous thromboembolism. N Eng J Med 2003;348:1425–1434.
174. Ouriel K, Green RM, DeWeese JA, et al. Activated protein C resistance: prevalence and implications
in peripheral vascular disease. J Vasc Surg 1996;23:46–51; discussion 51–52.
175. Poort SR, Rosendaal FR, Reitsma PH, et al. A common genetic variation in the 3′-untranslated
region of the prothrombin gene is associated with elevated plasma prothrombin levels and an
increase in venous thrombosis. Blood 1996;88:3698–3703.
176. Vicente V, González-Conejero R, Rivera J, et al. The prothrombin gene variant 20210A in venous
and arterial thromboembolism. Haematologica 1999;84:356–362.
177. Cumming AM, Keeney S, Salden A, et al. The prothrombin gene G20210A variant: prevalence in a
U.K. anticoagulant clinic population. Br J Haematol 1997;98:353–355.
178. Martinelli I, Sacchi E, Landi G, et al. High risk of cerebral-vein thrombosis in carriers of a
prothrombin-gene mutation and in users of oral contraceptives. N Eng J Med 1998;338:1793–1797.
179. Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of
myocardial infarction, stroke, and venous thrombosis in a large cohort of US men. Circulation
1999;99:999–1004.
180. Martinelli I, Taioli E, Bucciarelli P, et al. Interaction between the G20210A mutation of the
prothrombin gene and oral contraceptive use in deep vein thrombosis. Arterioscler Thromb Vasc Biol
1999;19:700–703.
181. Hillarp A, Zöller B, Svensson P, et al. The 20210 A allele of the prothrombin gene is a common risk
factor among Swedish outpatients with verified deep venous thrombosis. Thromb Haemost
1997;78:990–992.
182. Ferraresi P, Marchetti G, Legnani C, et al. The heterozygous 20210 G/A prothrombin genotype is
associated with early venous thrombosis in inherited thrombophilias and is not increased in
frequency in artery disease. Arterioscler Thromb Vasc Biol 1997;17:2418–2422.
183. Gerhardt A, Scharf RE, Beckmann MW, et al. Prothrombin and factor V mutations in women with a
history of thrombosis during pregnancy and the puerperium. N Eng J Med 2000;342:374–380.
184. McGlennen RC, Key NS. Clinical and laboratory management of the prothrombin G20210A
mutation. Arch Pathol Lab Med 2002;126:1319–1325.
185. De Stefano V, Casorelli I, Rossi E, et al. Interaction between hyperhomocysteinemia and inherited
thrombophilic factors in venous thromboembolism. Semin Thromb Hemost 2000;26:305–311.
186. den Heijer M, Blom HJ, Gerrits WB, et al. Is hyperhomocysteinaemia a risk factor for recurrent
venous thrombosis? Lancet 1995;345:882–885.
187. den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein
thrombosis. N Eng J Med 1996;334:759–762.
188. den Heijer M, Keijzer MB. Hyperhomocysteinemia as a risk factor for venous thrombosis. Clin Chem
Lab Med 2001;39:710–713.
189. Falcon CR, Cattaneo M, Panzeri D, et al. High prevalence of hyperhomocyst(e)inemia in patients
with juvenile venous thrombosis. Arterioscler Thromb 1994;14:1080–1083.
190. Fermo I, Vigano’D’Angelo S, Paroni R, et al. Prevalence of moderate hyperhomocysteinemia in
patients with early-onset venous and arterial occlusive disease. Ann Intern Med 1995;123:747–753.
191. Simioni P, Prandoni P, Burlina A, et al. Hyperhomocysteinemia and deep-vein thrombosis. A case-
control study. Thromb Haemost 1996;76:883–886.
192. Den Heijer M, Rosendaal FR, Blom HJ, et al. Hyperhomocysteinemia and venous thrombosis: a
meta-analysis. Thromb Haemost 1998;80:874–877.
193. Legnani C, Palareti G, Grauso F, et al. Hyperhomocyst(e)inemia and a common
methylenetetrahydrofolate reductase mutation (Ala223Val MTHFR) in patients with inherited
166
thrombophilic coagulation defects. Arterioscler Thromb Vasc Biol 1997;17:2924–2929.
194. Kottke-Marchant K. Genetic polymorphisms associated with venous and arterial thrombosis: an
overview. Arch Pathol Lab Med 2002;126:295–304.
195. Inherited causes of thrombosis. Indiana Hemophilia & Thrombosis Center. Available from:
http://www.ihtc.org/medical-professionals/blood-disorders/clotting-disorders/inherited-causes-of-
thrombosis/. Accessed May 27, 2016.
196. Schlesselman L. Novel risk factors for atherosclerotic disease. MedScape CME. 2001. Available from:
http://www.medscape.org/viewarticle/418378. Accessed May 27, 2016.
197. Mandel H, Brenner B, Berant M, et al. Coexistence of hereditary homocystinuria and factor V
Leiden–effect on thrombosis. N Eng J Med 1996; 334:763–768.
198. Hayashi T, Honda G, Suzuki K. An atherogenic stimulus homocysteine inhibits cofactor activity of
thrombomodulin and enhances thrombomodulin expression in human umbilical vein endothelial
cells. Blood 1992;79:2930–2936.
199. Loscalzo J. The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest 1996;98:5–7.
200. Rodgers GM, Conn MT. Homocysteine, an atherogenic stimulus, reduces protein C activation by
arterial and venous endothelial cells. Blood 1990; 75:895–901.
201. Tawakol A, Omland T, Gerhard M, et al. Hyperhomocyst(e)inemia is associated with impaired
endothelium-dependent vasodilation in humans. Circulation 1997;95:1119–1121.
202. Upchurch GR, Welch GN, Randev V, et al. The effect of homocysteine on endothelial nitric oxide
production. FASEB J 1995;9:A876.
203. George J, Alving BM, Ballem P. Platelets. In: McArthur JR, Benz EJ, eds. Hemotology - 1994.
Washington, DC: American Society of Hematologists 1994.
204. Ueland PM, Refsum H, Brattstrom L. Plasma homocysteine and cardiovascular disease. New York, NY:
Marcel Dekker; 1993.
205. Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease.
Thromb Haemost 2001;85:584–595.
206. Towne JB, Bandyk DF, Hussey CV, et al. Abnormal plasminogen: a genetically determined cause of
hypercoagulability. J Vasc Surg 1984;1:896–902.
207. Kwaan HC, Levin M, Sakurai S, et al. Digital ischemia and gangrene due to red blood cell
aggregation induced by acquired dysfibrinogenemia. J Vasc Surg 1997;26:1061–1068.
208. Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol 2001;114:249–
257.
209. Nilsson IM, Ljungner H, Tengborn L. Two different mechanisms in patients with venous thrombosis
and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of
plasminogen activator inhibitor. Br Med J (Clin Res Ed) 1985;290:1453–1456.
210. Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired
fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991;151:1721–1731.
211. van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable fibrinolysis inhibitor and the risk
for deep vein thrombosis. Blood 2000;95:2855–2859.
212. Paramo JA, Perez JL, Serrano M, et al. Types 1 and 2 plasminogen activator inhibitor and tumor
necrosis factor alpha in patients with sepsis. Thromb Haemost 1990;64:3–6.
213. Ishibashi S. Lipoprotein(a) and atherosclerosis. Arterioscler Thromb Vasc Biol 2001;21:1–2.
214. Liao JK, Shin WS, Lee WY, et al. Oxidized low-density lipoprotein decreases the expression of
endothelial nitric oxide synthase. J Biol Chem 1995;270:319–324.
215. Valentine RJ, Kaplan HS, Green R, et al. Lipoprotein (a), homocysteine, and hypercoagulable states
in young men with premature peripheral atherosclerosis: a prospective, controlled analysis. J Vasc
Surg 1996;23:53–61; discussion 61–63.
216. Griffin JH, Fernandez JA, Deguchi H. Plasma lipoproteins, hemostasis and thrombosis. Thromb
Haemost 2001;86:386–394.
217. Nowak-Gottl U, Junker R, Hartmeier M, et al. Increased lipoprotein(a) is an important risk factor
for venous thromboembolism in childhood. Circulation 1999;100:743–748.
218. Marcucci R, Liotta AA, Cellai AP, et al. Increased plasma levels of lipoprotein(a) and the risk of
idiopathic and recurrent venous thromboembolism. Am J Med 2003;115:601–605.
167
219. Ignatescu M, Kostner K, Zorn G, et al. Plasma Lp(a) levels are increased in patients with chronic
thromboembolic pulmonary hypertension. Thromb Haemost 1998;80:231–232.
220. Mosesson MW. Dysfibrinogenemia and thrombosis. Semin Thromb Hemost 1999;25:311–319.
221. Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999;353:1167–1173.
222. Harker LA. Platelets in thrombotic disorders: quantitative and qualitative platelet disorders
predisposing to arterial thrombosis. Semin Hematol 1998;35:241–252.
223. Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ, et al. Heritability of elevated factor VIII
antigen levels in factor V Leiden families with thrombophilia. Br J Haematol 2000;109:519–522.
224. Koster T, Blann AD, Briët E, et al. Role of clotting factor VIII in effect of von Willebrand factor on
occurrence of deep-vein thrombosis. Lancet 1995;345:152–155.
225. O’Donnell J, Mumford AD, Manning RA, et al. Elevation of FVIII: C in venous thromboembolism is
persistent and independent of the acute phase response. Thromb Haemost 2000;83:10–13.
226. Mansvelt EP, Laffan M, McVey JH, et al. Analysis of the F8 gene in individuals with high plasma
factor VIII: C levels and associated venous thrombosis. Thromb Haemost 1998;80:561–565.
227. Kyrle PA, Minar E, Hirschl M, et al. High plasma levels of factor VIII and the risk of recurrent
venous thromboembolism. N Eng J Med 2000; 343:457–462.
228. Miller CH, Dilley A, Richardson L, et al. Population differences in von Willebrand factor levels
affect the diagnosis of von Willebrand disease in African-American women. Am J Hematol
2001;67:125–129.
229. Meijers JC, Tekelenburg WL, Bouma BN, et al. High levels of coagulation factor XI as a risk factor
for venous thrombosis. N Eng J Med 2000; 342:696–701.
230. van Hylckama Vlieg A, van der Linden IK, Bertina RM, et al. High levels of factor IX increase the
risk of venous thrombosis. Blood 2000;95:3678–3682.
231. Lane DA, Grant PJ. Role of hemostatic gene polymorphisms in venous and arterial thrombotic
disease. Blood 2000;95:1517–1532.
232. Levi M, Toh CH, Thachil J, et al. Guidelines for the diagnosis and management of disseminated
intravascular coagulation. British committee for standards in haematology. Br J Haematol
2009;145:24–33.
233. Coppola A, Di Capua M, Di Minno MN, et al. Treatment of hemophilia: a review of current
advances and ongoing issues. J Blood Med 2010;1:183–195.
234. Fijnvandraat K, Cnossen MH, Leebeek FW, et al. Diagnosis and management of haemophilia. BMJ
2012;344:e2707.
235. Lusher JM, Arkin S, Abildgaard CF, et al. Recombinant factor VIII for the treatment of previously
untreated patients with hemophilia A. Safety, efficacy, and development of inhibitors. Kogenate
previously untreated patient study group. N Eng J Med 1993;328:453–459.
236. Larson PJ, High KA. Biology of inherited coagulopathies: factor IX. Hematol Oncol Clin North Am
1992;6:999–1009.
237. Ginsburg D. Biology of inherited coagulopathies: von Willebrand factor. Hematol Oncol Clin North
Am 1992;6:1011–1020.
168
Chapter 7
Inflammation
Matthew R. Rosengart and Timothy R. Billiar
Key Points
1 Innate immunity, a system already poised to respond prior to any stimulus, provides the initial
defense against microbes. Subsequent reinforcement is provided by the more specific adaptive
immune system, which possesses exquisite specificity for subsequent exposure to individual microbes
and the capacity to learn and modify subsequent responses to repeated exposures. Both are
composed of cellular and humoral components.
2 Implicit with the capacity for pathogen elimination is the potential for destruction of host tissues.
Numerous regulatory mechanisms provide temporal and spatial control of the inflammatory
processes, including programmed cell death (i.e., apoptosis).
3 Over 30 randomized controlled clinical trials have been conducted to assess the efficacy of
modulating inflammation, in particular systemic cytokine concentrations, in reducing mortality.
4 The TH1 inflammatory response (i.e., cell-mediated immunity or delayed-type hypersensitivity) is
induced by interleukin-12 (IL-12) derived from phagocytes and provides one major arm of the
adaptive immune response; it is mediated by CD4+ and CD8+ lymphocytes and macrophages, which
regulate production of opsonizing and complement fixing antibodies and are effectors of phagocyte-
dependent responses.
5 The principal stimulus for TH2 differentiation is IL-4, which is derived from T cells, mast cells, and
basophils. As the cellular effectors of humoral immunity, they provide the other major arm of the
adaptive immune response, which is mediated by TH2 CD4+ cells, B cells, plasma cells, and
antibodies.
6 The complement system is integral to both innate and adaptive immunity and has the capacity to
independently eliminate organisms and facilitate host defense by marking foreign particles for
phagocytosis through opsonization.
7 Additional systems, including the vascular (i.e., vasodilatation, adhesion receptors, kinin cascade)
and neuroendocrine (i.e., adrenocorticotropic hormone [ACTH], arginine vasopressin [AVP],
corticotropin-releasing hormone [CRH]), integrate with the immune system, sharing similar
mediators and their receptors, to orchestrate an intense, coordinated response to any injurious/septic
insult.
8 Danger-associated molecular patterns (DAMP) are the endogenous equivalent of PAMPS, represent
danger signals or “alarmins,” and share many characteristics similar to cytokines. They may be
released following nonprogrammed cell death, such as necrosis, or secreted as mediators by immune
cells, under which circumstance they may facilitate the inflammatory response.
9 Our immune system differentiates pathogens and damaged cells from self using evolutionarily
ancient sets of recognition molecules called pattern recognition receptors (PRR), which bind
conserved molecular structures found in large groups of pathogens, termed pathogen-associated
molecular patterns (PAMPs), an example being the toll-like receptors (TLR).
Our appreciation for the complexity and our understanding of the integrated mechanisms collectively
called “inflammation” has undergone considerable revision since the initial description of the four
cardinal signs and symptoms by Celsus in first century AD: “rubor et tumor cum calore et dolore,”
redness and swelling with heat and pain.1 Centuries lapsed before John Hunter postulated that
inflammation provides a survival mechanism to preserve the host. Ironically, he commented that an
exuberant inflammatory response could be deleterious. These are all too true, as the pathologic sequelae
of excessive inflammation (i.e., acute respiratory distress syndrome [ARDS], multiple organ dysfunction
syndrome [MODS]) are encountered ever more frequently as technology affords survival of the initial
169
insult.1 The 19th century witnessed milestone contributions to our understanding of this process as
Rudolph Virchow detailed the cellular pathology of inflammation, Julius Cohnheim provided
microscopic details of the acute phases of inflammation (vasodilatation, edema formation, and
leukocyte emigration), and Elie Metchnikoff described the events of phagocytosis.1–3 The integration of
these new data created a novel new paradigm of cellular and humoral concepts of inflammation, both of
which were deemed critical in host defense against foreign pathogens.
In the 20th century, technological advancements in molecular biology and biochemistry facilitated
more detailed investigation and enabled the rapid expansion of knowledge of the many interwoven
facets of the inflammation process. Evidence began to accumulate that the ramifications of these
processes extended beyond the confines of the insult. Many humoral mediators, in addition to local
effects, influenced distant targets as well, such as the liver and neurohormonal centers. Recently it has
become clear that the immune system, endocrine system, and nervous system comprise an integrated
network sharing similar mediators and their receptors. Such an integrative view, introduced by J. Edwin
Blalock, when combined with Hans Selye’s concept of stress, led to the contemporary understanding of
sickness behavior, defined by Robert Dantzer as a highly organized strategy of the organism to fight
infections and to respond to other environmental stressors. Hence, what originated nearly two millennia
ago as a simple concept founded upon a constellation of signs and symptoms is now considered an
intense, coordinated interplay of the nervous, vascular, endocrine, and immune systems to any injurious
insult. It is the culmination of millions of years of evolution. Without it, life would be an arduous,
painful, and brief existence, at best.
This chapter attempts to summarize this enormous quantity of information. An initial description of
the elements involved in inflammation will provide the foundation upon which to discuss the sequence
of events and interactions that comprise the inflammatory cascade.
INNATE VERSUS ADAPTIVE IMMUNITY

1 Innate immunity, a system composed of both cellular and humoral components, already poised to
respond prior to any stimulus, provides our initial security against invading microbes.4 Phylogenetically
it is ancient and conserved, notably providing the primary mechanism of invertebrate host defense. The
response it provides is uniform and consistent with each successive infection. Subsequent reinforcement
is provided by the more specific and targeted efforts of the adaptive immune system. In contrast to
innate immunity, and as the name would suggest, it “adapts” and subsequent exposure to the inciting
elicits responses of increased magnitude and defensive capabilities during.4 This exquisite specificity for
individual microbes, the capacity to “learn,” “remember,” and modify subsequent responses to repeated
exposures, has provided the impetus for the name.
Both arms of immunity are composed of cellular and serum components. In the adaptive immune
response this has been divided into humoral immunity, which is mediated primarily by antibodies, and
cell-mediated immunity. These are not distinct systems and form an integrated system of host defense.
CELLULAR COMPONENTS
Neutrophils
Neutrophils are integral to both innate and humoral immunity, providing the initial defense against
invading viral, bacterial, and parasitic pathogens. This importance is underscored by the fact that 55%
to 60% of the hematopoietic output of bone marrow is dedicated to the production of neutrophils.5 On
exiting the marrow they circulate for 7 to 10 hours before taking up residence in the tissues for 1 to 2
days (Table 7-1).6,7 They are uniquely sensitive to minute concentration gradients of microbial products
and inflammatory mediators and rapidly accumulate at sites of infection, where they ingest and dispose
of a wide array of pathogens with their vast microbicidal armamentarium. This pathogenicity, however,
carries with it an implicit capacity for host injury and accordingly, neutrophil function must be tightly
regulated.
Recruitment
Neutrophil recruitment, conceptually, is a sequence of events progressing from (1) initial adhesion to
activated endothelium, to (2) subsequent extravasation and emigration toward inflammatory foci, to (3)
170
the ultimate elimination of foreign microorganisms through phagocytosis, the generation of reactive
oxygen species (ROS), and the release of microbial substances.4
After injury, local and regional vasodilation induces hyperemia which facilitates the leukocyte
delivery to the focus of injury. Extravasation of plasma creates edema, and in combination with the
release of vasoactive substances leads to hemoconcentration, which promotes the peripheral
margination of leukocytes.8,9 Circulating neutrophils transiently interact with the endothelial cell
surface molecules during “rolling,” a process that involves a series of loose and reversible attachments
between the neutrophil and endothelium. (Fig. 7-1). These interactions, prerequisite for subsequent
tighter cell–cell interactions, are mediated by the family of selectin receptors which bind with their
counterligands, the sialyl Lewis family and other fucosylated and sulfated structures. E-selectin and P-
selectin are present on endothelium and L-selectin is found on leukocytes.4
After stimulation by inflammatory mediators (thrombin, histamine, complement fragments, oxygen
species, lipopolysaccharide [LPS], and cytokines such as IL-1, TNFα, and IFNγ), the vascular
endothelium expresses P- and E-selectin, which engage neutrophil surface glycoprotein P-selectin
glycoprotein ligand 1 (PSGL-1) or sialyl Lewis. P-selectin is stored intracellularly and can be rapidly
mobilized for expression within minutes of cellular activation. Endothelial cells also translocate ligands
for neutrophil L-selectin and release mediators like platelet-activating factor (PAF) and IL-8. Cytokines
such as TNFα, granulocyte-macrophage colony stimulating factor (GM-CSF), and granulocyte colony
stimulating factor (G-CSF) increase the affinity of leukocyte L-selectin for its counterreceptor. In
addition to mechanical anchorage, these selectins induce signal transduction pathways that influence
cellular function. P-selectin facilitates neutrophil degranulation and superoxide production, and cross-
linking L-selectin primes the neutrophil for increased superoxide production.10–12
After rolling, L-selectin is rapidly shed in preparation for leukocyte diapedesis and emigration into the
interstitium. Subsequent exposure to chemoattractant gradients results in conversion of the neutrophil
to a state of tight stationary adhesion (Fig. 7-1). The receptors mediating this interaction are members
of the β2 integrin family, most importantly leukocyte function antigen-1 (LFA-1, CD11a/CD18) and
Mac-1 (CD11b/CD18). Their expression is enhanced in response to selectin binding, and thus explains
the prerequisite nature of the early cell–cell interactions to neutrophil recruitment. Both integrin
receptors engage the intercellular adhesion molecules ICAM-1 and ICAM-2 in mediating adhesion; yet,
each provides additional important functions. Leukocyte emigration is primarily an LFA-1–dependent
process, as mice deficient in this receptor exhibit reduced neutrophil attachment to ICAM-1 and
endothelial cells. By contrast, mice lacking Mac-1 demonstrate impaired degranulation, superoxide
production, and phagocytosis. Mac-1 also binds fibrinogen, heparin, and factor X and is implicated in
neutrophil phagocytosis-induced apoptosis, a process essential for resolution of the inflammatory
process (see below). The very late antigen 4 (VLA-4) binds vascular cellular adhesion molecule 1
(VCAM-1) and may provide an additional mechanism for tight adhesion. In addition to providing
mechanical anchorage, these receptors interact with the cytoskeleton and other structural proteins and
signaling cascades and are thought to represent a biochemical link between the external environment and
intracellular signal transduction cascades that induce a cellular phenotype more appropriate for the
inflammatory environment (Fig. 7-2).13–15
Table 7-1 Leukocyte Subsets
171
Figure 7-1. Leukocyte recruitment. 1. Circulating leukocytes express integrins in a low-affinity conformation. 2. Exposure to
activated endothelium leads to rolling, which is mediated by L-selectin and P-selectin on the neutrophil and E-selectin on
endothelium. 3. Leukocyte exposure to cytokines released by macrophages phagocytosing pathogens induces a high-affinity
integrin conformation integrins. Tight leukocyte–endothelial adhesion involves integrin engagement with counterligand expressed
on the endothelium. 4. Subsequent exposure to chemokines leads to diapedesis, which is further mediated by the family of β1 and
β2 integrins. (Adapted from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed. Philadelphia, PA: Saunders; 2003.)
Once tightly adhered, neutrophils must diapedese between endothelial cells and across the basement
membrane to arrive at the focus of inflammation. Platelet/endothelial cell adhesion molecule 1
(PECAM-1) and integrin-associated protein are integral to transmigration (Fig. 7-1).13,14,16,17 PECAM-1
is concentrated along the intercellular junctions of endothelial cells, and both leukocyte and endothelial
PECAM-1 appear to be essential for neutrophil and monocyte diapedesis. Other candidate receptors
include the β1 integrins, or very late antigens (VLA), which possess affinity for many constituents of the
extracellular matrix, including laminin, fibronectin, and collagens, the β3 family of integrins including
the glycoprotein (gp) IIβIIIα and the vitronectin receptor.4 Further “directions” for migration to the
focus of inflammation are delivered by the concentration gradients of chemotactic factors, including
complement C5a, IL-8, LTB4, and the bacterial product N-formylmethionyl-leucyl-phenylalanine
(fMLP).18–20
The clinical significance of even minor derangements in any aspect of this process is evident in the
disease leukocyte adhesion deficiency, characterized by complete absence of CD18, and therefore all β2
integrins. Patients usually succumb to recurrent skin and mucosal infections within the initial 10 years
of life.4
Phagocytosis
Microbial elimination commences upon first encounter with a foreign pathogen. It is facilitated by
opsonization, a process in which microbes are coated by immune globulins and/or complement, which
subsequently bind to their respective cell surface receptors, FcγRs and Mac-1.21–23 Neutrophils
constitutively express low-affinity immune globulin receptors FcγRII and FcγRIII and can be induced to
express high-affinity FcγRI by incubation with IFNγ or cross-linking β2 integrins.5,24 Complement-
dependent phagocytosis is mediated by interactions between the leukocyte Mac-1 receptor and the
complement opsonin iC3b.
Once engaged, FcγRs are phosphorylated on tyrosine residues within an immunoreceptor tyrosine
activation motif (ITAM) by the Src family kinases.24 These phosphorylated sites serve as docking
regions for a variety of proteins, in particular Syk. The importance of Syk is underscored by the
observation that mice deficient in Syk are incapable of ingesting IgG-opsonized particles. A series of
enzymes are subsequently activated including phosphoinositol 3-kinase, phospholipase C (PLC), and
protein kinase C. Ultimately, the actin cytoskeleton undergoes rearrangement and the local
plasmalemma is remodeled in the formation and sealing of the phagosome.4,24
This immature phagosome undergoes a series of maturation steps, whereby it acquires the machinery
necessary for the killing and disposal of internalized microorganisms. Alterations in cytosolic calcium
concentration induce the fusion of secretory vesicles and granules containing the microbicidal
armamentarium with the immature phagosome.24 Proteins effected by calcium concentration and that
172
may govern phagosomal maturation include synaptotagmins, actin, calmodulin, and the Src family of
kinases.24 The soluble N-ethylmaleimide-sensitive-fusion-protein attachment protein receptor (SNARE)
proteins are thought to assist in fusion by engaging cognate receptors on the target membrane and
approximating the two membranes. Antibodies to the SNARE 5, syntaxin 6, and SNAP-23, inhibited
exocytosis of azurophilic and specific granules, respectively.24
Figure 7-2. Integrin Signaling. Integrins comprise a large family of cell surface receptors that are composed of 2 subunits, a and b,
and are activated by dimerization. The cytoplasmic tails are devoid of enzymatic activity, and hence, signal transduction is effected
by adapter proteins that connect the receptor to the cytoskeleton, cytoplasmic kinases, and transmembrane growth factor receptors.
As integrins bind the extracellular matrix they become clustered and associated with the cytoskeletal proteins talin, paxilin, and
vinculin and signaling complexes. Actin stress fibers form, which increase integrin clustering. Ultimately, focal adhesion kinase
(FAK) is recruited via interactions with talin and paxillin or with the b integrin subunit. Subsequent autophosphorlyation on
tyrosine 397 provides a binding site for the Src homology 2 (SH2) domain of Src. The Src kinase phosphorylates a number of focal
adhesion components including paxillin and tensin and pl30CAS, a docking protein that recruits Crk, which can subsequently
activate proximal elements in the JNK cascade of the MAPK family. FAK may also be phosphorylated by Src on tyrosine 925,
creating a binding site for the complex of the adapter Grb2 and Ras guanosine 5'-triphosphate exchange factor mSOS. These
interactions also lead to activation of MAPK cascades, and ultimately the induction of a variety of genes. (Adapted from Giancotti F
& Ruoslahti E. Integrin Signaling. Science 1999:1028-1032)
Neutrophil Granules and Secretory Vesicles

Neutrophils exhibit an oxygen-dependent “respiratory burst” pathway that generates toxic oxygen
derivatives and an oxygen-independent pathway that utilizes toxic proteinases.25 These two microbicidal
arms are compartmentalized into four distinct granules or vesicles (Table 7-2).26 They are mobilized in a
hierarchical fashion in response to gradual elevations in the intracellular calcium level, which parallels
the current needs of the cell.27 They also contain adhesion molecules and important inflammatory
mediators that help further orchestrate the involvement of other cells.
Primary, or azurophil (affinity for the dye azure A), granules target the destruction of phagocytosed
organisms (Table 7-2). The myeloperoxidase (MPO) within these granules generates hypochlorous acid
(HOCl) from products generated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and
also imparts the characteristic greenish color of pus.9,27 Other major constituents include (1) α-
defensins, cytotoxic proteins that scaffold into transmembrane pores within the microbial cell wall and
perturb the maintenance of vital transmembrane gradients, and (2) bactericidal/permeability-increasing
(BPI) protein, which binds to gram-negative organisms and induces rearrangement of membrane lipids
and inhibits growth.27–30 Elastase cleaves constituents of the extracellular matrix, including
173
proteoglycans, collagen (types I, III, IV), and fibronectin and, of course, elastin.31 Azurocidin is
chemotactic for monocytes and stimulates LPS-induced release of IL-6 and TNFα from monocytes.4,27
Table 7-2 Neutrophil Granules and Secretory Vesicles
Specific granules are rich in antimicrobial substances that are released extracellularly (Table 7-2).26
Lactoferrin, by sequestering iron, retards bacterial growth and can bind bacterial cell membranes and
induce irreversible membrane damage and lysis.27 Phospholipase A2 (PLA2) participates in the
degradation of bacterial membrane phospholipids. Lysozyme, present in all granules, is a cationic
antimicrobial peptide that cleaves peptidoglycan polymers of bacterial cell walls. Gelatinase and
collagenase are other extracellular matrix degrading enzymes.27 These granules also possess receptors
for a variety of extracellular matrix proteins and cell surface ligands (i.e., β2 integrin Mac-1) that
mediates firm adhesion to the endothelium. In addition to the mechanical function of cellular
anchorage, engagement of these receptors with their respective counterligands induces phenotypic
alterations such as degranulation and enhanced ROS production.4,27
Gelatinase granules contain matrix metalloproteases, zymogens that upon proteolytic activation
degrade the interstitial matrix including collagens, fibronectin, proteoglycans, and laminin; this may
facilitate neutrophil extravasation and migration (Table 7-2). They too are a source of cell surface
adhesion molecules.4,27,30
Secretory vesicles contain many of the cell surface adhesion molecules essential for leukocyte
recruitment. Their membranes are dense with the β2 integrins LFA and Mac-1, the complement receptor
CR1, the LPS receptor CD14, and the FcγRIII. Through fusion with the plasmalemma, the cell surface is
enriched with these receptors, which facilitates firm neutrophil-endothelial engagement and the capacity
to respond to a variety of stimuli.4,27 Not surprisingly, because of the essential nature of leukocyte
recruitment, secretory vesicles possess the lowest threshold for release and thus released earliest,
followed by gelatinase, specific, and azurophil granules (Table 7-2).27
174
Table 7-3 Major ROS and Their Metabolism
Oxidative Burst and Oxidant Metabolites

The generation of toxic oxygen metabolites and ROS is the cardinal characteristic of the neutrophil,
though is also a defensive quality of the monocyte/macrophage. Their essential antimicrobial properties
are equally destructive to host tissues and implicated in the pathophysiology of many inflammatory
disorders (Table 7-3). Thus, a delicate balance must be maintained between ensuring elimination of the
offending pathogen and minimizing host damage.
A free radical is any species possessing one or more unpaired electrons. They are categorized under
the broader term ROS, which encompasses all molecules capable of radical formation. Despite a very
brief existence (10−11 to 10−6 seconds) extensive damage may occur through the induction of free
radical chain reactions. Species underlying both physiologic and pathophysiologic inflammation include
the following: the superoxide anion (O2•−), the hydroxyl radical (•OH), hydrogen peroxide (H2O2), the
singlet oxygen, and the reactive nitrogen intermediates nitric oxide (NO) and peroxynitrite (ONOO−)
(Table 7-3). Counterintuitive to their role in cell destruction, recent evidence also supports a role of
ROS in intracellular signal transduction.32 Thus, in addition to their antimicrobial properties, ROS can
modulate the immune response by activating inflammatory cells and inducing proinflammatory cytokine
secretion.33,34
2 Implicit with the capacity for pathogen elimination is the potential for destruction of host tissues.
Hence, numerous regulatory mechanisms provide temporal and spatial control of the ROS production.
The NADPH oxidase complex itself exists in a disassembled state, and only upon cell activation and the
need for ROS production are the subunits approximated and enzymatic function enabled.35 In addition,
high plasma and tissue concentrations of proteinase inhibitors provide continuous surveillance and
systemic control. However, such regulation is incomplete as evidenced by diseases such as rheumatoid
arthritis, chronic obstructive pulmonary disease, and autoimmune vasculitis, which are the consequence
of damage due to neutrophil-derived products.35
NADPH oxidase is a heteromeric complex composed of six subunits: flavocytochrome b558, the
electron transporting apparatus comprises gp91(phox) and p22(phox); the cytosolic complex p40(phox),
p47(phox) and p67(phox); and the oxidase factor rac-2 (Fig. 7-3).35 Microorganisms or high
concentrations of chemoattractants bind to cell surface receptors and initiate oxidase activation,
heralded by phosphorylation of p47(phox). Cytochrome b558 (gp91 and p22), which exists within the
plasmalemma and the membranes of specific granules and secretory vesicles, is recruited by
phagocytosis and granule fusion. Phosphorylation of p47(phox) induces a conformation change that
enables its incorporation within the membrane, wherein it facilitates the translocation of rac2 and
p67(phox), and stabilizes the association of this cytosolic complex with cytochrome b558, thereby
rendering the complex functional.35
At the redox center of the oxidase an electron is transferred from NADPH to oxygen, thereby
generating superoxide.36
O2 + e-=O-2
Other mechanisms of superoxide production include uncoupling of xanthine dehydrogenase system,
uncoupling of mitochondrial and endoplasmic reticulum (ER) electron transport chains, and
nonenzymatic reactions such as autoxidation of hemoglobin.37,38
175
Figure 7-3. NADPH oxidase assembly. In the resting neutrophil, the cytochrome subunits gp91 and p22 are tightly bound in the
membrane. P47(phox), p67(phox) and rac-s complex are in the cytosol. On activation, GDI releases rac-2, and p47(phox) becomes
phosphorylated. This causes translocation of rac-2, p47(phox), and p67(phox) to the membrane and complex formation with the
cytochrome components, thereby completing the assembly of the active oxidase. (Redrawn from Burg ND, Pillinger MH. The
neutrophil: function and regulation in innate and humoral immunity. Clin Immunol 2001;99(1):7–17.)
Superoxide is relatively weak and of low bactericidal potency. However, its membrane permeability
and role as a reactant in reactions yielding highly toxic products confers upon it a high potential for
cellular and tissue damage.36
Superoxide can spontaneously or enzymatically (superoxide dismutase) dismutate into hydrogen
peroxide.35,36
It can also be converted to the more potent hydroxyl radical through the metal-catalyzed Haber–
Weiss reaction.35,36
or through the Fenton equation35,36
Under physiologic conditions, lactoferrin found in neutrophil specific granules provides the iron
catalyst for the Haber–Weiss reaction. In the Fenton reaction, superoxide or other biologic reducing
agents such as lactate or ascorbate donate electrons to generate the ferrous ions required to react with
hydrogen peroxide to produce the hydroxyl radical.35,36,39
The hydroxyl anion is highly reactive and induces DNA strand breaks and base hydroxylations leading
to adenosine triphosphate (ATP) depletion and gene mutations. It can attack lipid side chains of
membrane phospholipids to form hydrogen peroxide and lipid hydroperoxides in a process called lipid
peroxidation. These products can disrupt membrane function, serve as substrates for the production of
cytotoxic aldehydes, or uncouple calcium-ATPase and increase cytosolic calcium concentration. Recent
data also support a mechanism by which oxidation of critical sulfhydryl residues on the ryanodine
receptors induces an “open” configuration and a leak of intracellular ER calcium into the cytosol.40 This
elevation of cytosolic calcium activates calcium-dependent proteases and phospholipases that propagate
cellular damage.39
Superoxide can react with nitric oxide to produce peroxynitrite (ONOO–) and hydroxyl radical.36,41
The hemoprotein MPO yields the potently bactericidal HOCl from the reactants chloride and H2O2.
HOCl oxidizes amino acids, nucleotides, and hemoproteins, can activate neutrophil collagenases and
permit unabated elastase injury by inhibiting α1-antitrypsin, and contribute to hydroxyl radical and
singlet oxygen production.33,39,42 Though short-lived, subsequent reactions with secondary amines
generate secondary chloramines, which are equally toxic but much more stable. These metabolites can
oxidize similar cellular components. They can combine with halide anions to generate toxic free halides
or with taurine chloramines that induces membrane attack complex (MAC) complement
formation.33,39,42
176
In light of the pivotal role of MPO during inflammation and pathogen elimination, it is surprising that
MPO deficiency is common and relatively benign. Though MPO-deficient neutrophils show early
depressed bacterial killing, bactericidal function normalizes within 60 minutes.43 It is hypothesized that
though bacterial killing is impaired, post-phagocytosis-oxidase–dependent neutrophil apoptosis is
normal, resulting in appropriate regulation of the inflammatory response.43
Singlet oxygen, a highly reactive and extremely short-lived species, is formed by an input of energy
to O2 that reverses the spin direction of one of the outermost unpaired electrons away from a parallel
spin. It is produced during reactions of the MPO–H2O2–halide system and is a potential product of
superoxide dismutation and the Haber–Weiss reaction. It is highly electrophilic, reacting with
compounds containing electron-rich double bonds and may react with membrane lipids to produce
peroxides.39
The destructive potential of these ROS for both host and pathogen necessitates a mechanism of
continuous tight spatial and temporal regulation. The oxidase complex itself exists spatially
disaggregated; only upon cellular activation are its constituents assembled and enzymatic function
restored (Fig. 7-3).35,43 As elegant is the mechanism by which to control ROS production, so too are the
measures employed to eliminate these products when no longer needed. Superoxide, the proximal
reactant necessary for many of the ROS generating reactions, is removed by both spontaneous and
enzymatic (superoxide dismutase) dismutation to H2O2 (Fig. 7-4). H2O2 is subsequently reduced to
oxygen and water by catalase.36,39 In the extracellular environment, this function is performed by GSH
peroxidase, a selenium-dependent enzyme that reduces H2O while oxidizing reduced GSH to its oxidized
form. The utilization of N-acetylcysteine, a reducing agent that restores GSH, reduces hepatocellular
injury in an animal model of warm liver ischemia/reperfusion.32 It has also been shown to reduce
contrast-induced nephropathy in patients undergoing imaging procedures requiring the use of iodinated
contrast.44 Mechanisms for preventing hydroxyl radical-induced tissue damage include the binding of
transition metal ions by albumin, ceruloplasmin, haptoglobin, lactoferrin, and transferrin.33,36,39 Taurine
is a scavenger for HOCl. Other antioxidants that may assist in controlling the reaction include vitamins
E (tocopherol) and C. Vitamin C has many antioxidant properties, including the ability to regenerate α-
tocopherol. It can prevent activation of neutrophil-derived collagenase and is a powerful scavenger of
HOCl, superoxide, singlet oxygen, and hydroxyl radicals. Carotenoids have long double bonds to attract
and sequester free radicals. Uric acid is a powerful scavenger of water-soluble radicals such as HOCl and
singlet oxygen. It can also bind copper and iron ions to suppress hydroxyl radical formation. Stress
proteins or heat-shock proteins (HSPs) are induced by oxygen radicals and ischemia and may play a role
in defense. Furthermore, heme oxygenase-1 (HO-1) catalyzes the cleavage of heme to biliverdin, which
is subsequently converted to bilirubin, an efficient free radical scavenger.33,36,39
All of the aforementioned participants of the NADPH oxidase are vital for health, as evidenced by
those who suffer from chronic granulomatous disease (CGD).35,43 These patients have deficient
superoxide production and experience ineffective inflammatory reactions to infection. They commonly
suffer from repeated bacterial infections (pneumonia, cutaneous abscesses and hepatic and perihepatic
abscess, and osteomyelitis) by organisms that are catalase positive (Staphylococcus aureus). Organisms
that produce large amounts of peroxide are less of a threat as the neutrophils can utilize bacterial
peroxide to produce toxic metabolites. The use of prophylactic antibiotics and IFNγ has reduced the
frequency of serious infections in this patient population.35,43
177
Figure 7-4. Scavengers of ROS. (Redrawn from Klebanoff SJ. In: Gallin JI, Snyderman R, eds. Inflammation: Basic Principles and
Clinical Correlates. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999:723.)
Neutrophil Extracellular Traps and NETosis

The arsenal of antimicrobial products and mediators possessed by neutrophils to fulfill the tasks of
killing and eliminating pathogens is vast and impressive. However, another distinct antimicrobial
“weapon” was recently described, in which neutrophils extrude a lattice of chromatin and histones to
entrap and then kill invading pathogens. The characteristic feature is the presence of neutrophil nuclear
DNA in the extracellular space. These structures were entitled neutrophil extracellular traps (NETs), and
the process of NET formation called NETosis. Attached to this DNA backbone is an array of microbicidal
agents that are typically compartmentalized inside the azurophilic, specific and gelatinase granules:
neutrophil elastase (NE), cathepsin G, and MPO. Distinct from apoptosis, the process does lead to cell
death, though clearly contributes to pathogen control. It is conserved in various vertebrates, insects, and
even plants, and several microorganisms exhibit mechanisms of resistance to NETs, both of which may
highlight the importance of this process. Recent data suggest that excessive NETosis or ineffective NET
clearance may underly diseases or syndrome characterized by excessive inflammation, including
autoimmunity.45–47
Pathogens (i.e., bacteria, fungi, viruses, and protozoa) and their subcellular components, such as LPS,
M1 protein, and fMLP induce NET formation. Similarly, sterile insults, inflammatory stimuli (e.g., PAF,
IL-8, TNFα, NO), and chemical compounds (PMA, ionomycin) all can stimulate NETosis. The process
begins with engagement of the aforementioned stimuli with TLRs, Fc receptors, cytokine, and
complement receptors located on the neutrophil cell surface. Subsequent calcium release stimulates PKC
activity and assembly of functional NADPH oxidase, leading to ROS and NO production. ROS is/are
requisite for NET formation, as antioxidant scavengers (e.g., N-acetylcysteine) attenuate the process.
Interestingly, individuals with CGD, a disease characterized by insufficient ROS production, inefficiently
produce NETs. The chromatin undergoes decondensation followed by mixing of nuclear and cytoplasmic
components with granulate antimicrobial contents. Plasma membrane rupture ensues with the release of
chromatin decorated with granular proteins into the extracellular space.45–47
NETs are able to trap almost all pathogens, including those too large to be phagocytosed. Indeed, it is
proposed that trapping by NETs is one of the most important functions that limits microbial spread. The
antimicrobial functions of NETs are mediated by the microbicidal compounds accompanying the
chromatin: NE, MPO, histones, cathepsin G, proteinase 3, lactoferrin, calprotectin, and antimicrobial
peptides such as defensive or the cationic LL37. However, the histones H1, H2A, H2B, H3 and H4
themselves also possess powerful antimicrobial effects.
As fundamental as NETosis is for microbial defense, excessive formation or ineffective clearance of
NETs is proposed to lead to several pathologic conditions. During acute lung injury a high concentration
of stimulating factors promotes NETosis and the release of NE, LL-37, and ROS, which may exacerbate
injury. In cystic fibrosis, the high concentrations of DNA due to NETosis are thought to underlie the high
mucus viscosity.45–47 Several autoimmune diseases are also characterized by perturbed NETosis, and
more than 70% of NET components are potent autoantigens. Small vessel vasculitis is characterized by
antineutrophil cytoplasmic antibodies reactive against PR3 and MPO. Externalization of IL-17 in the
178
extracellular traps of neutrophils and mast cells is now thought to be central to the pathogenesis of
psoriasis. In systemic lupus erythematosus (SLE), an imbalance between NET formation and clearance
may underlie the systemic tissue damage that occurs. In fact, decreased NET degradation correlates with
renal disease. NETs may also activate complement, thereby amplifying the disease. Furthermore, the
neutrophils from patients with various autoimmune diseases appear more prone to NETose.45–47
NETs may also serve as a link between inflammation and thrombosis. They can provide a stimulus
and scaffold for thrombus formation by promoting platelet and RBC adhesion and by concentrating
effector proteins and coagulation factors. Activated endothelium produces compounds that, upon contact
with neutrophils, stimulate NETosis, which in turn, promotes endothelial damage.45–47
Regulation of Neutrophil Activity

In addition to the previously described mechanisms for controlling the inflammatory response of
neutrophils, there is substantial evidence supporting the role of apoptosis in halting and resolving the
neutrophil-derived inflammation (Box A).48 Within 90 minutes of phagocytosis, over 250 genes are
induced, of which more than 30 encode proteins integral to at least three distinct apoptotic pathways.48
These observations suggest that the mechanism inducing apoptosis is initiated quite proximal in the
inflammatory cascade, in fact, just subsequent to phagocytosis. The timely execution of a controlled cell
death program in human PMNs is essential for preventing damage to healthy tissues and for the
resolution of infection. Furthermore, evidence suggests that the phenotype of other immune cells,
including monocytes and macrophages, is altered after encountering and phagocytosing apoptotic
neutrophils. Thus, apoptotic neutrophil particles may function to downregulate the inflammatory
function of neighboring cells. In some circumstances of infection or trauma, neutrophil apoptosis may
be delayed, which might contribute to prolonged or a failure to resolve inflammation.
The inflammatory capacity of neutrophils is also transcriptionally regulated. Genes encoding
proinflammatory mediators or signal transduction molecules such as receptors for IL-8, IL-10, IL-13 are
downregulated early after activation and decrease rapidly after the initiation of apoptosis.48 In addition,
regulating oxidative stress and ROS achieve high priority as the genes involved in glutathione and
thioredoxin metabolism and heme catabolism are upregulated as is the production of reduced
glutathione.48 Hence, activation-induced apoptosis in neutrophils stimulates self-directed regulation, an
event that likely facilitates removal of neutrophils by macrophages. As aforementioned, removal of
apoptotic neutrophils by activated macrophages also appears to serve a role in modifying their function
and halting the inflammatory response.
Mononuclear Phagocytes
Monocytes circulate for about 1 to 2 days, whereafter, they constitutively hone to a particular tissue
(i.e., lung, peritoneum) to differentiate into macrophages possessing a phenotype specific to the
resident tissue (dendritic cells [DCs] of the skin, kupffer cells of the liver) (Table 7-1).4,49,50 Resident
macrophages are typically found at interfaces with blood (liver and spleen) and with lymph, where they
can readily detect, ingest, and destroy invading organisms.39 Mononuclear cells function as antigen-
presenting cells (APC) in T cell–mediated adaptive immune responses, presenting antigen in the
appropriate context to effector T cells. They provide service integral to both innate and adaptive
immune responses. Evidence also supports their role in providing an “alarm” both locally and
systemically through the release of intracellular proteins (i.e., high-mobility group box 1 [HMGB1])
expressing DAMP that can function as a danger signal (see below).
Recruitment
Monocytes are recruited and emigrate to foci of inflammation utilizing similar mechanisms of adhesion
and diapedesis as described for neutrophils (Fig. 7-1). PAF, C5a, the CC chemokines, regulated on
activation, normal T cell–expressed and secreted (RANTES), MIP-1α, and chemokines of the membrane
cofactor protein (MCP) family are potent monocyte-macrophage chemotaxins.51,52 The selectin family of
adhesion receptors mediates the initial tethering of monocytes to endothelial cells.18 Firm adhesion to
the endothelium involves the interactions of β1 and β2 integrins on monocytes with the endothelial
adhesion molecules ICAM-1 and VCAM-1.18
Phagocytosis
Phagocytosis involves the IgG receptor (FcγR) and the receptor for the complement factor C3b.
Terminal sugar patterns on microbial surfaces also allow recognition by macrophages for nonspecific
179
phagocytosis through the mannose lectin pathway.22 However, phagosomal maturation differs from that
which occurs in the neutrophil. Monocytes and macrophages have an endocytic pathway targeting the
phagosome to a lysosome.24 After endocytosis of a receptor–ligand complex, the contents of a vesicle
are targeted to an early endosome; the ligand and receptor dissociate, and the receptor is then recycled
to the cell surface.24 This early endosome undergoes a series of maturation steps in which it is acidified
(pH 5.5 to 6.0). This acidification is requisite for optimal protease and hydrolase activity involved in
pathogen killing. It may also be integral for phagosome maturation as titrating the acidity inhibits
phagosome–lysosome fusion.24 Ultimately, the endosome fuses with a lysosome, which is characterized
by its extreme acidity (pH <5.0) and elevated concentration of proteases.24 Lysosomes are the terminal
destination of phagocytosed material targeted for degradation.
After fusion, MPO released into phagosomes can react with hydrogen and halides to yield toxic
hypohalous acids, superoxide anion, hydrogen peroxide, and hydroxyl radical (Table 7-3). Macrophages
may also use peroxidase generated by adjacent neutrophils, eosinophils, and monocytes and acquired
through endocytosis to generate these ROS. In addition to supporting the inflammatory response,
macrophages also play an important immunoregulatory role in inflammation by scavenging apoptotic
neutrophils at sites of inflammation.39
Activation
IFNγ derived primarily from T cells is the primary activator of macrophages.4,50,53 Optimal macrophage
activation requires both interferon IFNγ and a sensitizing agent, both of which can be provided by
activated T lymphocytes. CD40 ligand on T cells can bind CD40 on macrophages to sensitize the cell.
Alternatively, membrane-associated TNFα or lymphotoxin from lymphocytes can activate macrophage
TNFα synthesis and thereby sensitize the macrophage to IFNγ.39 IL-10 promotes monocyte maturation
and macrophage differentiation.54 Other activators include GM-CSF, TNFα, IL-1, and LPS.
Activated monocytes and macrophages can produce approximately 100 different products, including
GM-CSF, M-CSF, G-CSF, IL-1, TNFα, G-CSF, and NO.39,55 Mononuclear phagocytes are important sources
of chemoattractants such as IL-8, PAF, and leukotriene B4 (LTB4) that recruit neutrophils and other
leukocytes. Their release of HMGB1 and other DAMP molecules serves as an endogenous “danger”
signals to other immune cells in the local environment. These bind to various PRR to alter cell function.
However, systemic release of HMGB1 may also be causally related to mortality in such inflammatory
states as sepsis and trauma.56,57 The respiratory burst and subsequent production of toxic ROS mirrors
that of neutrophils.
Antigen Presentation
T cells recognize only those antigens associated with surface major histocompatibility complex (MHC)
molecules. MHC class I molecules are expressed on all nucleated cells, whereas MHC class II molecules
are restricted to APC. After phagocytosing pathogen, mononuclear cells process and display antigen to T
cells, and in doing so, initiate the development of the adaptive response (i.e., antibody formation).
There is evidence that the HSP receptor CD91 may also participate in this process (see below). This
processed antigen is presented on the APC cell surface in the context of MHC molecules that are
specifically recognized by T-cell receptors (TCRs) and essential for T-cell activation. CD4+ T cells, or
helper T cells (TH), recognize antigen coexpressed with MCH class II molecules and induce B-cell
differentiation into either memory or antigen-specific antibody-producing plasma cells. These TH cells
can also induce macrophage production of NO, ROS, and other inflammatory mediators. CD8+ cytotoxic
T lymphocytes (CTL) recognize antigen in the context of MHC class I molecules and induce target cell
lysis; they destroy host cells infected with intracellular pathogens or cells of malignant potential.58
Activated mononuclear phagocytes release IL-12, a potent stimulus for TH cells and the production of
inflammatory cytokines, and elaborate IL-15, the function of which mirrors that of IL-2.59,60
The three professional APC are DCs, macrophages, and B cells. DCs are a specialized APC, which
process and present antigen to naïve T cells. Monocytes stimulated with GM-CSF, IL-4, or IL-13
differentiate toward DC. Maturation of the DC requires TNFα or LPS stimulation.39 Epidermal
Langerhans cells, after encountering antigen, migrate through the lymphoid organs and differentiate
into mature DC. DC cells are particularly effective at presenting viral antigen. They present antigen in
the context of both MHC I and MHC II, and thereby induce both a TH1 and a TH2 response, respectively.
DC can also present antigens derived from apoptotic cells in the context of MHC I.61–63
Macrophages present antigenic peptides from ingested pathogens that persist in the phagosomes.
These peptides, usually of bacterial origin, are expressed in conjunction with MHC II molecules. B cells,
180
by contrast, bind specific soluble molecules (insect toxins, venom, and allergens) via immunoglobulin.
This is endocytosed, processed, and presented on surface MHC II.39,63–65
Lymphocytes
B, T, and NK cells comprise this lineage of inflammatory cells (Table 7-1). B and T cells are central to
the adaptive immune response, whereas NK cells lack antigen specificity and primarily function during
innate immune response. NK cells are the first line of defense against many viral infections. The loss of
surface expression of MHC class I molecules as occurs with virus-infected cells serves as a target for NK
cells.39,66 Alternatively, NK cells bind cell-bound antibody and participate in antibody-dependent cell
cytotoxicity. Cells targeted by either mechanism are induced to undergo cell death.
B Lymphocytes
B cells, though of bone marrow origin, attain full maturation within extramedullary sites such as lymph
nodes, the spleen, and the mucosal lymph nodules of tonsils and Peyer patches. With activation, B cells
differentiate into antibody-producing plasma cells, which through the elaboration of antibody, aid the
neutralization of viruses and bacterial toxins, and facilitate opsonization for phagocytosis and
complement activation.4 Activation requires antigen binding to cell surface receptors and stimulation by
TH cell–derived cytokines; they do not need the assistance of APCs. Polyclonal B-cell activation can
occur in a T-cell–independent mechanism if the antigen has a large repeating polymeric sequence.39,67
T Lymphocytes
Development of T lymphocytes begins within the marrow and is completed in the thymus. The final
population profile is determined by apoptotic processes of both positive and negative selection.68 Any
protein or antigen of host origin is presented by APCs, and thymocytes reactive to these self-proteins are
deleted.69 Alternatively, expansion of cell lines recognizing foreign, or rather nonself antigen, occurs
through positive selection. IL-7 provides the stimulation for proliferation and differentiation of
developing T cells. Ultimately, two lines of mature cells, CD4+ and CD8+, will develop.69
Lymphocytes, the smallest of the leukocytes, constitute approximately 20% of circulating leukocytes.4
Most circulating lymphocytes are T cells, and 60% of those are CD4+, a marker of a TH phenotype. The
other 40% are CD8+, called cytotoxic T cells, TC. The normal ratio of CD4+/CD8+ is 2:1.4 Lymphocytes
continuously recirculate through lymph nodes, spleen, lymphatics, lymph nodules, and blood, providing
continuous surveillance. Encounter with a particular antigen initiates activation toward an effector T
cell. Activation of a T cell requires bind to its specific antigen plus a costimulatory signal provided by
the interaction between costimulatory molecules on the APC and their cognate receptors on the T cell.39
Naïve T cells circulate continuously between blood and lymphoid organs, making contact with many
APCs and the epitopes of the antigens they express.70 Initially, lymphocytes enter the cortical region of
lymph nodes by migrating across the high endothelial venules, a process mediated by the selectin family
of receptors. L-selectin, which is found constitutively on all lymphocytes, binds sialyl Lewis
carbohydrate on the endothelium.39 For example, L-selectin on lymphocytes binds GlyCAM-1 on the
high endothelial venules in lymph nodes. In mucosal tissues, L-selectin and endothelial MAdCAM-1
guide emigration. Migration across the endothelium requires integrins, in particular LFA-1 and its
interaction with ICAM-1 and ICAM-2 on endothelial cells.71 Most lymphocytes are carried back to the
blood by the efferent lymphatics. If a T lymphocyte recognizes its specific antigen on the surface of an
APC, it remains for several days, then returns to the blood as an armed effector T cell.39
Adhesion molecules mediate many of the transient interactions between T cells and APCs that are
required for the T cell to sample each antigen it encounters. Lymphocyte LFA-1 can bind the APC in a
loose, reversible fashion by any of the ICAM molecules on APCs. If a match between T cell and antigen
is found, conformational changes in LFA-1 greatly increase its affinity for ICAM-1 and ICAM-2 to
stabilize the interaction. The T cell can then proliferate and differentiate into an effector cell. Effector T
cells lose surface expression of L-selectin and no longer circulate through lymphoid tissue. Instead they
express VLA-4, an integrin, which binds vascular endothelium at sites of infection, and the cell is
retained at the focus. Effector T cells have increased LFA-1 and CD2 adhesion molecule expression that
facilitate tight binding to target cell.72,73
Antigen binding in the appropriate context provides the signal for clonal expansion and differentiation
of T cells into effector and memory lymphocytes. The appropriate contact is composed of antigen
complexed with MHC class II molecules on APCs, costimulators, and cytokines produced by the APCs
and by the T cells themselves. This first encounter of naïve T cells with antigen is the primary immune
181
response, which serves to induce the formation of effector and memory T cells. These activated T cells
hone to peripheral tissues where, upon reexposure to their specific antigen, they activate macrophages
to eliminate phagocytosed microbes and induce B-cell differentiation and antigen-specific antibody
secretion. The CD8+ CTLs kill infected host cells and tumor cells that display class I MHC-associated
antigen. Naïve T cells require activation by DCs, whereas effector T cells can respond to antigens
presented by a wider variety of APCs, such as macrophages and B lymphocytes. Not surprisingly,
differentiated effector and memory T cells possess lower thresholds for costimulation and require lower
antigen concentration for activation than naïve T cells.
In general, antigen presented on MHC II molecules is the prototypical stimulus for CD4+ T-cell
activation and the subsequent production of a variety of cytokine mediators, including IL-2, which
stimulate further expansion and activation. However, the circumstances under which this activation
occurs may dictate disparate paths of differentiation, producing T-cell subsets with distinct cytokine
profiles and effector functions. These differing phenotypes have been utilized to characterize two
distinct subsets: TH1 and TH2.59,60,74 IL-12 derived from phagocytes infected with intracellular pathogen
provides the necessary signal for TH1 differentiation.39 IL-12 also stimulates production of IFNγ, the
principle macrophage activator, by NK cells and CD4+ lymphocytes. Interferons stimulate TH1
development by augmenting phagocytic IL-12 production and by maintaining IL-12 receptor expression
on CD4+ T cells. The principal effector action of TH1 cells is the activation of macrophages through the
production of IFNγ, GM-CSF, TNFα, CD40L, and FasL.39,59,60,74 They regulate production of opsonizing
and complement fixing antibodies and are effectors of phagocyte-dependent responses. This
inflammatory response, also referred to as cell-mediated immunity or delayed-type hypersensitivity,
provides one major arm of the adaptive immune response; it is mediated by CD4+ and CD8+
lymphocytes and macrophages.
The principal stimulus for TH2 differentiation is IL-4, which is derived from T cells, mast cells, and
basophils.59,60,74 These cells are the cellular effectors of humoral immunity and provide the other major
arm of the adaptive immune response, which is mediated by TH2 CD4+ cells, B cells, plasma cells, and
antibodies. They produce IL-4, IL-5 and CD40L, thereby inducing B-cell activation and antibody
production, and a host of other proinflammatory and anti-inflammatory cytokines.39 Activation of mast
cells and eosinophils by extracellular pathogens is associated with activation of TH2 cells. TH2 cells quell
the inflammatory response by inhibiting macrophage functions and TH1 responses. They are considered
the anti-inflammatory arm of cell-mediated inflammation. Helper T cells that express both TH1 and TH2
patterns of cytokine expression have been called TH0 cells, and further studies will certainly discern
other subsets of T cells.4,74
T-cell activation, differentiation, and expansion are orchestrated by the T cell itself. The responding T
cell, in an autocrine fashion, serves as both source and target of a variety of mediators stimulating
growth. The principal autocrine growth factor is IL-2, which is induced by signaling regulated by the
phosphatase calcineurin (see below).75 IL-15 stimulates the proliferation of CD8+ T cells, especially
memory cells of the CD8+ subset. After antigen exposure, the numbers of T cells specific for that
antigen may increase to about 1 in 10 for CD8+ and 1 in 1000 to 10000 for CD4+ cells.4
After activation, some proliferating T cells will differentiate into effector cells that eliminate antigens
and activate other immune cells. Mature CD4+ cells induce the activation of mononuclear phagocytes
and B cells. CD8+ cells differentiate into CTL that recognize viral and other intracellular pathogen
antigens that are presented in the context of MHC class I molecules and induce target cell death by
releasing the cytotoxins perforin and granzymes from cytoplasmic granules. Granzymes are serine
proteases that trigger DNA fragmentation and apoptosis. Perforin stimulates cell membrane pore
formation that facilitates granzyme entrance into cells. Apoptosis can also be induced by the binding of
Fas ligand on CTL to Fas on the target cell. CTLs also release the cytokines IFNγ, TNFα, and CC
chemokines. IFNγ and certain CC chemokines have antiviral properties, and both are potent activators
of macrophage function. IL-2 produced by CTL and local helper CD4+ lymphocytes expands the CTL,
and IL-12 released by APC stimulates CTL activity. As with CD4+ cells, early evidence suggests that the
population CD8+ may be divided into TC1 and TC2 cells based on their cytokine profiles and effector
functions.39,58–60
Other T cells will mature into long-lived functionally quiescent memory cells. Upon antigen
reexposure, a cell surface rich in adhesion molecules (i.e., integrins, CD44) facilitates rapid and efficient
migration to peripheral sites of infection.4 These cells accumulate over time and in the adult human
comprise more than half of the circulating T cells.
182
Mere antigen exposure is insufficient for activation of naïve T cells. Proliferation and differentiation
require costimulatory signals provided by molecules on APCs. The best characterized costimulator
pathway involves the T-cell surface molecule CD28 and its counterligands B7-1 and B7-2 expressed on
activated APCs.4,39 CD28 delivers signals that enhance T-cell survival, by increasing expression of the
antiapoptotic protein Bcl-X, the production of cytokines such as IL-2 and the IL-2 receptor, and the
differentiation of immature T cells. In vitro, purified populations of CD4+ cells challenged with antigen
by APCs that express B7, proliferate and secrete cytokines. This does not occur if B7 is absent. The
costimulatory signal must come from the same APC that provides the initial signal. DCs are the most
potent APC because they express both classes of MHC molecules and the B7 molecules, whereas
macrophages and B cells must be activated to express the costimulatory molecules. This expression of
costimulators is regulated so as to ensure that T-cell activation is temporally and spatially appropriate.
For instance, during T-cell activation, engagement of CD40 ligand with CD40 induces upregulation of
B7 costimulators on the APCs. In addition, it increases the secretion of cytokines such as IL-12 that
promote T-cell differentiation, and cytokines are secreted that promote T-cell differentiation and
activation. A protein CTLA-4, expressed on activated T cells, is homologous to CD28 and binds B7-1 and
B7-2. Unlike CD28, CTLA-4 functions to terminate T-cell responses and plays a role in self-tolerance. On
the basis of many experimental studies of costimulators, antagonists against B7 molecules and CD40L
are in clinical trials to prevent the rejection of organ allografts.4,39
The differentiation of naïve CD8+ T cells to CTL requires a stronger costimulatory signal. This can be
provided by either DC, as they have the greatest intrinsic costimulatory activity, or by a CD4+ helper T
lymphocyte. Naïve helper T cells attached to the same APC as the CD8+ T cell can be activated to
elaborate IL-2. Attached effector T helper cells can stimulate the APC to express more costimulatory
molecules. In the case of virulent viruses, cytotoxicity can substitute for CD28 costimulation, and so the
typical costimulatory signal is not required for activation. For less virulent viruses, costimulation is
necessary for CTL induction.39,76 The absence of costimulation results in an unresponsive, or anergic T
cell. Recently this has been shown to be mediated by the serine/threonine kinase calcium/calmodulin-
dependent protein kinase (CaMK) II (see below).77 Anergic T cells do not produce IL-2 and therefore
cannot proliferate and differentiate into effector cells even when presented with antigen at a later
time.39
The affinity of most TCRs for peptide–MHC complexes is low, with dissociation constants of the order
of 10−5 to 10−7 and an estimated TCR–antigen interaction of less than 10 seconds. Furthermore, on any
APC fewer than 1000 of the 105 available MHC molecules are likely to be displaying any one peptide at
any particular time. Therefore, one APC can engage a small fraction of the 104 to 105 antigen receptors
on a single T cell.4 Activation of an individual T cell may require multiple sequential engagements of
that cell’s antigen receptors by peptide–MHC complexes on APCs. With engagement, there is clustering
of membrane receptors, tyrosine phosphorylation of several proteins, and recruitment and activation of
adaptor proteins.
TCRs are devoid of enzymatic activity and must utilize other signal-transducing proteins.4 After TCR–
MHC engagement, several membrane surface proteins and intracellular signaling proteins are rapidly
recruited: TCR complex, CD4 or CD8, receptors for costimulators such as CD28, and enzymes and
adaptor proteins.4 After TCR clustering, activated tyrosine kinases associated with and phosphorylate
tyrosine residues on CD3 and TCR (Fig. 7-5). These phosphorylation sites provide docking sites for
other tyrosine and protein kinases, such as Lck, an Src family tyrosine kinase, and ZAP-70, a tyrosine
kinase. These kinases become activated with phosphorylation. Activated ZAP-70 phosphorylates several
adaptor proteins that subsequently induce a variety of signal transduction cascades. Adaptor proteins
contain structural domains that bind other proteins and thereby facilitate the correct spatial orientation
that is required for signal transduction. The ras pathway is also activated, which is an early step in the
activation of the mitogen-activated protein kinases (MAPK) that can activate a variety of transcription
factors. Ras is a member of a family of guanine nucleotide-binding proteins (GDP/GTP) that are
involved in diverse activation responses in different cell types. This pathway is an amplification process
by which few upstream kinases lead to the activation of several downstream kinases. Ultimately
activation of the terminal extracellular regulated kinase (ERK 1/2) leads to the phosphorylation of the
protein ELK, which stimulates the transcription of fos, a component of the activation protein 1 (AP-1)
transcription factor (Table 7-4). Concomitantly, c-Jun N-terminal kinase (JNK) is activated, which
phosphorylates c-Jun, the second component of AP-1. The third member of the MAPK family, p38, is
also activated. The activities of the MAPKs are terminated by specific protein tyrosine/threonine
phosphatases that are regulated by the MAPKs themselves. Hence, the entire system is self-regulated by
183
a negative feedback system.4
Figure 7-5. T-cell signaling and activation. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed.
Philadelphia, PA: Saunders; 2003.)
Table 7-4 Transcription Factors
Activation of TCR also leads to the induction of PLC, in particular PLCγ1 (Fig. 7-5). Phosphorylated
PLCγ1 catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-
triphosphate (IP3) and diacylglycerol (DAG), and activates enzymes that generate additional active
transcription factors. IP3 increases cytosolic calcium that leads to a large influx of both intracellular and
extracellular calcium with subsequent activation of calcium- and calmodulin-dependent proteins.
Calcineurin, a calcium/calmodulin-dependent phosphatase is integral to T-cell activation via modulation
of the activation of the transcription factors nuclear factor of activated T cells (NFAT) and NFκB (Table
7-4).4,75 These transcription factors are essential for the induction of cytokine transcription, in particular
IL-2 production. However, in the absence of costimulation, activation of the CaMK II opposes the
actions of calcineurin as described above and produces an anergic cell.77 DAG activates protein kinase C,
which activates additional transcription factors. The role of PKC and calcium in T-cell function is made
evident by studies in which pharmacologic activation of PKC and/or elevation of intracellular calcium
concentration stimulates T-cell cytokine secretion and proliferation.4 Regulation of those kinases
operant in T-cell signaling involves protein tyrosine phosphatases. Through dephosphorylation they
modulate TCR signaling. Two phosphatases induced with TCR clustering are SHP-1 and SHP-2.
The ultimate goal of all these signaling transduction pathways is to activate transcription factors that
bind to promoter regions and enhance transcription. Three transcription factors that are activated in T
cells and appear critical for most T-cell responses are NFAT, AP-1, and NFκB (Table 7-4).
A third mechanism of T-cell activation involves lipid antigens, such as cell wall protein from
intracellular bacteria. These antigens bind CD1, a MHC-related cell surface molecule that presents these
184
antigens to certain subtypes of T cells. A superantigen is an unprocessed bacterial or retroviral product
that binds the MHC molecule and the TCR outside the usual antigen-binding sites. This engagement
leads to a polyclonal and nonspecific stimulation of a large proportion of the T-cell population. An
overwhelming activation of all arms of the immune system ensues and underlies much of the
pathophysiology of toxic shock syndrome (TSS). Intravenous immunoglobulin (IVIG), by binding this
antigen, is thought to be of therapeutic benefit.
Eosinophils
Eosinophils are marrow-derived granulocytes that share some properties of neutrophils, act in
conjunction with basophils and mast cells as primary effectors in allergen inflammation and are
involved in the eradication of helminthic infections (Table 7-1). Upon exiting the marrow, their
intravascular half-life is but a few hours, whereafter they enter the mucosa of the lung, gastrointestinal,
and genitourinary tracts.39,78 IL-3, GM-CSF, and IL-5 promote eosinophil differentiation, the induction of
effector functions, and survival, the last by inhibiting apoptosis.78 Emigrating through inflamed
endothelium they release inflammatory mediators and toxic agents from cytoplasmic granules. They
generate superoxide anion and hydrogen peroxide, though less efficiently than neutrophils. They express
IgE receptors and stimulate histamine release from basophils and mast cells through major basic protein
(MBP). They can also regulate basophil and mast cell function by releasing enzymes that inactivate
histamine and slow-reacting substance of anaphylaxis (SRS-A).
Recruitment and Activation

Eosinophils are recruited primarily to sites of parasitic infection and allergen challenge. Mast cells and
macrophages responding to either secrete mediators (IL-5, PAF, LTB-4) that upregulate expression of
endothelial adhesion molecules. Eosinophils themselves are more responsive to CC chemokines (MIP-1
α, RANTES, and MCP-3) and the cytokines produced with TH2 activation. Engagement of eosinophil β1
integrin VLA4 with VCAM-1 and fibronectin on the endothelium initiates the process of emigration. IL-4
can activate both the binding and the upregulation of endothelial cell VCAM-1. Diapedesis and tissue
infiltration also involves members of the β2 integrin family (Mac-1 and LFA) similar to that which
mediates neutrophil recruitment.39,79
Eosinophils are activated by IL-3, GM-CSF, IL-5, PAF, CC chemokines, and C3a and C5a of
complement. IL-5 is a potent activating agent and enhances the ability of eosinophils to release granule
contents on FcR cross-linking. A positive feedback cycle ultimately is established, in which recruited
eosinophils produce cytokines and chemokines that recruit more eosinophils and other leukocytes.
Granules
Eosinophils possess a compartmentalized armamentarium of toxic substances that assist in the
elimination of organisms, in particular helminths. Their specific granules contain GM-CSF and MBP, the
latter of which is cytotoxic to parasites and normal cells. Further, it functions as a stimulus for
histamine release from mast cells and basophils.80 The granule matrix contains eosinophil peroxidase
(EPO), eosinophil-derived neurotoxin, lysosomal enzymes, catalase, TNFα, TGFβ, and eosinophilic
cationic proteins that stimulate formation of transmembrane pores to increase target cellular
permeability.81 EPO is released extracellularly on target cell surfaces where it generates hydrogen
peroxide and hydrogen halides. Approximately 30% of oxygen consumed by stimulated eosinophils is
utilized in the formation of halogenating species. Thiocyanate may be the major halide for the EPO–
H2O2 system.82 If ingested by a neighboring phagocyte, EPO can combine with H2O2 and halides to
form hypohalous acids. EPO also stimulates neutrophil aggregation and adhesion to endothelial cells.
Although they express Fc receptors for IgG, IgA, and IgE, they are relatively insensitive to activation by
antigen-mediated cross-linking of these receptors. However, they can kill microorganisms by antibody-
dependent cell-mediated cytotoxicity.4,39
The primary targets of eosinophils are extracellular parasites. The size of these pathogens prohibits
phagocytosis, and their integument is relatively resistant to the microbicidal products of neutrophils and
macrophages; however they can be killed by MBP, which is released after cross-linking of Fc-bound IgE
coating the parasite. The TH2 response to parasitic invasion produces IL-4, IL-5, and IL-13. IL-4
stimulates the production of specific IgE antibodies, which opsonize helminths. IL-5 activates
eosinophils, which bind to the IgE-coated helminthes via Fc receptors. Activated eosinophils then release
their granule contents and generate ROS and hypohalous acids. EPO also stimulates neutrophil
aggregation and adhesion to endothelial cells. The sparse uncompartmental granules contain Charcot–
185
Leyden crystals and have lysophospholipase activity. Finally, eosinophils produce and release lipid
mediators such as PAF, prostaglandins, and LTs, which probably contribute to the process of allergic
diseases.4,83,84
Basophils and Mast Cells

Basophils and mast cells are central to the development of allergic inflammation and produce cytokines,
lipid mediators, vasoactive amines, and proteases that can also participate in nonallergic inflammatory
responses (Table 7-1). Both cells share a common progenitor cell, which diverges early during
differentiation. The primary growth factors for basophil development are IL-3 and GM-CSF, whereas
stem cell factor is the primary stimulus for mast cell maturation.85 Although basophils and mast cells are
distinct cell types, they are often grouped together because of the similarity of their granule content,
the stimuli inducing activation, and their effector functions.39
Mature basophils constitute only 0.5% to 1% of the circulating leukocytes. Mast cells are primarily
tissue-fixed residents of connective tissue. Engagement of IgE-bound antigen with the high-affinity IgE
antibody receptor, FceR, provides the primary stimulus for basophil and mast cell activation and
degranulation. In addition, diverse agents such as contrast media, opiates, anaphylatoxins, chemokines,
and neuropeptides may serve as activators. Basophils and mast cells elaborate both preformed, as well
as, newly synthesized inflammatory mediators. The main basophil proteoglycan is chondroitin sulfate A,
whereas mast cells contain heparin, chondroitin sulfate, and chondroitin sulfate E and also store neutral
proteases.86 The lipid mediators LTB4, LTC4, and PGD2 are synthesized de novo in response to
stimulation. The LTs are powerful vasoconstrictors, bronchoconstrictors, and chemoattractants for
neutrophils and eosinophils. PGD2 inhibits platelet aggregation and is chemotactic for neutrophils. Both
basophils and mast cells synthesize and secrete histamine. Histamine, or 2-(4-imidazolyl)-ethylamine, is
formed by the carboxylation of histidine. It is stored in preformed granules at acid pH as a complex
with proteins and proteoglycans. Mast cells carry greater quantities of histamine than do basophils. The
classic vasoactive properties of arteriolar dilatation, increased vascular permeability, and
bronchoconstriction are mediated by the H1 receptors. H2 receptors are involved in modulation of the
immune response and stimulating gastric output and mucus secretion. H3 receptors participate in
neuroconduction.39,86,87
Platelets
Though classically considered in the context of hemostasis, studies confirm that platelets are also
integral to normal and pathologic inflammation and link the processes of hemostasis, inflammation, and
tissue repair. They are activated in a variety of inflammatory conditions, such as rheumatoid arthritis
and inflammatory bowel disease, a testimony to their role in inflammation.88 Upon activation, they
release factors that enhance vascular permeability, chemokines, microbicidal proteins, and mitogens for
endothelial cells, smooth muscle cells, and fibroblasts. They assist leukocytes in promoting the
inflammatory reaction and killing microbes by providing an adhesive surface to facilitate emigration, by
stimulating adhered leukocytes, and by further modulating chemokine synthesis (Table 7-5).88,89
Humans possess about 150 to 400 × 109 platelets per liter of blood.88 Thrombopoiesis is regulated by
thrombopoietin as well as a variety of other mediators (IL-3, IL-4, IL-6, IL-7, and IL-11). In fact, human
IL-11 is in clinical use to stimulate thrombopoiesis in patients undergoing chemotherapy.90 After release
from the marrow, platelets circulate with a half-life of approximately 12 days. Interferon α is inhibitory
for megakaryocyte growth, and the elevated levels induced with some viral and inflammatory
conditions may explain the relative thrombocytopenia observed in these conditions.88,91
Recruitment and Activation

Platelets are activated by and aggregate in response to thrombin or activated endothelium. Clot
formation triggers the release of vasoactive agents (PGE2, PGI2, PGF2α, and platelet-derived growth
factor [PDGF]) and inflammatory mediators. Serotonin, PGE2, and PAF increase vascular permeability.
The adhesion molecule PECAM-1 and the β3 integrins mediate platelet plug formation, endothelial cell
adhesion, and leukocyte emigration. The integrin IIb/IIIa and P-selectin facilitate platelet interactions
with other inflammatory cells. The α granules are rich in membrane-bound P-selectin; upon fusion with
the cell surface membrane they enhance the cell surface density of this receptor. On stimulation, both
receptors are expressed on the platelet surface in an activated state. IIb/IIIa binds various adhesive
proteins containing the RGD sequence (i.e., fibrinogen), which serve as a mechanical link to other
186
platelets, leukocytes, and the endothelium. Possibly, the immobilization of activated P-selectin–
expressing platelets on the vessel wall may biochemically and functionally promote the adhesion of
neutrophils to endothelial cells.88,91
Table 7-5 Platelet-Derived Mediators
Platelets are a primary source of chemoattractants for neutrophils. Neutral proteinases released from
stimulated platelets cleave complement factor C5, liberating the chemoattractant C5a. PDGF binds
strongly to the extracellular matrix, providing a long-acting source of chemoattractant. Platelet factor 4
(PF4) is a cationic protein that penetrates the vascular wall and is a chemoattractant. Activated platelets
also bind monocytes via P-selectin and PSGL-1 and induce the expression and secretion of monocyte
chemotactic protein-1 (MCP-1) and IL-8. Thrombospondin released from activated platelets mediates
monocyte binding to platelets. Together these substances promote leukocyte margination, activation,
and recruitment to the sites of injury.39
Granules
The vasoactive substances and inflammatory mediators of platelets are either stored in cytoplasmic
granules or synthesized de novo. A platelet contains about 35 α granules and 5 dense bodies. The dense
granules contain adenosine diphosphate (ADP), ATP, serotonin, and calcium that are required during the
earlier stages of inflammation. ADP is the principal platelet agonist during platelet aggregation and
augments the oxidative burst of neutrophils. Serotonin increases vascular permeability and enhances the
superoxide production by macrophages.88
The more abundant α granules contain fibrinogen, RANTES, MIP-1α, thrombospondin, P-selectin,
PF4, PDGF, TGFβ, β-thromboglobulin, high–molecular-weight kininogen (HMWK), and many other
biologically active proteins. PF4 and β-thromboglobulin initiate leukocyte recruitment and activation.
PF4 induces neutrophil adherence to unstimulated endothelium and the release of secondary granules. It
inhibits monocyte apoptosis and promotes macrophage differentiation. PF4 can also stimulate histamine
release from basophils. RANTES is deposited on the endothelium and recruits monocytes from the
circulation. PAF induces platelet aggregation, increases vascular permeability, enhances phagocyte free
radical formation, and the adhesion of platelets to neutrophils. Platelet activation appears to occur in
187
allergic asthma and may precede the delayed accumulation of eosinophils in the lung after allergen
exposure. The α granules also carry several important growth factors, including vascular endothelial
growth factor (VEGF), PDGF, and TGFβ. VEGF promotes extravasation and aids recruitment of
leukocytes. PDGF is chemotactic for neutrophils and monocytes. TGFβ is chemotactic for and activates
neutrophils and monocytes early during inflammation, but displays immunosuppressive effects during
later stages of inflammation.88
Platelets are an important source of eicosanoids, including thromboxane, prostaglandins F2α and E2.
Thromboxane synthetase in platelets is responsible for the production of TXA2, a potent vasoconstrictor
that also increases vascular permeability and stimulates platelet aggregation. Aspirin and other
nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit platelet function by inhibiting TXA2 production.
As this effect is irreversible, new platelets must be produced (7 to 10 days) to restore normal clot
formation. In emergent circumstances (management of intracranial hemorrhage) platelet administration
is required. Recently, an aspirin response test has been developed that assists in guiding therapy and
targeting transfusion to those with functional evidence of platelet inhibition. It has also assisted in
monitoring the response to transfusion. PGF2α causes vasoconstriction, whereas PGE2 vasodilates and
modulates pain.92,93
Platelets participate in transcellular lipoxygenase (LO) metabolism, which refers to the production of
eicosanoids through interactions with neighboring inflammatory cells. Endothelial cells utilize platelet-
derived endoperoxides to synthesize PGI2. Platelets interact with neutrophils in several pathways,
providing a direct link between thrombosis and inflammation. 12-hydroxyeicosatetraenoic acid (12-
HETE) released from activated platelets can be used by unstimulated neutrophils to produce the
chemoattractant 12,20-HETE. 12-HETE and 5-HETE from activated platelets and neutrophils,
respectively, can combine in either cell type to form 5,12 diHETE, an anti-inflammatory compound,
which diverts production away from the proinflammatory LTs. 12-LO from platelets and LTA4 formed
by neutrophils can produce the intermediate 5(6)-epoxytetraene. This intermediate produces lipoxins A4
and B4 that have primarily counterinflammatory functions.39,89,92,94
In addition to modulating inflammation platelets possess some direct microbicidal activity. Platelets
are activated and degranulate when exposed to certain bacteria. Electron microscopic studies have
shown that activated platelets internalize bacteria and viruses. The α granules contain antibacterial
proteins called thrombocidins (TC) in humans that support the killing of adherent bacteria. The two
antibacterial proteins isolated from human platelets (TC-1, TC-2) are bactericidal for Escherichia coli and
S. aureus.88
NONCELLULAR COMPONENTS
Cytokines
Cytokines are soluble protein mediators secreted by the cells of the innate and adaptive immunity in
response to microbes and other antigens, including intra- and extracellular proteins, and mediate many
of the functions of these cells (Table 7-6). They regulate and influence the host response to both PAMPs
on bacterial, viruses, fungi, and parasites and DAMPs released during trauma, burns, allograft rejection,
ischemia/reperfusion injury, and autoimmune disease. They govern lymphocyte differentiation during
adaptive immunity and activate effector cells of both arms of inflammation to eliminate microbes.
Cytokines play important roles in tumor biology and angiogenesis. Though essential for a normal
immune response, excessive cytokine release underlies a variety of pathophysiological inflammatory
states such as ARDS and MODS.95–98
Table 7-6 Cytokines
188
Cytokine secretion is brief, and as cytokines typically are not stored preformed, they must be
transcribed and synthesize de novo synthesis, which is also transient as the messenger RNA is unstable.
189
Their functions are pleiotropic and redundant, which has been interpreted to represent a teleological
safety mechanism. However, such protective characteristics greatly limit the therapeutic utility of either
cytokine administration or blockade. In fact, over 30 randomized controlled clinical trials have been
conducted to assess the efficacy of modulating inflammation, on reducing mortality in a variety of
contexts: trauma, sepsis. The majority have involved manipulating systemic cytokine concentrations.
Only one, activated protein C, was briefly FDA approved for use; it was recently removed from the
market due to lack of benefit.99
Cytokines often influence the synthesis and actions of other cytokines, such as IL-1–induced T-cell IL-2
production; this interaction may be synergistic (additive or multiplicative) or antagonistic. They may
function in an autocrine, paracrine, or even endocrine function, although the inability to correlate
plasma cytokine concentrations with the extent of tissue damage suggests that they are designed for
local rather than systemic inflammation.4,39,95
Cytokine actions are mediated by specific membrane receptors on target cells to which they bind with
high affinity (kD α 10−10 to 10−12). Hence, only minute quantities are necessary to elicit a response.
Such efficiency is accompanied by a narrow therapeutic index and potential for unwanton global effects
(i.e., MODS) with even small systemic concentrations. The receptors and the cells expressing them are
regulated by external stimuli, which provide some degree of specificity to the response, even though the
cytokines themselves are not antigen specific. Receptor binding alters cellular gene transcription
(induction or suppression) that may result in proliferation, differentiation, and the acquisition of new or
suppression/enhancement of pre-existing functions.4
All cytokine receptors consist of at least one transmembrane protein with an extracellular portion for
ligand binding and an intracellular domain mediating signal transduction. Current receptor classification
is based on structural homologies among the extracellular cytokine binding domains. Type I cytokine
receptors contain a domain with two conserved pairs of cysteine residues and a membrane proximal
sequence of tryptophan-serine-X-tryptophan-serine, where X is any amino acid (WSXWS). Type II
resemble type I receptors, however the WSXWS motif is absent. The Ig superfamily consists of receptors
with extracellular Ig domains. TNF receptors belong to a family of receptors with conserved cysteine-
rich extracellular domains. Finally seven-transmembrane α-helical receptors mediate the functions of
cytokines called chemokines through GTP-binding (G) proteins.4
Translating ligand engagement to the signaling events that alter cellular phenotype involves a variety
of signaling cascades dependent upon the structure of the cytoplasmic tail of the particular receptor
(Table 7-6). This is another method by which to classify cytokine receptors. These individual signaling
cascades will be discussed in the context of the various cytokines and respective receptors employing
them.
Early Cytokines/Innate Immunity

TNF-α
TNFα is the principal initiating mediator of the inflammatory response to gram-negative bacteria and
other infectious pathogens. It is an important early mediator of inflammation and is essential for the
normal initiation, maintenance, and repair of tissue injury. However, aberrant production may underlie
the pathologic sequelae of many inflammatory and infectious states (i.e., MODS, rheumatoid arthritis,
Crohn’s disease). Mononuclear phagocytes are the principle source of TNFα, usually in response to the
potent prototypical stimulus lipopolysaccharide of gram-negative organisms.100,101 TNFα production
may be augmented by concomitant stimulation with IFNγ, IL-4 and IL-10, whereas, corticosteroids are
suppressive.102 Secondary sources include mast cells, NK cells, and T and B lymphocytes. Other stimuli
inducing production and release include complement C5a, GM-CSF, hypoxia, IL-1, NO, ROS, and TNFα
itself.39
TNFα is expressed on the cell membrane as a bioactive protein and is cleaved into its soluble form by
a specific TNFα converting enzyme. There are 2 distinct TNF receptors present on virtually all cell types
(Fig. 7-6).103 Ligand binding to TNF-RII leads to recruitment of TNF receptor-associated factors (TRAFs)
that ultimately activate the transcription factors NFκB and AP-1, and thereby influence gene expression
and cellular phenotype.4 Alternatively, binding to TNF-RI activates caspases and triggers apoptosis, in
addition to signaling transcription factors. The manner by which either a proinflammatory or apoptotic
path is chosen is unknown, although the net effect of TNFα binding is probably the culmination of
differential adaptor protein expression and downstream signal transduction cascades. TNF-RI appears to
be more important in host defense as knockout TNF-RI mice show a greater degree of impairment in
host defense than mice lacking TNF-RII.4
190
Shedding of extracellular domains of the two TNFα receptors by metalloproteinases can further alter
the biologic activity of TNFα by decreasing the number of cell signaling sites on target tissues and
increasing the amount of circulating inhibitors. Unlike other members of the TNF family that are
primarily involved in regulation of cell proliferation, TNFα has both proinflammatory and apoptosis-
inducing properties.95,104
Figure 7-6. TNF receptor signaling pathway. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed.
Philadelphia, PA: Saunders; 2003.)
The principal function of TNFα is to recruit neutrophils and monocytes to foci of infections and to
activate these cells to eradicate microbes. TNFα activates the endothelium to upregulate the expression
of the adhesion molecules E- and P-selectin, ICAM-1, PECAM-1, and VCAM-1. It potently stimulates
these cells and macrophages to secret chemokines (IL-8, MIP-1α, and Gro-α) that enhance the affinity of
leukocyte integrins for their ligands and induce leukocyte chemotaxis and recruitment.105 TNFα also can
induce HMGB1 release by activated macrophages, which generates a forward feedback mechanism, as
HMGB1, by signaling through RAGE (see below), also induces TNFα release.106,107 TNFα by stimulating
the release of tissue factor, PAF, von Willebrand factor, and thromboplastin generates a state of
hypercoagulability. By inhibiting tissue-type plasminogen activator and thrombomodulin, it suppresses
fibrinolysis, decreases protein C and S activation, and increases thrombin formation. However, TNFα
also induces the release of a variety of anticoagulants (prostacyclin), fibrinolytics (urokinase-type
plasminogen activator), and vasodilators (NO, PGE2), which may offset or balance the tendency toward
procoagulation. Most likely, the ultimate effect of TNFα depends on the location and quantity in which
it is produced and the vascular bed with which it interacts.4,95
3 Though clearly vital for host defense and microbial elimination, in severe infections, exuberant
production and aberrant release of TNFα wherein it possess endocrine function and can cause a plethora
of pathological sequelae. These systemic effects include fever by stimulating the production of PGE2 by
the hypothalamus (hence the name endogenous pyrogen), acute-phase protein production by the liver,
cachexia, inhibition of myocardial contractility and vascular tonus, and intravascular thrombosis due to
loss of normal anticoagulant properties of the endothelium and the production of tissue factor. TNFα is
central to the pathogenesis of systemic inflammatory response syndrome (SIRS) and septic shock, and
either state can be reproduced by the exogenous administration of TNFα.108,109 The organ dysfunction
characteristic of these states may result from the hypercoagulability and subsequent tissue ischemia
induced by this cytokine. Antagonists of TNFα can prevent mortality in experimental models, but
clinical trials with anti-TNFα antibodies or with soluble TNFα receptors have been to no avail.4,108 That
being said, anti-TNFα therapy has been pivotal in treating the more chronic diseases of rheumatoid
arthritis, psoriasis, and Crohn’s disease.
Soluble TNF receptors formed by proteolytic processing of both types of receptors bind and neutralize
TNFα and serve as an endogenous regulator of cytokine activity.39 TNFα also directly induces the
191
expression and release of TNFα inhibitors, including IL-10, corticosteroids, and prostanoids, which in a
negative feedback loop suppress TNFα production and processing.95 Hence, TNFα serves as its own
regulator.
Interleukin-1
IL-1 posseses similar functions to TNFα in mediating a proinflammatory host response to insult; it is
frequently released concomitantly with TNFα (Table 7-6).110 The major source of IL-1 is the
mononuclear phagocyte. Synthesis and release are induced by LPS, cytokines such (TNFα, IL-2, TGF-β,
all the interferons), antigen–antibody complexes, C5, and hypoxia.95 IL-1 is also produced by
neutrophils, B cells, helper T cells, epithelial cells, fibroblast, renal mesangial cells, and endothelial
cells. There are two forms of IL-1; IL-1α and IL-1β. Both forms are active, bind to the same receptors
and mediate the same effects. Most IL-1 found in circulation is IL-1β.4
The two IL-1 receptors (IL-1R) are members of the Ig superfamily. IL-1RI is universally expressed and
transduces the majority of IL-1 responses.111,112 IL-1RII expression is restricted to B cells, but may be
induced on other cells. There is little evidence that this latter receptor serves any function, and in fact,
may serve as a decoy.113 The cytoplasmic portion of IL-1RI is homologous to a domain of TLR, which
mediate the cellular responses to endotoxin (Fig. 7-7). Engagement of IL-1 with IL-1RI induces the
activation of the IL-1 receptor-associated kinase (IRAK) and the subsequent induction of the
transcription factors NFκB and AP-1.4,112
Figure 7-7. Toll-like receptor (TLR) signaling pathway. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology.
5th ed. Philadelphia, PA: Saunders; 2003.)
The functions of IL-1 mirror those of TNFα, and synergy between the two cytokines is evident.110 IL-1
activates endothelial cells to increase cell surface expression of adhesion molecules and the production
of prostaglandins, PAF, and a variety of CSFs. In doing so, it facilitates the recruitment and activation of
appropriate leukocyte populations for specific localized immune responses. IL-1 also induces a
procoagulant state by suppressing fibrinolysis through enhanced plasminogen activator inhibitor-1 and
decreased tissue-type plasminogen activator activity. It increases thrombosis by stimulating tissue
factor–like procoagulant and thromboplastin production and suppressing thrombomodulin release. It
induces the synthesis of PAF, a potent vasoconstrictor and stimulus for platelet and leukocyte activation.
However, similar to TNFα, it also stimulates the production of prostacyclin and urokinase-type
192
plasminogen activator, which promotes an antithrombotic state.114 At larger concentrations, its effects
become systemic causing fever, the synthesis of acute-phase proteins, cachexia, myalgia, somnolence,
and hypotension. It stimulates arachidonic acid and prostaglandin metabolism, and the release of
pituitary stress hormones. It stimulates collagenase release and is a potent mitogen for neutrophils.
Though similar in effect to TNFα, probably by activating similar signaling cascades and transcription
factors, IL-1 does not induce apoptosis. Even at high concentrations IL-1 does not cause the physiologic
derangements of septic shock.39,110
Mononuclear cells produce the natural inhibitor of IL-1, IL-1ra. This IL-1 structural homologue is an
inactive competitive inhibitor and may function as an endogenous regulator of IL-1. As with TNFα,
attempts to inhibit IL-1 have not been of clinical benefit in human trials of sepsis.39
Chemokines
This is a large family of cytokines that primarily govern leukocyte chemotaxis, hence the name115–119
(Table 7-6). Those bound on the endothelial surface induce leukocyte integrins to express a high-affinity
state for their ligands, which is critical for tight leukocyte adherence and subsequent migration into the
extravascular space. However, they also assist in orchestrating the migration of immune cells into
lymphoid organs. Unlike other chemoattractants, members of this family possess a degree of specificity,
influencing the recruitment of discrete subsets of leukocytes. They mediate their effects both directly
and indirectly through the induction of other mediators such as histamine and ROS. Though some
chemokines, in particular those regulating cell traffic through tissues, are constitutively produced (MIP-
3β and RANTES), most necessitate cellular stimulation for synthesis and release, in particular, those
involved in inflammatory reactions. They are typically produced by macrophages, leukocytes,
endothelial cells, fibroblasts, and many other cell types stimulated by LPS, phagocytosis, and
inflammatory cytokines such as IL-1, TNFα, IL-6, and IFNγ.39
Chemokines can be classified into four families based on the number and location of N-terminal
cysteine residues. The two major families are the CC chemokines, in which the cysteine residues are
adjacent, and the CXC chemokines, in which one amino acid is interposed between these cysteine
residues. This amino acid sequence appears to account for the disparate influence, either promotion or
inhibition, on neutrophil chemotaxis. The three amino acids that immediately precede the first cysteine
are critical in defining receptor binding and neutrophil activation.120,121 This area has been designated
the ELR motif. The other two chemokine families are represented by lymphotactin (C chemokine) and
fractalkine (CX3C chemokine).39
Chemokine receptors are seven transmembrane receptors that signal by G proteins and the formation
of the second messengers, IP3 and DAG (Fig. 7-5). Currently 6 CXC chemokine receptors, 11 CC, and 1
receptor each for the last two subfamilies have been identified and defined. The pattern of cellular
expression of the receptors determines the specificity of the cellular response to binding.4,121
CXC chemokines primarily govern the chemoattraction and activation of neutrophils, and to a lesser
degree lymphocytes, in particular T cells. At least 12 different chemokines have been identified. They
are clustered on chromosome 4 and demonstrate 20% to 50% homology at the amino acid level. IL-8 is
the prototypical CXC chemokine.98 It is produced by an array of immune and nonimmune cells including
monocytes, alveolar macrophages, neutrophils, keratinocytes, mesangial cells, epithelial cells,
fibroblasts, and endothelial cells. TNFα and IL-1 are key molecules for inducing IL-8. It is chemotactic
for all granulocytes and influences nearly every aspect of neutrophil function. It stimulates neutrophil
degranulation, phagocytosis, transendothelial migration and shedding of L-selectin, upregulation of β2
integrins, and augments superoxide production. It is also a potent angiogenic factor. It binds to both the
CXCR1 and CXCR2, receptors that also engage the chemokines GCP-2, GRO-α, and ENA-78. ENA-78 is a
potent neutrophil chemotaxin produced by the endothelium in response to TNFα or IL-1, neutrophils, or
monocytes. Studies have demonstrated that ELR-containing CXC chemokines are angiogenic, whereas
those lacking this motif are angiostatic.39,95,120–122
The interferon-influenced chemokines, IP-10 and Mig do not target neutrophils, and the ELR motif is
absent. They induce IFNγ production and may play a more prominent role in mediating the
inflammatory response to viral infections and autoimmune disorders. Mig is chemotactic for tumor
infiltrating lymphocytes, activated T cells, and monocytes and promotes CTL activity. IP-10 is
chemotactic for monocytes, T cells, and NK cells and augments T-cell adhesion. Both chemokines bind
the CXCR3 receptor found on IL-2–activated T cells. IFNγ attenuates the expression of both IL-8 and
ENA-78, and hence may serve as an important mechanism to the control and regulate inflammation.39,95
Stromal cell–derived factor-1 (SDF-1) is the only known ligand for the CXCR4 receptor and in the
193
presence of IL-7 stimulates proliferation of pre–B-cell clones and growth of bone marrow B progenitor
cells. The receptor has gained much interest since it was identified as a coreceptor for HIV-1. PF4 and
neutrophil-activating protein-2 are CXC chemokines of platelet origin. PL-4 has angiostatic properties
and inhibits the growth of various cancer cell lines in a manner that appears to be related to its
angiostatic properties. It binds heparin with high affinity to stimulate coagulation.39
The CC chemokines recruit monocytes, granulocytes, T cells, NK cells and DCs. RANTES is produced
by stimulated T cells, platelets, and endothelial cells and is constitutively produced in resting T cells,
which implies a homeostatic function. MIP-1α and β are produced by activated T cells and are
chemotactic for neutrophils, monocytes, eosinophils, basophils, and T lymphocytes. They are also
mitogenic for hematopoietic progenitor cells and upregulate TNFα, IL-1, and IL-6. The MCP family of
chemokines influences the recruitment of monocytes and T cells. Their influence upon the function of
these target cells is dictated by the cell’s specific profile of receptor expression. MCP-1 is produced by
nonlymphocytic cells (endothelial cells, epithelial cells, fibroblasts, smooth muscle cells, macrophages
and mast cells). Binding to CCR1 enhances chemotaxis, whereas activation of CCR2 increases the release
of intracellular substances such as histamine and LTs from basophils.39
Lymphotactin is the only member of the C chemokine family and is produced by CD8+ lymphocytes,
thymocytes, and NK cells, and, to a lesser degree, by DC and activated mast cells. It selectively recruits
lymphoid cells.39
Fractalkine is the sole CX3C chemokine and is produced by the endothelium. In its membrane-bound
form it may act as a solid-phase adhesion molecule, but upon cleavage serves as a soluble
chemoattractant for lymphoid cells and monocytes.39
Interleukin-12 (NK Cell Stimulatory Factor, Cytotoxic Lymphocyte Maturation Factor)

IL-12 is integral in the innate immune response (Table 7-6). It is produced early during innate immune
reactions and is critical for initiating a sequence of responses involving macrophages, NK cells, and T
lymphocytes that results in the eradication of intracellular microbes. It stimulates subsequent adaptive
responses that confer further host protection against these pathogens. Hence, it is an important link
between innate and adaptive immune responses. IL-12 is primarily derived from activated mononuclear
phagocytes and DCs, and most importantly stimulates IFNγ from T cells and NK cells. There are two
pathways leading to IL-12 production: a T-cell dependent and an independent pathway. During innate
immunity, LPS, infection by intracellular bacteria, and viral infections may induce IL-12 production. In
addition, interactions between CD40 ligand and CD40 on activated lymphocytes and APC, respectively,
induce the release of APC IL-12.123,124 Thus, IL-12 is produced during the induction of and the effector
phases of cell-mediated immune response when APCs present antigens to T cells.4,39
The IL-12 receptor is a heterodimer composed of β1 and β2 subunits, the latter of which is involved
in signaling, although both are required for engaging ligand. The receptor signals through the
JAK/STAT pathway (Fig. 7-8).4 This signal transduction pathway is employed by numerous cytokines
including interferons, IL-6, IL-12, IL-2, IL-7, IL-9, IL-4, and IL-10. A characteristic of this cytokine is the
generation of a positive amplification loop, which heightens the inflammatory response. Expression of
the IL-12 receptor is induced by IFNγ. Activated NK cells and TH1 cells produce IFNγ that potentiates
macrophage IL-12 production. IL-12 stimulates further production of IFNγ by NK cells and T
lymphocytes, which continues to fuel the reaction in a positive feedback mechanism. Ultimately, IFNγ
activates macrophages to kill and degrade phagocytosed microbes. IL-12 potentiates bacterial LPS-
induced macrophage TNFα production. IL-12 antagonists reduce mortality in experimental models of
LPS-induced septic shock; however, there is no evidence of their efficacy in human clinical trials.4
4 5 CD4+ helper T lymphocytes, under the influence of IL-12, differentiate into TH1 cells, which
subsequently activate phagocytes in cell-mediated immunity. It enhances the cytolytic functions of
activated NK cells and CD8+ CTLs, and suppresses TH2 cell differentiation and effector activity. The
inhibition of TH2 and IL-4 activity confers antiallergic properties to IL-12. IL-12 knockout mice
demonstrate diminished IFNγ production and defective TH1 cell development and cell-mediated
immunity against intracellular organisms.4,39
194
Figure 7-8. JAK/STAT signaling pathway. JAK (Janus Kinase) components are associated in an inactive form with the cytoplasmic
portion of cytokine receptors. Cytokine binding leads to receptor aggregation. Adjacent JAK proteins become activated and
phosphorylate each other and tyrosine residues. Through the Src homology domain, STAT proteins bind phosphotyrosine residues
on the cytoplasmic portion of cytokine receptors. Bound STAT proteins are phosphorylated by bound JAK proteins and
subsequently dissociate. Phosphorylated STAT proteins dimerize and then move to the nucleus where they induce transcription by
binding to STAT binding regions within the promoter. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology.
5th ed. Philadelphia, PA: Saunders; 2003.)
Interleukin-6
IL-6 regulates the acute-phase response to inflammation, characterized by altered thermoregulation
(i.e., fever), perturbation in nitrogen balance (i.e., cachexia and catabolism), and the generation of the
acute-phase reactants of innate immunity by the liver (Tables 7-6 and 7-7).95,125 It functions in both
innate and adaptive immunity to enable the host to recover. Despite in vitro data demonstrating that a
variety of cells can produce IL-6, the most prominent in vivo sources of IL-6 are monocytes and
macrophages stimulated with LPS or IL-1 or fibroblasts and endothelial cells stimulated with TNFα.126
Steroids inhibit the induction of IL-6. The receptor for IL-6 consists of cytokine-binding protein and a
signal-transducing subunit, which belong to the type I cytokine receptor family. It signals through the
JAK-STAT pathway (Fig. 7-8).4
In conjunction with IL-1 and TNFα, IL-6 regulates the systemic manifestations of the acute-phase
response.125 It potentiates the immune response by inducing B-cell differentiation and activating T cells.
It interacts with TNFα to enhance T-cell proliferation and promotes neutrophil activation and
accumulation. In adaptive immunity, IL-6 stimulates the growth of B lymphocytes that have
differentiated into antibody-producing plasma cells. IL-6 antagonizes LPS-induced TNFα production and
TNFα-induced IL-1 production.127,128
Table 7-7 Acute-Phase Proteins
195
High Mobility Group Box 1 Protein
HMGB1 was initially identified as an architectural chromatin-binding factor that bends DNA and directs
protein assembly on specific DNA targets. It is abundant, ubiquitous, and evolutionarily conserved, as
evident by the 99% amino acid homology between rat and human proteins.56 Thirty years after its
original discovery, Tracey at al. demonstrated that HMGB1 acts as a late mediator of mortality in
murine endotoxemia and sepsis. HMGB1 appeared 8 hours poststimulation and plateaued at 16 to 32
hours, very distinct from the acute rise and fall of early mediators (TNFα, IL-1β) of severe sepsis and
septic shock.56 Recent studies show that systemic concentrations are elevated in those patients who die
of sepsis.129
HMGB1 is the prototypical DAMP. When cells die by necrosis (i.e., nonprogrammed cell death),
HMGB1 is released into the extracellular medium. In contrast, apoptotic cells modify their chromatin so
that HMGB1 irreversibly binds, and thus is not released.130,131 However, HMGB1 may also be released
by activated macrophages and NK cells, via an active process that necessitates shuttling the protein from
nucleus to cytoplasm; this event does not require further synthesis.130–132 Acetylation of HMGB1
appears essential for release, however acetylation of histones as occurs during apoptosis, strengthens its
interaction with chromatin and inhibits release.130,131 Interestingly, though apoptotic cells do not
release HMGB1, macrophages engulfing apoptotic cells do. Recent studies have shown that
nucleocytoplasmic shuttling of HMGB1 involves serine phosphorylation by CaMKIV that enables it to be
translocated to the cytoplasm by 14-3-3 and CRM1 chaperones.133,134 Subsequent release of cytoplasmic
HMGB1 appears to involve active secretion through a secretory lysosomal pathway.130,132
HMGB1 has many of the intercellular signaling activities characteristic of cytokines and therefore is
often classified as a proinflammatory cytokine and potent regulator of the inflammatory response. In
light of the fact that it is released by macrophages responding to bacterial challenge or by injured cells,
it may mediate inflammation consequent to sepsis or trauma. After release, signaling is thought to occur
by binding to RAGE with subsequent activation of p21ras, MEK, the MAPK kinases, and NFκB.106,135
This receptor is expressed on mononuclear phagocytes, vascular smooth muscle cells, and neurons.
Blocking antibodies to RAGE fails to completely prevent cellular activation suggesting the presence of
an alternate receptor. Recent studies suggest that both TLR2 and TLR4 may mediate HMGB1-induced
activation of NFκB in macrophages and neutrophils. This observation is very important as it
demonstrates that a receptor classically considered specific for microbial danger signals, may interact
with an endogenous molecule.56,106,135
HMGB1-RAGE interactions induce numerous proinflammatory events. Endothelial cells increase the
expression of adhesion molecules and secrete TNFα and IL-8.136 In neutrophils, HMGB1 activates
MAPKs and enhances the expression of proinflammatory cytokines in a NFκB-dependent manner. In
addition, it is chemotactic for neutrophils, monocytes, macrophages, and DCs.106 Intratracheal
administration of HMGB1 to LPS-resistant mice stimulated lung neutrophil accumulation and the local
production of proinflammatory cytokines.106 HMGB1 has potent immunostimulatory actions and
196
promotes the maturation of both myeloid and plasmacytoid DCs. Systemic levels are markedly elevated
in patients who die of sepsis, and animal studies suggest that this association is causal.129 Recombinant
HMGB1 mimics the lethality of high-dose LPS and induces the release of TNFα by macrophages.
However, intravenous administration of HMGB1 does not cause shock like TNFα. More recent data call
into question whether HMGB1 itself can directly promote the secretion of proinflammatory cytokines
(TNFα, IL-1α/β, IL-6, IL-8) and chemokines (MIP1α/β) as initially reported. A direct proinflammatory
activity of HMGB1 has not been reproduced consistently, raising some concern that this might be based
on the formation of specific complexes with other molecules such as LPS. Recent studies show that
highly purified recombinant HMGB1 has very weak direct proinflammatory activity.137
In a series of elegant studies, anti-HMGB1 antibodies conferred a dose-dependent protection in animal
models of endotoxemia, even when the first dose of anti-HMGB1 antibodies was delayed for 2 hours.57
This occurred without changes in TNFα, IL-1β, or MIP-2 concentrations. Even more striking are the in
vivo CLP models, in which anti-HMGB1 administration up to 24 hours after CLP significantly increased
survival, 72% versus 28%.57 This wider therapeutic window may enable the development of inhibitors
of HMGB1 for treat of sepsis.106,138–140 These observations have stimulated the search for other
inhibitors of HMGB1. Ethyl pyruvate a nontoxic food additive, dose dependently inhibits HMGB1
release, and confers significant protection against the lethality of sepsis, even when the first dose is
administered 24 hours after the onset of sepsis. In addition, it inhibits the translocation of NFκB and p38
MAPK signaling.106,138,141,142
HMGB1 may also serve as a danger signal for other perturbations in homeostasis, as it can also be
released passively by necrotic or injured cells but not apoptotic cells.131,140,143,144 Hypoacetylation of
chromatin on the induction of apoptosis enhances HMGB1 binding, thereby preventing release during
apoptotic processes. Thus, HMGB1 binding to chromatic depends on the viability of the cell and clearly
distinguishes necrotic from apoptotic cells. This enables the innate immune response to respond to
injury and further induce inflammation.131,140,143,144
HMGB1 is also elevated during hemorrhage shock.145 In a clinical case, serum HMGB1 levels
increased significantly within 24 hours of hemorrhagic shock and returned toward basal levels as the
clinical condition improved.146 HMGB1 also appears to mediate cell damage and death in other
noninfectious insults. In a model of warm liver ischemia reperfusion, HMGB1 inhibition attenuates
hepatocellular injury.32 Interestingly, this protection, as well as reduced systemic concentrations of
HMGB1, was also afforded by inhibiting CaMK.32
High levels of HMGB1 have also been found in other conditions of sterile inflammation such as
rheumatoid arthritis.147–149 In human arthritis, overexpression of HMGB1 at the site of joint
inflammation may be detected in the synovial fluid of rheumatoid arthritis patients.148,149 HMGB1 may
in fact amplify the effect of local cytokines as suggested by its ability to stimulate macrophages derived
from synovial fluid of rheumatoid arthritis patients to release TNFα, IL-1β, and IL-6.147,150 Hence,
HMGB1 may serve as a signal of danger from endogenous threats or perturbations.
Interleukin-15
IL-15 is produced by various cells in response to LPS and other stimuli, though the principal cellular
source is mononuclear phagocytes. (Table 7-6). It is structurally homologous to IL-2, as is its receptor
and the IL-2R. IL-15 stimulates the proliferation of NK cells similar to the manner by which IL-2
functions later in the adaptive immune response. It also acts as a T-cell growth and survival factor
especially for long-lived memory CD8+ T cells.4
Interleukin-18
IL-18 is structurally homologous to IL-1 and utilizes a similar IRAK signaling pathway (Table 7-6).
Macrophages responding to microbial challenge or exposure to LPS are the principal source. Its primary
function is to stimulate the production of IFNγ by NK cells and T cells, and in synergizing with IL-12,
augments cell-mediated immunity. Knockout mice lacking IL-18 are deficient in IFNγ production, and
concomitant IL-12 deficiency eliminates all IFNγ production and any TH1 response.4
Interferons (Type I)
Type I interferons possess potent antiviral and antitumor properties (Table 7-6). It is from this ability to
“interfere” with viral infection that the name is derived. They are subcategorized into α and β
interferons. Mononuclear phagocytes are the major source of interferon α, whereas many cell types
produce interferon β. The most potent stimulus inducing the synthesis and release of either is viral
infection, particularly double-stranded RNA produced during viral replication. Other inducers include IL-
197
1, TNFα, LPS, and antigen-activated T cells. Both groups bind to the same cell surface receptor and
induce similar responses by signaling through the JAK/STAT pathway (Fig. 7-8).
These cytokines provide the first line of defense against viral infection and promote cell-mediated
immunity against intracellular pathogen. They are secreted from virally infected cells to protect
neighboring uninfected ones by inducing the synthesis of a number of enzymes that interfere with viral
RNA or DNA transcription and viral replication. Through enhanced expression of class I MHC molecules,
the type 1 interferons facilitate recognition of class I–associated viral antigens on infected cells by CTLs
and increase the efficiency of CTL-mediated killing. Type I interferon stimulates the development of TH1
cells by promoting these cells to express IL-12 receptor. They can also stimulate B-cell development,
proliferation, and immunoglobulin heavy chain switching from IgM to IgG.151–153 Knockout mice
lacking the receptor for these cytokines are susceptible to viral infections. Interferons are currently in
clinical use for hepatitis B and C infection, multiple sclerosis, CML, and Kaposi’s sarcoma.151–153
Interleukin-10 (Cytokine Synthesis Inhibiting Factor)

IL-10 inhibits activated macrophages and APC and functions in a counterregulatory mechanism to
suppress innate immune reactions (Table 7-6). It is produced mainly by macrophages, and hence
functions by negative feedback. T lymphocytes, particularly the TH2 subset, B cells, and some other
nonlymphoid cells produce IL-10, in response to a variety of stimuli including LPS, TNFα, IL-2, IL-4, and
IL-13.
IL-10 binds to a type II (interferon) receptor. Though the manner by which it effects curtailment of
the inflammatory response is unknown, its presence inhibits NKκB activation and the generation of
inflammatory mediators. Thus, it may inhibit, in some manner, the activation of signal transduction
cascades and gene activation in proinflammatory pathways.4,154
IL-10 terminates many of the functions of activated macrophages and participates in reestablishing
homeostasis as the infection resolves. It downregulates proinflammatory cytokine (TNFα, IL-1, IL-6, and
IL-8) production, suppresses the production of IL-12, and inhibits IFNγ production and the innate and
cell-mediated immune responses.4,59,95 It represses the expression of costimulators and class II MHC
molecules on APC, thereby terminating T-cell activation and inhibiting cell-mediated immunity.4 In
neutrophils it inhibits cytokine release, superoxide generation, migration, and even survival.155 In
combination with IL-4 it inhibits IFNγ release and IL-12 production to limit differentiation and function
of TH1 cells, favoring a TH2 profile.59
IL-10 knockout mice develop inflammatory bowel disease, which is hypothesized to result from
unregulated macrophage reaction to enteric microbes.156 In observational studies of ARDS or MODS,
serum IL-10 levels were often elevated, and those patients with the highest systemic concentrations
died.154 It is unclear whether this is actually a pathologic response, or merely a marker of disease
severity. Contemporary belief is that IL-10 is not a mediator of immunosuppression, but rather,
important for immunoregulation.
Late Cytokines/Adaptive Immunity

Interleukin-2 (T-Cell Growth Factor)
IL-2 stimulates the growth and proliferation of T lymphocytes and is responsible for T-cell clonal
expansion after antigen recognition (Table 7-6).157 IL-2 is produced by CD4+, and to a lesser extent
CD8+ T cells. The receptor is heterotrimeric, consisting of three noncovalently associated proteins α, β,
and γ. The α and β chains are involved in cytokine binding, and the β and γ chains mediate signal
transduction.4 Antigen recognition enhances the expression of functional IL-2 receptors, which confers a
degree of specificity, as those T cells recognizing antigen are preferentially induced to proliferate in
response to IL-2. Though, the α chain appears on T cell activation and binds IL-2, signal generation
necessitates the β and γ chains. Cells expressing the complete α, β, and γ complex bind IL-2 with higher
affinity (kD of 10−11 M), and growth stimulation of such cells occurs at a low IL-2 concentration.4 Upon
antigen receptor–mediated T-cell activation, IL-2R α is rapidly upregulated, which reduces the
concentration of IL-2 needed to stimulate growth. Therefore, antigen-stimulated T cells are more
responsive to IL-2 than naïve T cells. This receptor signals through numerous signal transduction
pathways including the JAK/STAT and MAP kinase pathways (Figs. 7-5 and 7-8).
IL-2 functions in an autocrine and paracrine fashion to induce the proliferation of the antigen-specific
cells. After exposure to IL-1, there is a rise in cyclins and activation of cyclin-dependent kinases that
stimulates the progression of the cell cycle from the G1 to the S phase. A reduction in p27, an inhibitor
of cyclin–kinase complexes, facilitates this progression, and the induction of Bcl-2, an antiapoptotic
198
protein, facilitates survival. It also stimulates the production of other cytokines such as IFNγ and IL-4.4
IL-2 promotes the proliferation and differentiation of many immune cells. NK cells are stimulated to
grow and transform into lymphocyte-activated killer cells. In combination with IFNγ and IL-12, IL-2 can
trigger a positive feedback cycle of NK activation. IL-2 stimulates B-cell growth and antibody synthesis.
Repeated activation of CD4+ T cells in the presence of IL-2 sensitizes these cells to apoptosis by fas-fas-
ligand. IL-2 may also stimulate the development of regulatory T cells, and IL-2 knockout mice develop
autoimmunity. Knockout mice lacking the γ chain develop X-linked severe combined immunodeficiency
syndrome. This is probably due to an inability of immature T cells to respond to IL-7. IL-2 has been used
in the management of cancer, in particular renal cell carcinoma.158
Interleukin-4
IL-4 is the major stimulus for the production of IgE antibodies and for the development of TH2 cells
from naïve CD4+ T cells (Table 7-6). The principle cellular sources are CD4+ T cells, mast cells, and
basophils. The IL-4 receptor belongs to the type I cytokine receptor family and signals through the
JAK/STAT pathway.159 (Fig. 7-8). IgE is integral in orchestrating the defense against parasitic
infections. It stimulates IgE production and mast cell/eosinophil-mediated reactions, and induces B cell
Ig heavy chain class switching to the IgE isotype. However, IL-4 also serves a counterregulatory role by
inducing TH2 cell differentiation and growth. IL-4 antagonizes the macrophage-activating effects of IFNγ
and thus inhibits cell-mediated immunity.
Interleukin-5
IL-5 is produced by TH2 cells and activated mast cells and activates eosinophils, (Table 7-6). It signals
through the type I cytokine receptor and the JAK/STAT pathway (Fig. 7-8). IL-5 is an inducer of
eosinophil growth, differentiation, and activation, and also participates in the eradication of helminthic
infection. IL-5 also stimulates the proliferation of B cells and the production of IgA antibodies.4
Interleukin-13
IL-13 is produced by TH2 cells and some epithelial cells and is structurally homologous and functionally
similar to IL-4 (Table 7-6). The receptor is found mainly on nonlymphoid cells and can be activated by
either IL-13 or IL-4. IL-13 downregulates the expression of Fcγ on monocytes and macrophages, thereby
decreasing antibody-dependent cellular cytotoxicity. It increases 15S-HETE and lipoxin A4, both of
which antagonize proinflammatory LTs. However, they can increase the expression of MHC class II and
costimulatory molecules on monocytes, and thereby serve an immunostimulatory function. The major
action is to inhibit the activation of macrophages and to antagonize IFNγ.160
Interferon γ
IFNγ is produced by NK cells, TH1 cells, and CD8+ cells, and as the principal stimulus for macrophage
activation, provides necessary functions during both innate and adaptive immune responses (Table 7-6).
It modulates cellular differentiation, cytotoxicity, cytokine production, cellular adhesion, and oxidative
metabolism. During innate immunity, NK cells secrete IFNγ upon exposure to pathogen or stimulation
by IL-12. CD8+ T cells and the TH1 subset of CD4+ T cells produce it in response to MHC-bound peptide
antigen with a costimulatory signal. The IFNγ receptor is composed of two homologous proteins
belonging to the type II cytokine receptor family and functions through the JAK/STAT pathway (Fig. 7-
8).4
The antiviral and antitumor properties of IFNγ are redundant with those of type I interferons. In
concert with TNFα and IL-12 it forms one arm of a positive feedback loop fueling the activation of both
NK cells and macrophages. Stimulated macrophages activate NK cells by releasing TNFα and IL-12.
These NK cells produce IFNγ, which further stimulates macrophages to secrete more TNFα and IL-
12.161,162
IFNγ induces the genes encoding the enzymatic machinery required for generating ROS generation
and provides the principle stimulus for macrophages to kill phagocytosed microbes. It regulates the
expression of MHC class I and class II molecules and costimulators of APC, and induces the transcription
of enzymes regulating antigen processing.161,162
IFNγ synergizes with TNFα to activate the endothelium and upregulate adhesion molecule expression;
in doing so it facilitates lymphocyte recruitment and leukocyte recruitment. Interferon promotes the
differentiation of naïve CD4+ cells into TH1 cells and inhibits the proliferation of TH2 cells, in part, by
inducing IL-12, the major TH1-inducing cytokine, from activated mononuclear phagocytes. It promotes
199
B-cell switching to certain IgG subclasses, notably IgG2a, and inhibits the switching to IL-4–dependent
isotypes such as IgE and IgG1. These IgG subclasses bind the Fcγ receptors on phagocytes and activate
complement, thereby promoting phagocytosis of opsonized microbes. It activates PMNs and stimulates
the cytolytic activity of NK cells. The net effect is to promote macrophage-rich inflammatory reactions
while inhibiting IgE-dependent eosinophil-rich reactions. IL-10, by suppressing macrophage release of
TNFα and IL-12, negatively regulates IFNγ production.
IFNγ also demonstrates counterregulatory properties. It selectively inhibits LPS-induced expression of
CXC chemokines. It upregulates macrophage production of IP-10, MIG, and ELR-negative chemokines
that inhibit neutrophil chemotaxis and activation and decreases macrophage release of ELR-positive CXC
chemokines (e.g., IL-8), which are chemotactic for neutrophils.4
Transforming Growth Factor β

Transforming growth factor β (TGFβ) is a homodimer synthesized and secreted by activated T cells,
macrophages, and many other cells (Table 7-6). It is primarily immunosuppressive and inhibits the
proliferation and activation of lymphocytes and other leukocytes. It promotes wound healing by
increasing extracellular matrix protein synthesis and stimulating mononuclear cell and fibroblast
influx.163–165 Though the family consists of three closely related isoforms, most cells utilize TGFβ. Its
effects are mediated through two high-affinity TGF receptors (type I and II) that signal through a
serine/threonine kinase domain that phosphorylates transcription factors called SMADS.4
TGFβ inhibits the proliferation and differentiation of T cells and the activation of macrophages. It
favors differentiation of CD4+ cells to the TH2 subset, and inhibits MHC class II surface expression. By
suppressing the expression of MHC class II antigen, it abrogates the adaptive immune response.
Macrophages demonstrate diminished ROS production and TNFα and NO release. It directly counteracts
the influence of proinflammatory cytokines on PMNs and endothelial cells, and in combination with IL-
4, IL-13, and IL-10 can antagonize the production or effects of these proinflammatory mediators.
Knockout mice, deficient in TGFβ develop uncontrolled inflammatory lesions.4,39
Cytokines that Stimulate Hematopoiesis

Cytokines are necessary for normal hematopoiesis. Several of the cytokines stimulated during both
innate and adaptive immune responses are mitogenic for and induce differentiation of bone marrow
progenitor cells. CSFs are cytokines made by activated T cells, macrophages, endothelial cells, and bone
marrow stromal cells that stimulate increased production of inflammatory leukocytes by bone marrow
progenitors. Receptors for GM-CSF and G-CSF are of the class I family of cytokine receptors. GM-CSF is
expressed by T and B cells, macrophages, mast cells, fibroblasts, and endothelium in response to stimuli
such as IL-1, IL-2, LPS, and TNFα. It stimulates neutrophils, monocytes, macrophages, and DC and is a
powerful inducer of hematopoiesis. It enhances cytokine release, degranulation, and phagocytosis of
opsonized particles in neutrophils. In monocytes and macrophages it enhances cytotoxicity and cytokine
release. It promotes the activity of APCs and the maturation of bone marrow cells into DCs and
monocytes.166 G-CSF is produced by macrophages, endothelial cells, fibroblasts, and bone marrow
stromal cells. It functions as an endocrine hormone to mobilize neutrophils and induces subsequent
leukocyte proliferation and maturation. In 1991, the FDA approved the use of G-CSF for use in patients
with neutropenia.167,168
Stem cell factor or c-Kit ligand is synthesized by marrow stromal cells and binds to a cell surface
tyrosine kinase receptor on pluripotent stem cells that is the protein product of the cellular proto-
oncogene c-kit. Its effects appear to be permissive, as it is corequisite for stem cell responsiveness to
other CSFs, yet in isolation does not stimulate colony formation. It may also play a role in sustaining
the viability and proliferative capacity of immature T cells in the thymus.4
IL-3 is a product of CD4+ T cells that promotes the differentiation of immature marrow progenitors
into all known mature cell types. It also promotes the growth and development of mast cells.
Surprisingly, despite these important functions, murine knockouts do not manifest noticeable
impairment of hematopoiesis.4
IL-7 is secreted by bone marrow stromal cells and promotes the growth and survival of immature
precursors committed to the B and T lymphocyte lineages. Knockout mice, deficient in IL-7 or its
receptor, are lymphopenic and possess diminished populations of B and T cells.4
The Complement System

6 The complement system is integral to both innate and adaptive immunity. It has the capacity to
200
independently eliminate organisms and to facilitate host defense by marking foreign particles for
phagocytosis through opsonization. Many pathophysiologic inflammatory diseases, immune complex
diseases, ischemia/reperfusion injury, and ARDS are considered consequences of excessive or
unregulated induction of this system.169–172
The system consists of three pathways comprised of approximately 30 serum and cell surface proteins
that interact with one another and with other molecules of the immune system in a highly coordinated
fashion. These cascades involve the sequential proteolytic activation of zymogens to generate enzymes
with proteolytic activity. This mechanism for activation amplifies the response because each individual
enzyme activated can cleave numerous zymogens in the next step and generate multiple activated
enzyme molecules. Ultimately, the products of complement activation adhere to microbial cell surfaces
or to antibody-bound microbes and other antigens to directly or indirectly eliminate these pathogens.
Temporal and spatial regulation to the focus of infection is ensured both by the transience of activation
of these enzymes in the absence of microbes or antigens and by several circulating proteins that provide
surveillance.169,171
The complement cascade is divided into three distinct pathways: (1) the classical pathway (humoral
immunity), which is activated by antibody bound to antigen, (2) the alternative pathway (innate
immunity) in which complement is activated by components of microbial cell surfaces, and (3) the
mannose/lectin pathway (innate immunity), which is activated by a plasma lectin that binds to mannose
residues on microbes. Despite differences in which the cascade is activated, all three complement
pathways ultimately result in the cleavage of C3 and share the same late cascade.169,171
The alternative pathway functions in the absence of antibody and is phylogenetically the oldest
pathway (Fig. 7-9). Bacteria, viruses, fungi, and parasites all function as stimuli. Initial activation begins
with the cleavage of C3 and the stable attachment of its product C3b to the microbial surface. Bound
C3b finds factor B, which is subsequently cleaved by a plasma serine protease called factor D to
generate Bb. The C3bBb complex is called the alternative pathway C3 convertase and functions to
cleave more C3. In doing so the convertase serves as an amplification step in both the classical and
alternative pathways. Properdin prolongs the half-life of C3 convertase by delaying the release of Bb
from C3bBb. C3b is the recognition component of the alternate pathway and is responsible for the
opsonization of bacteria. C3a in conjunction with C5a and C4a induces acute inflammation by activating
mast cells and neutrophils. These inflammatory mediators play a significant role in increasing blood
vessel permeability, vasodilatation, edema formation, neutrophil adhesion and activation, chemotaxis,
and the release of toxic oxygen species and lysosomal enzymes from phagocytic cells. The binding of
another C3b to this complex generates the alternative pathway C5 convertase, C3bBb3b.4,169,171
Figure 7-9. Complement pathways. Alternate Pathway: 1. C3 is cleaved to C3b. 2. C3b binds and cleaves B to Bb to form C3
convertase (C3bBb). 3. Another C3b binds C3 convertase to form C5 convertase (C3bBbC3b). Classical Pathway: 1. C1 binds
immunoglobulin. 2. C1 binds and cleaves C4 and C2 to C4b and C2a to form C3 convertase (C4b2a). 3. C4b2a binds another C3b
to generate C5 convertase (C4b2aC3b). Late Pathway: 1. C5 convertase cleaves C5 to form C5b, which integrates into the
plasmalemma. 2. C6–8 are recruited, forming the C5b-8 complex. 3. C5b-8 recruits numerous C9 subunits, which form a pore in
the pathogen cell wall. (Redrawn from Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed. Philadelphia, PA:
Saunders; 2003.)
201
Activation of the alternative pathway is restricted to the cell surface of microbes, as mammalian cells
possess several regulatory proteins to rapidly degrade any C3bBb. Excessive amplification is regulated
by factor H and factor I. H accelerates the decay and delays the formation of C3bBb. It also acts as a
cofactor for I to degrade C3 into iC3b, which is unable to bind B to generate C3 convertase. Decay
acceleration factor hinders C3 convertase assembly and mediates its dissociation in all three pathways.
Also, the protein properdin, which stabilizes this alternative pathway C3 convertase, has a higher
affinity for microbial than mammalian cell surfaces.4,169,171
The classical pathway is the primary mediator of adaptive humoral immunity and is initiated by
binding of the complement protein C1 to IgG or IgM molecules engaged with antigen (Fig. 7-9). Other
substances such as lipid A in endotoxin and mitochondrial membranes may activate this pathway
independent of antigen–antibody complexes in vitro.169,173
C1 is a calcium-dependent trimeric protein consisting of C1q, which recognizes and binds the Fc
region of the immunoglobulin, and C1r and C1s, which are proteases. C1q engages the Fc portion of the
immunoglobulin μ and γ heavy chains. Each Fc region has a single C1q binding site, yet for activation,
each C1q molecule must bind to two Ig heavy chains. Hence, multiple antibodies must be approximated
for activation, which restricts activation to foci of immunoglobulin engagement. IgM exists as a
pentamer enabling it to bind to two C1q molecules, and hence it is more efficient at complement
activation.4,169,173
Interaction between C1q and the immunoglobin Fc region induces a conformational change in C1q
that activates C1r, which subsequently cleaves and activates C1s. C1s cleaves C4 to generate C4b and
C4a. The C4a anaphylatoxin possesses properties similar to those described for C3a. C4b localizes to
immune complexes on the cell surface. C2, after complexing with C4b, is cleaved by C1s, thereby
generating the classical C3 convertase C4b2a complex, which has the ability to cleave C3. The C3b
generated can bind Bb, producing more C3 convertase and amplifying the signal. The key early steps of
the alternative and classical pathways are analogous: C3 and factor B of the alternative pathway are
homologous to C4 and C2 in the classical pathway. C3b can also combine with the classical C3
convertase to generate C4b2a3b, the classical C5 convertase.4
Numerous regulatory mechanisms exist to restrict activation to sites of inflammation. Excessive
classical C3 convertase activity is prevented by the rapid decay of C2a from the complex, which renders
the complex unstable. C1 inhibitor covalently binds C1s, reducing the half-life of activated C1 to only
13 seconds. C4-binding protein enhances spontaneous dissociation of C4b2a and also acts as a cofactor
for C3b/C4b inactivator, which degrades C4b.39
The mannose-binding lectin (MBL) pathway is activated by microbial polysaccharides bound to
circulating lectins; MBL serves as the recognition unit of the MBL pathway. This pathway recognizes
polysaccharides with high mannose content and other oligosaccharides with characteristic linkages
found exclusively on pathogens and not on normal host components. Binding is calcium dependent and
results in the activation of mannose-binding lectin-associated serine proteases (MASP-1 and MASP-2).
Activated MASP-2 cleaves and activates C4 and C2 in the same fashion as the classical complement
pathway. Subsequent steps of complement activation of the MBL pathway mirror those of the classical
complement pathway.169,174,175
The C5 convertases generated during either the classical or alternative pathway initiate a cascade of
events that culminates in the formation of the cytocidal MAC. Specifically, C5 convertase cleaves C5,
yielding C5a and C5b. C6 and C7 bind to generate the C5b67 complex. This hydrophobic moiety
penetrates deeply into the lipid bilayer as a high-affinity receptor for C8. Binding of C8 forms the
complex C5b-8 that recruits numerous C9 subunits, which polymerize to form pores in the plasma
membrane of bacteria. The pores structurally resemble the membrane pores formed by perforin, the
cytolytic granule protein found in CTLs and NK cells. Their diameter may span 100 Å, which prevents
the maintenance of vital ionic gradients, induces osmotic lysis, and ultimately the death of target cells
or pathogens. Patients with deficiencies in the terminal components of C5, C6, C7, and C8 are
susceptible to meningococcal and gonococcal infections.4,176 By contrast, recent studies suggest that
aberrant induction of the complement system, specifically C5a, plays an integral role in inducing
paralysis of the innate immunity and the development of ARDS and MODS.
The effects of complement are in part mediated through several complement receptors. Opsonization
and phagocytosis are important mechanisms for pathogen destruction, and phagocytic cells express
receptors for complement factor C3 components. Complement receptor type I (CR1), the C3b receptor
for C3b and C4b, mediates engagement of and facilitates phagocytosis of complement-bound microbes
and the clearance of immune complexes from the circulation. It is expressed on a variety of cells
202
including RBC, neutrophils, monocytes, eosinophils, and T and B cells. RBCs facilitate elimination by
transporting these opsonized particles to the liver and spleen where the immune complexes are removed
by phagocytes. CR2 stimulates humoral immune response by enhancing B cell activation by antigen and
by promoting the trapping of antigen–antibody complexes in germinal centers. In humans, this receptor
is the receptor for EBV. CR3 and CR4 are β2 integrins that bind the iC3b-processed fragment of C3 and
promote macrophage and neutrophil phagocytosis of iC3b-opsonized antigen.4,39
This entire cascade is under strict regulation to ensure that activation is restricted to sites of
inflammation and infection. This regulation is needed as low-level activation is always occurring, and if
not quelled, would certainly damage normal tissues. Even when locally activated, byproducts may
damage nearby cells and tissues. Several circulating proteins function to do this. C1r and C1s are
inhibited by C1 inhibitor, a serine protease inhibitor that mimics C1r and C1s. C1 inhibitor targets
activated C1qrs, and after attachment, C1r-C1s dissociates and activation of classical complement
ceases. This inhibition prevents the accumulation of active C1r-C1s, thereby limiting the duration during
which active C1r-C1s can initiate the cascade.4 C1 inhibitor also inhibits other circulating inflammatory
serine proteases including kallikrein and factor XII, both of which can activate the formation of
bradykinin.4 Hereditary angioneurotic edema is an inherited deficiency of C1 inhibitor and manifests as
acute intermittent edema of the skin and mucosa causing abdominal pain, vomiting, diarrhea, and
airway obstruction.
MCP, type 1 complement receptor (CR1) and DAF are regulatory proteins that bind to C3b and C4b
deposited on cell surfaces and competitively inhibit the binding of other components of the C3 and C5
convertases, such as Bb and C2a, and thereby block further progression of the cascade. These proteins
are only produced by mammalian cells. Deficiency of an enzyme required to form the linkages
necessary to express DAF underlies paroxysmal nocturnal hemoglobinuria, a disease characterized by
recurrent intravascular hemolysis due to unregulated complement activation on the surface of
erythrocytes. Cell-associated C3b is proteolytically degraded by a plasma serine protease called factor I
which is active only in the presence of regulatory proteins such as MCP, factor H, C4BP and CR1. MAC
formation is inhibited by CD59, a membrane protein that incorporates itself into growing MACS and
inhibits the incorporation of C9. It is not present in microbes. The function of these regulatory proteins
may be overcome by increasing amounts of complement activation.4
Lipid Mediators
Eicosanoids
7 Eicosanoids are 20-carbon lipid inflammatory mediators that are derived from membrane arachidonic
acid and are involved in numerous homeostatic processes and inflammation. These lipid mediators are
not stored in tissues, but are synthesized de novo within seconds in response to a variety of stimuli,
including mechanical trauma, specific cytokines, growth factors, and other mediators (Fig. 7-10).
Although most cells are capable of producing eicosanoids, neutrophils and macrophages are the
predominant sources. They are rapidly degraded in the circulation, which limits their role primarily to
that of autocrine and paracrine mediators of local inflammatory changes.177–179
The liberation of the precursor molecule, arachidonic acid, is the major rate-limiting step. The family
of PLA2, in particular type IV cytosolic PLA2, is responsible for eicosanoid production; cells lacking type
IV PLA2 are devoid of eicosanoid synthesis.180 Many PLA2 are transcriptionally regulated by IL-1 and
TNFα, whereas others are regulated by the MAP kinase pathway and by calcium-dependent
translocation to membranes. Once formed, arachidonic acid metabolism proceeds along one of the two
pathways.177–179
Cyclooxygenase Pathway (Prostaglandins)

Cyclooxygenase catalyzes the initial step of a series of reactions that converts arachidonic acid to
prostanoids (Fig. 7-10). There are two isoforms, COX1 and COX2; the former is constitutively
expressed, whereas COX2 is inducible. COX2 is considered more important during inflammatory
processes such as fever, hyperalgesia, and edema formation. Either enzyme catalyzes the conversion of
arachidonic acid to the endoperoxidase PGG2, which is subsequently converted to PGH2. PGH2 serves as
the precursor to numerous specific prostaglandins. All of these products possess very short half-lives and
are rapidly inactivated.180,181
Prostaglandins mediate their effects through G protein signaling (Table 7-8). Prostacyclin (PGI2) is
produced by the endothelium as a potent vasodilator and inhibitor of platelet aggregation and adhesion;
203
these characteristics enhance tissue perfusion. PGI2 inhibits neutrophil chemotaxis and activation and
interacts synergistically with PGE2 to increase vascular permeability through the bradykinin pathway.
PGE2 is the predominant anti-inflammatory prostaglandin and is produced by nearly all inflammatory
cells. It is produced in response to IL-1 and mediates the hypothalamic fever response and synergizes
with bradykinin and histamine to mediate pain. It is a bronchodilator, inhibits both IL-1 production and
T-cell responsiveness to IL-1, and at low concentrations suppresses TNFα production. It also inhibits
neutrophil chemotaxis and activation and TH1 lymphocyte proliferation.180,181 There is some suggestion
from animal studies that PGE2, PGE1, and PGI2 may be beneficial in response to sepsis through their
endogenous counterregulatory properties. Administration of each of these has been shown to improve
survival in several animal models of hypovolemic and traumatic shock, though clinical trials have failed
to identify benefit.181 PGD2 is a potent bronchoconstrictor that inhibits neutrophil chemotaxis and
activation. TXA2, PGG2, and PGH2 oppose the actions of prostacyclin by promoting platelet aggregation
and inducing bronchoconstriction. TXA2 produced by platelets and macrophages is a powerful
vasoconstrictor that induces neutrophil accumulation and increases vascular permeability.177–179,182
There is substantial evidence that TXA2 plays a significant role in early acute-phase organ injury.181
Lipoxygenase Pathway (Leukotrienes and Lipoxins)

LTs and lipoxins are leukocyte-derived molecules synthesized by the oxidation of arachidonic acid by
three LO enzymes: 5-LO, 12-LO, and 15-LO (Fig. 7-10). 5-LO associates with the perinuclear membrane
protein 5-LO-activating protein (FLAP) to catalyze the formation of 5-hydroperoxyeicosatetraenoic acid
(5-HPETE). 5-HPETE is subsequently converted to LTA4 by the combined efforts of a dehydrase and 5-
LO. LTA4 serves as the precursor for either LTB4 or LTC4. LTC4 can in turn be successively hydrolyzed
to the dipeptide derivative LTD4 and the LTE4. Additional LO activity results in the production of 12-
HPETE, 12-HETE, and 15-HPETE. These compounds exhibit biological activity, although they are not as
potent as the LTs or prostaglandins. The LTs are inactivated by oxidation followed by
dehydration.178–180,182,183
Figure 7-10. Eicosanoid production. 1. Phospholipases; 2. Cyclooxygenase; 3. Hydroperoxidase; 4. Thromboxane synthetase; 5.

Prostacyclin synthetase; 6. E-isomerase; 7. D-isomerase; 8. F-reductase; 9. 5-Lipoxygenase; 10. Glutathione peroxidase; 11.
Hydrolase; 12. Glutathione S-transferase; 13. γ-Glutamyl transpeptidase; 14. Cysteinyl glycinase; 15. 12-Lipoxygenase; 16.
Peroxidase; 17. 15-Lipoxygenase; 18. GSH-cis-11-trans lipoxin A4; 19. α-Glutamyl transferase; 20. Dipeptidase.
204
The major LO product of neutrophils is LTB4, though macrophages may also synthesize this
compound. This compound is potently chemotactic for both neutrophils and eosinophils. By
upregulating endothelial cell surface adhesion molecules it promotes leukocyte recruitment. It increases
vascular permeability, either directly or through interaction with neutrophils and endothelial cells. LTB4
has also been shown to induce hyperalgesia.94,180
LTC4, LTD4, and LTE4 comprise the family of slow-reacting substances of anaphylaxis (SRSA),
compounds synthesized by mast cells during anaphylactic reactions. LTC4 is the major eicosanoid
product of eosinophils and the only mast cell–derived product of LO. These three LTs are potent
vasoconstrictors and the most powerful bronchoconstrictors in humans, being three orders of magnitude
more potent than histamine. They also increase vascular permeability and are vasodilatory in skin.43,180
Lipoxins are biosynthesized by several routes in a tissue-specific manner. Current evidence implicates
the eosinophil. A 5(6)-epoxytetraene intermediate can be formed by 5-LO activity on 15-HPETE. This
reaction, when carried out in blood vessels, requires the interaction of platelets and neutrophils. On
mucosal surfaces, 12-LO and 5-LO activity on LTA4 can result in the formation of this lipoxin
intermediate through leukocyte–epithelial interactions. The 5(6)-epoxytetraene intermediate is then
converted to lipoxin A4, lipoxin B4, or lipoxin C4, the last of which serves as the precursor for lipoxins
D4 and E4.92,184,185
Table 7-8 Prostanoid Effects
Though many of the functions of lipoxins have yet to be elucidated, they appear to counterregulate
the actions of LTs. They inhibit LT production by downregulating 5-LO as 15-LO is upregulated. The
anti-inflammatory cytokines IL-4 and IL-13 further contribute to suppression of inflammatory responses
by enhancing 15-LO activity. In addition to inhibiting synthesis, lipoxins inhibit the actions of LTB4 and
LTD4. Lipoxins A4 and B4 are potent vasoactive compounds. Lipoxins influence smooth muscle and
vascular tonus by increasing NO and prostacyclin production, increasing arachidonate release, and
reversing endothelin-induced vasoconstriction. Counterinflammatory functions of lipoxin A4 include
inhibition of LTs, fMLP, and other chemoattractants. Lipoxin A4 also downregulates LTB4-mediated
delayed type hypersensitivity reactions.92,184–186
A large number of anti-inflammatory drugs, many of which are in clinical use, act by interfering with
eicosanoid synthesis. The anti-inflammatory properties of corticosteroids are mediated at least in part
by the inhibition of PLA2 through the induction of lipocortin. They have been shown to selectively
inhibit COX2 activation without affecting COX1. NSAIDS block the synthesis of both prostaglandins and
thromboxanes by inhibiting COX activity. In contrast to the other NSAIDS, aspirin inhibits COX in an
irreversible manner, and restoration of platelet function necessitates the administration of platelets.
Aspirin, by either acetylating COX2 or by inducing the oxidation of arachidonic acid by cytochrome
p450 or 5-LO, has been shown to stimulate the formation of 15R-HETE in endothelial or epithelial cells.
These 15-epilipoxins exhibit higher potency in suppressing inflammation because of their prolonged
half-lives. A potential complication of NSAID use and COX inhibition is the shunting of arachidonate
through the 5-LO pathway and subsequent greater production of proinflammatory LTs (asthma). Such
consequences minimize any benefit achieved from reducing other eicosanoid levels. In addition, NSAIDs
act systematically in a nonselective manner, so that inhibition of prostaglandin synthesis can result in
dangerous side effects in locations where prostaglandins normally exert cytoprotective effects
(stomach).181,185,187
PLATELET-ACTIVATING FACTOR
PAF is a heterogeneous mixture of 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholines that plays a
205
prominent role in both physiologic and pathologic inflammatory states. It does not exist preformed, but
is rapidly produced by activated cells. Synthesis involves either the remodeling of membrane
phospholipids by PLA2, usually more important under inflammatory conditions, or by de novo synthesis
as occurs in resting cells. De novo synthesis is regulated by substrate availability and involves a
constitutively active enzyme that produces PAF in small basal amounts.188 The membrane phospholipid
precursor is present in high amounts in neutrophils. Other cells that can synthesize PAF include
platelets, basophils, monocytes, eosinophils, mast cells, and vascular endothelial cells. Similar to
eicosanoid production, the synthesis of PAF is initiated by calcium-dependent activation of PLA2, which
yields 1-0-alkyl-sn-glycerophosphocholine (lyso-PAF); subsequent acetylation generates PAF. PAF may
be released from the cell, or it may be converted back to lyso-PAF by an acetylhydrolase and to the
precursor ether-phosphatidylcholine.188
The actions of PAF are mediated by G-protein activation. As the name implies, PAF induces platelet
aggregation and degranulation; yet also possesses many other critical functions for inflammation. Its
vasoactive properties include vasodilation and increased permeability, and it is an equally potent
bronchoconstrictor. PAF enhances arachidonic acid metabolism, leading to increased leukocyte motility,
degranulation, and free radical formation. PAF plays an integral role in promoting activation and
adherence of inflammatory cells to the endothelium.189 During the early inflammatory response,
activated endothelial cells synthesize and express PAF on the cell surface. Leukocytes tethered by
selectins to the endothelium are activated by endothelial PAF, which results in the induction of tight
integrin-dependent adhesion and subsequent emigration and chemotaxis toward the inflammatory focus.
Acyl-PAF, the major acetylated lipid from mast cells, basophils, and endothelial cells, is a less potent
derivative of PAF that likely plays a similar role in the regulation of neutrophil recruitment. PAF also
promotes platelet and neutrophil aggregation, thereby contributing to the prothrombotic state of acute
inflammation. In circumstances of persistent pathologic stimuli, PAF may be liberated systemically,
thereby causing the sequelae of an excessive inflammatory response. As a mediator of sepsis, PAF
augments endotoxin-induced hypotension and neutrophil and platelet accumulation in the lungs. There
is evidence that the NO-induced hypotension in experimental models of endotoxemia is mediated by
PAF.190 PAF infusion leads to a shock state that is similar to septic shock in that there is tissue
hypoperfusion despite adequate fluid resuscitation. In animal studies, PAF has been shown to contribute
many manifestations of sepsis including coronary vasoconstriction, reduced cardiac contractility,
reduced preload, peripheral vasodilation, pulmonary vasoconstriction, increased microvascular
permeability, gastrointestinal hemorrhage, and thrombocytopenia.181 Two prospective randomized,
placebo-controlled trials of PAF inhibition in sepsis have suggested a benefit.181
PAF acetylhydrolase, an enzyme regulated by dexamethasone, estrogen, and PAF itself, is the enzyme
responsible for degradation of PAF.
Kinins
Kinins (i.e., bradykinin and lysyl bradykinin) are small vasoactive peptides generated during the
inflammatory response (Fig. 7-11). Three sources and mechanisms of kinin formation occur during
inflammation: (1) plasma proteins; (2) tissue proteins; (3) cellular proteinases.191–194
Production of Bradykinin
Biosynthesis commences with the activation of Hageman factor (HF), or factor XII of the coagulation
cascade (Fig. 7-11). HF is activated by exposure to anionic surfaces such as the basement membrane of
injured endothelium, heparin, or lipid A of endotoxin. It can also be proteolytically cleaved and
activated by kallikrein. Prekallikrein circulates complexed with HMWK, a nonenzymatic protein.
Kininogen enhances the binding of prekallikrein to negatively charged surfaces. Activated HF converts
prekallikrein to kallikrein, which in turn activates more HF in a positive feedback cycle. HFf, a cleavage
product of activated HF, is also capable of activating prekallikrein. Kallikrein in plasma, tissues, and
secretions specifically cleaves HMWK to release the nonapeptide bradykinin. In addition to bradykinin
production, kallikrein participates in the activation of plasminogen and C1q of the complement system;
yet another link between inflammation and the coagulation system. The only major plasma inhibitor of
activated HF is C1 inhibitor. The primary inhibitors of kallikrein in plasma are C1 inhibitor and α1
macroglobulin.39,191
Kinin Production in Tissue

Lysyl-bradykinin (kallidin) is the cleavage product of either HMWK or LMWK by tissue kallikreins,
206
which are proteins distinct from their plasma counterparts. LMWK is present in higher concentrations
intracellularly compared with HMWK. Whereas both HMWK and LMWK can be converted to lysyl-
bradykinin by tissue kallikrein, only HMWK is cleaved by plasma kallikrein. Kallidin itself can be
converted to bradykinin by a plasma aminopeptidase. Both kallidin and bradykinin use the same
receptors and perform similar functions, but kallidin is approximately 85% as potent as bradykinin.
Tissue kallikrein is synthesized from a preproenzyme and is converted intracellularly to tissue
Prekallikrein by enzymes that are not yet well-characterized. The secreted Prekallikrein is then
converted to tissue kallikrein extracellularly by plasmin or plasma kallikrein. The only significant
inhibitor of tissue kallikreins is α1-proteinase inhibitor.39,191
Figure 7-11. Kinin pathway. (Modified from Proud D, Kaplan AP. Kinin formation: mechanisms and role in inflammatory
disorders. Annu Rev Immun 1988;6:49.)
Cellular Kininogenase Activity

Neutrophils, mast cells, and basophils are sources of kininogenase activity. Neutrophils produce
leukokinins by way of cathepsin D. Their role in inflammation is unclear. Bradykinin is metabolized
sequentially to the partially active eight amino acid peptide, des-Arg-bradykinin, by carboxypeptidase
N, and then to inactive five-amino acid and three-amino acid fragments by the angiotensin-converting
enzyme (ACE). ACE is the predominant enzyme to inactivate bradykinin in the pulmonary vasculature.
Arginine released as a byproduct of the carboxypeptidase N reaction may contribute further to the
modulation of inflammation by acting as a substrate for the formation of NO.39,191,195
There are three kinin receptors, of which two are well-characterized.191,193 B1 receptors are expressed
primarily on the vasculature under pathologic conditions such as tissue injury. They bind des-Arg-
bradykinin and des-Arg-kallidin and mediate the hypotension characteristic of sepsis and pain.191,196
Both B1 and the more widely distributed B2 receptors are G protein–coupled receptors. Activation of B2
receptors stimulates IP and PLC, resulting in the accumulation of the second messengers IP3, DAG, and
calcium. The B2 receptors are more important in mediating the effects of inflammatory kinins, such as
bradykinin and lysyl-bradykinin. These kinins induce arteriolar dilatation and mediate pain. Similar to
histamine, bradykinin increases the gaps between postcapillary venule endothelial cells leading to
increase in vascular permeability. It is a potent constrictor of bronchial, uterine, and gastrointestinal
smooth muscle, and the coronary and pulmonary vasculature.193 Activation of endothelial B2 receptors
stimulates production of NO to further enhance vasodilatation. Kinins have been implicated in
mediating the antihypertensive and cardioprotective effects of ACE inhibitors.197 ACE, in addition to
catalyzing the formation of angiotensin II from angiotensin I, promotes the hydrolysis of bradykinin to
inactive metabolites. In addition, bradykinin can modulate platelet function by stimulating endothelial
cell secretion of PGI2 and thromboxane through activation of PLA2.191
Neuropeptides
Neuropeptides may provide a neuroendocrine link between psychological stress and inflammatory
diseases such as psoriasis and inflammatory bowel disease. Like cytokines, their actions are pleiotropic
207
and redundant. Neuropeptides execute their inflammatory and immunomodulatory effect by binding to
specific G protein–coupled receptors on the surfaces of target cells, and the resultant effect may be
proinflammatory, anti-inflammatory, or both. For example, substance P mediates the hypothalamic
fever response to PGE2 induced by IL-1 and TNFα, whereas ACTH, AVP, and α-melanocyte stimulating
hormone (α-MSH) suppress it. The pituitary peptides prolactin, CRH, and AVP have been shown to
augment immune responses by enhancing TH1 activity.39,198,199
Tachykinins are important proinflammatory neuropeptides that mediate pain and vasodilatation and
promote the classic inflammatory signs of erythema and edema. Substance P stimulates monocyte and
neutrophil influx and neutrophil phagocytosis. Its inflammatory effects appear to be mediated by the
proinflammatory cytokines TNFα and IL-1 from mast cells, monocytes, macrophages, bone marrow, and
endothelial cells. During allergic inflammation, substance P stimulates histamine release from mast
cells. As an effector of immune function, substance P promotes T-cell proliferation and antibody
production. Substance P released locally by nerve terminals is important in mediating the perception of
pain.39,191
CRH induces the release of IL-1, IL-6, and superoxide anion from macrophages and negatively
regulates its own proinflammatory effects through cortisol release. Cortisol downregulates production
of proinflammatory cytokines such as IL-1, TNFα, and IL-2, metalloproteinases, and iNOS, and through
this negative feedback loop, inhibits the production of CRH, ACTH, and AVP. AVP, growth hormone,
and prolactin are other important proinflammatory neuropeptides.39,198,199
Vasoactive intestinal peptide (VIP) and its homologues display both proinflammatory and anti-
inflammatory effects. VIP is widely distributed throughout the central and peripheral nervous systems
and serves as a chemoattractant for macrophages, neutrophils, and T cells, and may play an important
role in granulomatous reactions. VIP stimulates the release of histamine and IL-5 and is a potent
vasodilator. It inhibits IL-6, TNFα, and IL-12 release and iNOS expression in activated macrophages. VIP
has also been shown to stimulate the production of the anti-inflammatory cytokine IL-10 by
macrophages and to inhibit T lymphocyte proliferation and the production IL-2 and IFN-γ.200
Somatostatin and α-MSH are primarily anti-inflammatory in action. Somatostatin, which colocalizes
with substance P in sensory nerves, inhibits IgE formation and NK cell activity, whereas α-MSH inhibits
leukocyte chemotaxis, IFN-γ production, and downregulates TH1 activity. ACTH, calcitonin, and β
endorphin are other neuropeptides with predominantly anti-inflammatory properties.39
Calcitonin gene-related peptide (CGRP) is an immunomodulator that inhibits the activity of T cells
and macrophages, in part through the induction of IL-10. It also is an inhibitor of antigen presentation.
CGRP promotes vasodilatation and neutrophil influx, and synergizes with bradykinin and histamine to
promote edema formation.
Nitric Oxide
Endogenous NO was first discovered in 1987, and NO was the first gaseous molecule shown to be
synthesized for the purpose of cell signaling.201 NO is a weakly reactive radical that diffuses short
distances from cell to cell independent of membrane channels or receptors. Its half-life is short because
of its rapid inactivation by hemoglobin and other endogenous substances; thus, it functions primarily in
a paracrine and autocrine fashion. The enzyme NO synthase (NOS) catalyzes the formation of NO and
citrulline from the substrates L-arginine and oxygen.53,202–204 NOS contains prosthetic groups for flavin-
adenine dinucleotide, flavin mononucleotide, tetrahydrobiopterin, iron protoporphyrin IX, and zinc.
Three isoforms of NOS have been identified. The calcium-dependent constitutive isoforms, neuronal
NOS (nNOS) and endothelial NOS (eNOS), generate the small amounts of NO necessary for those
processes maintaining physiologic homeostasis, such as neurotransmission and endothelial regulation of
vascular tone. The expression of inducible NOS (iNOS), however, requires stimulation and produces
larger, sustained amounts of NO that possess both cytoprotective and cytotoxic properties. This
distinction is not absolute, as certain cell populations express low basal levels of iNOS, and constitutive
NOS transcripts can be enhanced by certain stimuli such as shear stress and hypoxia.53,202–204
Many of the physiologic effects of NO are mediated by the activation of soluble guanylate cyclase.
Increased levels of intracellular cyclic guanosine monophosphate trigger a reduction in calcium
concentration and promote vascular smooth muscle relaxation and the inhibition of platelet aggregation
and adhesion. The cellular response to NO also likely involves multiple signal transduction mechanisms,
including the MAPK pathway.
Inflammation secondary to endotoxemia, hemorrhagic shock, and ischemia/reperfusion are associated
with increased NO production by iNOS. First described in macrophages, iNOS can be expressed in
208
essentially any cell type in response to immunologic stimuli. Unlike nNOS and eNOS, iNOS does not
depend on elevations in intracellular calcium levels for its activity.53,202–204 Important inducers of iNOS
upregulation include LPS, IL-1, TNFα, and IFN-γ. Expression is primarily transcriptionally regulated,
although stabilization of iNOS mRNA also appears to play a role. IFN-γ stabilizes iNOS mRNA, whereas
TGFβ can destabilize it. Transcription of the iNOS gene is controlled by NFκB, IFNγ-responsive element,
and TNF-responsive element. Induction of iNOS can be inhibited by glucocorticoids, thrombin,
macrophage deactivation factor, PDGF, IL-4, IL-8, IL-10, and IL-13.53,202–204 Dexamethasone may inhibit
iNOS induction by impairing the DNA binding capacity of NFκB and by increasing levels of IκB.205,206
The endothelial dysfunction and vascular hyporeactivity that characterizes septic shock is
consequential, in part, to iNOS production of NO.207 NO has been shown to be the effective mediator of
the negative myocardial inotropy of TNFα, IL-6, and IL-2 and the TNFα-induced vasodilatation in the
systemic and microcirculations.208 NO may indirectly increase prostaglandin production by increasing
the catalytic activity of cyclooxygenase and decrease LT production by inhibiting 5-LO.209 NO plays an
autoregulatory role in the TH1 subset of TH cells by limiting their own proliferation.210
NO can mediate tissue injury in inflammation by modulating organ perfusion, mediating interactions
with neutrophils, contributing to proinflammatory signaling, and by regulating apoptosis.211 Whereas
eNOS primarily regulates perfusion during homeostasis, both eNOS and iNOS modulate organ flow in
pathophysiologic states. Basal NO production from eNOS prevents the adherence of neutrophils to the
endothelium and inhibits chemotaxis under physiologic conditions. Animal studies have demonstrated
that pharmacologic inhibition of iNOS or genetic deletion of iNOS attenuates neutrophil accumulation in
organs after ischemia/reperfusion injury.212 Conversely, similar experiments in endotoxemia implicate
an antiadhesive role for iNOS, suggesting that the effect of induced NO on neutrophil accumulation is
insult specific.211 Activated neutrophils can be stimulated by fMLP, PAF, LTB4 to produce NO. NO
produced by neutrophils at sites of inflammation can combine with superoxide to form peroxynitrite as
another means of effecting toxicity.39,213
The reaction of NO with superoxide is the only reaction that outcompetes the reaction of superoxide
with superoxide dismutase. Small amounts of peroxynitrite are produced under basal conditions from
constitutively produced NO and superoxide from mitochondria and other cellular sources. However,
endogenous antioxidants such as GSH, vitamins E and C, and superoxide dismutase likely limit its
toxicity. A low concentration of peroxynitrite has been shown to inhibit neutrophil adhesion. Higher
concentrations of peroxynitrite can initiate a wide range of toxic oxidative reactions through a
peroxynitrous acid intermediate. These include the initiation of tyrosine nitration, lipid peroxidation,
and direct inhibition of mitochondrial respiratory enzymes. The balance between superoxide and NO
determines the reactivity of peroxynitrite; excess NO reduces the oxidation elicited by peroxynitrite. In
addition, peroxynitrite may contribute to cytotoxicity by a more indirect pathway. Peroxynitrite-
induced single strand breaks in DNA activate the nuclear enzyme poly (ADP-ribose) synthetase, leading
eventually to irreversible energy depletion of the cells and necrotic-type cell death.39,41
Inducible NOS plays a key role in host defense, with NO or peroxynitrite exhibiting potent
antimicrobial activity against a number of pathogens including viruses, fungi, and bacteria. Although
microbicidal susceptibility to NO-mediated killing can vary considerably between species, essential roles
have been identified in tuberculosis and bacterial peritonitis.214 Induced NO has been shown to be
essential for the upregulation of the inflammatory response in hemorrhage shock and other
inflammatory processes. NO produced by iNOS leads to the activation of NFκB.215 This is followed by
the induction of proinflammatory cytokines and increased leukocyte recruitment and activation.
NO possesses both proapoptotic and antiapoptotic effects depending upon the circumstances. NO
derived from eNOS may inhibit apoptosis.216 Proapoptotic effects appear to be associated with
pathophysiologic conditions in which iNOS is upregulated. Low concentrations of peroxynitrite have
also been shown to induce apoptosis, whereas higher concentrations promote cell necrosis in vitro. The
role of NO-mediated apoptosis in the regulation of the inflammatory response is yet to be more clearly
defined.
In summary, NO mediates tissue injury both directly through the formation of peroxynitrite, as well
as, indirectly through the amplification of the inflammatory process. Like many mediators, NO has dual
regulatory functions, and it is therefore difficult to characterize NO as distinctly proinflammatory or
anti-inflammatory. In general, basal levels of NO produced by constitutive NOS may confer anti-
inflammatory effects, whereas induced NO may tend to promote the upregulation of the inflammatory
response. It is likely that an optimal level of NO is necessary in host defense; too little NO may be as
harmful as too much.
209
Heme Oxygenase
HO catalyzes the breakdown of heme to iron, biliverdin, and carbon monoxide.217 Three isoforms of HO
have been identified. HO-2 is constitutively expressed in many tissues, whereas HO-3 expression
appears to be limited to the brain. HO-1 is not expressed constitutively in most tissues, but is rapidly
upregulated by both heme and nonheme cellular stresses, including hypoxia, redox stress, and
inflammation. Additionally, NO is a potent inducer of HO-1. HO-1 has profound antiapoptotic and anti-
inflammatory effects. These cytoprotective effects have been attributed to the individual catalytic
products of heme metabolism. Biliverdin is converted to bilirubin by biliverdin reductase, and bilirubin
has been demonstrated to act as a potent intracellular antioxidant. Carbon monoxide alone can mimic
many of the actions of HO-1 and has been shown to protect in models of sepsis, hemorrhagic shock, and
ischemia/reperfusion when administered as an inhaled gas. The mechanisms of action of carbon
monoxide have both similarities and dissimilarities with NO, and is an area of active investigation.217
Hydrogen Sulfide
Hydrogen sulfide is a colorless, flammable gas, with the typically malodor of putrid eggs. It is highly
lipophilic and freely penetrates the cell wall, which greatly facilitates its biological activity.218 Recent
evidence highlights the widespread distribution of H2S in the plasma, brain, and other tissues. H2S is
formed in mammalian cells largely by the activity of two pyridoxal phosphate–dependent enzymes,
cystathione γ lyase (CSE), and cystathionine β synthetase (CBS) that utilize cysteine and homocysteine
to form H2S.219 Large amounts of these enzymes occur in the brain (CBS), liver (CSE), kidney (CSE) and
blood vessels (CSE). Interestingly, lipopolysaccharide exposure induces the expression of CSE,
suggesting that H2S may regulate inflammation.218 Both pro- and anti-inflammatory actions have been
described. H2S levels and CSE expression are increased in animal models of endotoxemia, sepsis, and
hemorrhagic shock.218,220,221 It has been shown to increase leukocyte attachment and rolling in jejunal
blood vessels and to increase ICAM-1 expression.222 In human monocytes, H2S donors induce the
formation of proinflammatory cytokines and chemokines via an NFκB mechanism.223 Inhibitors of CSE
reduce the inflammation in these animal models of sepsis and hemorrhage. By contrast, H2S decreases
LPS-induced upregulation of NFκB in RAW 264.7 macrophages, and H2S-releasing derivatives of
diclofenac exhibit greater anti-inflammatory activity in endotoxic shock.218,219,224
RECOGNITION AND ACTIVATION PROCESSES

Exogenous and Endogenous Danger Recognition
Multicellular organisms have evolved an essential mechanism of surveillance, defense, and repair of
injured cells. Implicit with this system is the ability to differentiate pathogens and damaged cells from
self. The initial response is orchestrated by the evolutionarily ancient and more universal innate
immune system, which employs monoclonal sets of recognition molecules called PRR.225,226 PRRs bind
conserved molecular structures found in large groups of pathogens, termed PAMPs. PAMPs are a
diverse set of microbial molecules, which share a number of different recognizable biochemical features
that alert the organism to intruding pathogens.225–227 These PAMPs are recognized by cells of innate and
acquired immunity, primarily through the Toll-like PRRs. Activation induces several signaling pathways,
most notably NFκB.225,227 Consequent to this activation, an immune response is triggered to destroy the
pathogen and/or pathogen-infected cells, and an adaptive response is initiated to select pathogen-
specific T cells and antibodies for future occasions.
However, pathogens are not the only causative agents of tissue and cell damage. Cells, and thus
tissues, can be injured by various noxious insults: heat, cold, chemicals, radiation, ischemia, or direct
mechanical injuries. Evolution has enabled us to deal with these damages, which though not caused by
pathogens, still necessitate repair. It is becoming apparent that specific receptors exist by which to
recognize extrinsic threats (i.e., pathogen) and intrinsic altered self (cytokines, oxidized mitochondrial
DNA, HSPs, and uric acid).227
Danger-Associated Molecular Patterns

8 DAMPs, the endogenous equivalent of PAMPS, represent danger signals or “alarmins” and share many
characteristics similar to cytokines.227 DAMPs may be released following nonprogrammed cell death,
such as necrosis, and under such circumstances tend to elicit inflammation. By contrast, programmed
210
cell death (i.e., apoptosis) incorporates mechanisms such as acetylation, to minimize the release of these
mediators and any subsequent inflammatory response. Cells of the immune system also can be induced
to secrete these mediators.227 This secretion may occur by specialized secretion systems or by the
classical ER–Golgi secretion pathway.227 Under these circumstances, DAMPs may facilitate the
inflammatory response by aiding the recruitment of innate immune cells, most notably DCs. In doing so,
they indirectly orchestrate the subsequent adaptive immune response and facilitate tissue repair.227 The
prototypical alarmin, HMGB1, has already been discussed.
S100 Proteins
The family of S100 proteins incorporates over 20 related calcium-binding proteins.227 S100A8 and
S100A9 form heterocomplexes in the cytosol of granulocytes, monocytes, and macrophages, whereas
S100A12 exists as homodimers in the cytoplasm of granulocytes. S100 proteins are actively secreted at
sites of inflammation via a nonclassical pathway. The receptors mediating their effects are still being
defined, though it appears that S100A12 and S100B interact with RAGE, whereas S100A8/9 may
interact with TLR receptors. S100 proteins have been shown to induce increased vascular permeability
and a prothrombotic effect. Recent studies implicate S100 proteins in the pathogenesis of autoimmune
arthritis and psoriasis.227
Uric Acid
Uric acid is released after cellular injury, and upon exposure to the extracellular environment,
precipitates to form monosodium urate (MSU).227 Uric acid stimulates dendritic maturation and, when
coinjected with antigen in vivo, significantly enhances the generation of responses from CD8+ T
cells.227 It has significant proinflammatory properties that are best evidenced in the disease gout, in
which uric acid accumulates in tissues and induces inflammation-dependent arthritis. MSU crystals
engage the inflammasome, resulting in the production of IL-1β and IL-18.227 Macrophages from mice
deficient in IL-1R or in various components of the inflammasome, such as caspase-1, ASC, and NALP3
are defective in MSU-induced cytokine secretion and have reduced inflammation.227 Extracellular uric
acid is eliminated by uricase.227
Receptors for Danger Recognition

9 Innate immunity is not antigen specific, but rather programmed to respond to groups of evolutionarily
conserved macromolecules that represent “patterns of danger” and signal a potential threat to the host.
PRRs identify these PAMPS and include the TLR and NOD-like receptors. Recent studies highlight the
promiscuity of these PRRs in also recognizing and mediating DAMP-dependent signaling. In fact,
multiple positive feedback loops between DAMPS and PAMPs and their overlapping receptors may
represent the molecular basis for the observation that infections, as well as nonspecific stress factors,
can trigger flares of autoimmune diseases (i.e., rheumatic).148 Additional novel receptors have
subsequently been identified and designated PRRs, including RAGE.226,227
CD14
The prototypical receptor identifying external infectious threat (i.e., gram-negative infection) is CD14.
CD14 was identified as the LPS receptor when transfection of CD14-negative CHO cells with CD14
conferred responsiveness to LPS.228 Its critical role in LPS recognition is underscored by the LPS-
hyporesponsive phenotype of CD14–deficient mice. It has been identified on cells of the myeloid
lineage, B cells, liver parenchymal cells, and fibroblasts. Differential expression is observed; ranging
from high levels on peritoneal and pleural macrophages to lower levels on Kupffer cells, alveolar
macrophages, monocytes and PMN. Expression may be modified; human PMN express low levels of
CD14 that is upregulated by TNFα, G-CSF, GM-CSF, and fMLP. Prototypically, CD14 binds LPS bound to
LPS-binding protein (LBP) in combination with MD-2 and presents it to TLR4.228 MD-2 is required for
cellular responsiveness to LPS, as demonstrated by both transfection studies and an analysis of a CHO
cell line with mutated MD-2 gene. Most of the available evidence indicates that a complex of TLR4/MD-
2/CD14 directly binds LPS.228 CD14 is also important in TLR2 signaling, whereby it presents bacterial
products other than LPS.
Toll-Like Receptors
CD14 is a glycosylphosphatidylinositol-linked receptor devoid of any transmembrane domain. This, in
combination with the identification of a soluble form of CD14, necessitated identifying the manner by
which LPS induced activation.229 In 1996 the Toll protein in Drosophila was shown to be necessary for
211
an effective immune response to the fungus Aspergillus fumigatus.225 In 1998, Poltorak et al.230
discovered that the lps gene in LPS-hyporesponsive C3H/HEJ mice encoded a murine member of the
TLR family. These data provided the initial evidence that mammalian TLRs function as PRRs.
Subsequent studies have confirmed that TLR4 is the “LPS receptor” and that it is essential for the
defense against gram-negative microorganisms.228
Thirteen mammalian TLR receptors have been characterized. Each recognizes a specific set of
conserved microbial molecules, and as a family, they can detect most microbes.228 Interestingly, the
subcellular localization of different TLRs correlates to some extent with the molecular patterns of their
ligands and their function.231 TLR1, TLR2, and TLR4 are located on the cell surface and are recruited to
phagosomes after activation by their respective ligands. They are the receptors mediating the response
to exogenous insults including bacterial infection and trauma. By contrast, TLR3, TLR7, and TLR9, all of
which are involved in the recognition of nucleic-acid–like structures (i.e., viral DNA), are expressed
intracellularly.225,232
TLR4 is required for the innate response to gram-negative organisms and LPS, though other TLR, such
as TLR2, can also recognize and mediate this response.226 TLR4 has been shown to trigger the response
to additional ligands, including lipoteichoic acid (LTA) and peptidoglycans from gram-positive bacteria
and the fusion protein of the respiratory syncytial virus.233 Polymorphisms in the receptor confer
variability in function. Individuals with the D299G polymorphism in TLR4 demonstrate increased risk of
gram-negative infections, and other studies have linked this with an increased incidence of SIRS.234 In
addition, this polymorphism has been associated with alterations in the susceptibility to other
inflammatory and potentially infectious processes (carotid artery atherosclerosis, coronary artery
disease).234 HSP60 of Chlamydial origin has been found in atherosclerotic plaques and can bind TLR4.
Perhaps recognition of HSP60 by human TLR4 might exacerbate the inflammatory component of
atherosclerosis, whereas people with D299G polymorphism might be at least partly protected from this
exacerbation.234 TLR4 has been well-characterized as a PRR for DAMPS, including HSPs (HSP60, HSP70,
gp96), hyaluronate, heparan sulfate, and other matrix proteins. Because of its ability to recognize
endogenous proteins, TLR4 is implicated in a variety of diseases, including arthritis and
atherosclerosis.148,232
TLR2 recognizes lipoproteins derived from the cell wall of bacteria such as Treponema pallidum and
Mycoplasma fermentans, LTA from gram-positive bacteria (i.e., Streptococcal species), lipopeptides, LPS,
and lipid A.226,232,233 It also can recognize a host of DAMPs, including the HSPs, fibronectin, fibrinogen,
heparan sulfate and hyaluronate. Recent data suggest that TLR2 forms heterodimers with other TLR,
including TLR1 or TLR6 to recognize these DAMPs. A likely consequence of this cooperation is an
increased repertoire of ligand specificities. The R753Q polymorphism in the TLR2 is associated with
decreased response to these bacteria and may increase susceptibility to staphylococcal infections or
tuberculosis.232,234
Additional TLRs involved in inflammation include TLR9, which recognizes unmethylated CpG motifs
present in bacterial DNA. By contrast, most of the host mammalian genome is methylated. TLR9-ligand
engagement occurs intracellularly, in either endosomes or lysosomes, presumably following bacterial
lysis. Recent evidence suggests that TLR9 can identify host DNA released by dead or dying cells, and
hence, may be involved in the autoimmune diseases such as SLE.225 TLR5 recognizes flagellin of
bacterial flagella.235 TLR3 recognizes double-stranded RNA of both viral and endogenous sources.
Because of the later characteristic, TLR3 has been implicated in autoimmune arthritis.
TLRs induce signal transduction via their cytoplasmic Toll-interleukin-1 receptor (TIR) domains that
promotes the subsequent expression of a variety of host defense genes. These include inflammatory
cytokines and chemokines, antimicrobial peptides, costimulatory molecules, MHC molecules, and other
effectors. A considerable portion of the functional response is mediated by activating intracellular
signaling pathways that culminate in the induction of the transcription factor NFκB. Specifically, the
CD14/MD-2/TLR4 complex, upon engagement with LPS-LBP recruits the adapter protein MyD88, which
engages the serine/threonine kinase IRAK. IRAK undergoes autophosphorylation and recruits TRAF6.
Ultimately, activated IκK phosphorylates and targets for degradation the NFκB inhibitor IκB, which
enables the nuclear translocation of NFκB and transcription of inflammatory genes. AP-1 and members
of the MAPK transduction cascade are also activated by this mechanism. This pathway is critical to the
production of IL-12, TNFα, and IL-6. All TLRs signal through this conserved signaling cascade, and for
some MyD88 (TLRs 2, 6, 9) is their sole receptor-proximal adaptor. For instance, MyD88 is essential for
clearance of S. aureus, a gram-positive bacteria, which signals through TLRs 2, 6, 9.225,226,233
Subsequent studies utilizing MyD88-deficient mice suggested that alternate TLR pathways existed.
212
These mice, in response to many TLR ligands, including peptidoglycan and unmethylated CpG motifs,
did not activate NFκB or MAPK. Surprisingly, however, LPS could still activate NFκB and MAPK, though
in a delayed fashion. Subsequently, a MyD88-independent pathway has been characterized that is
utilized by TLR4 and utilizes a distinct adaptor protein called TIR domain–containing adapter protein
TIRAP or Mal. A dominant negative mutant of TIRAP specifically impairs TLR4- and TLR2- but not IL-
1R or TLR9-induced NFκB, indicating a specificity of TIRAP for the TLR4 pathway. A third TIR-
containing adaptor molecule, TIR-domain containing adaptor inducing IFN-β (TRIF) also appears to
mediate a MyD88-independent pathway.225,226,233
Most of this research has occurred in the realm of sepsis and provided insight into the manner by
which organisms identify infectious threats and activate the inflammatory pathway to preserve the host.
However, several circumstances of sterile inflammation suggest a role of the TLRs in mediating
inflammation in response to endogenous danger signals (uric acid, mitochondrial DNA, HMGB1).228
Hepatocellular injury consequent to ischemia/reperfusion has been shown to be dependent on TLR4.32
RAGE
RAGE is an immunoglobulin superfamily molecule that belongs to the multiligand receptors that
recognize families of ligands rather than a single polypeptide.97,227,236,237 It has a single transmembrane
spanning domain and a highly charged cytoplasmic tail that though lacking known signaling motifs, is
critical for cellular activation. Though RAGE knockout mice are viable and fertile, they display a wide
range of defects. Most of these defects are subtler than expected, leading to the suggestion that other
receptors with overlapping function might exist. Signaling appears to necessitate clustering into a
particular orientation, which facilitates binding of cytosolic signaling complexes.97,236 Its ligands include
products of nonenzymatic glycosidation (e.g., advanced glycation endproducts or AGEs), the amyloid-β
precursor protein, the S100/calgranulin family of proinflammatory cytokine-like mediators, and the
high mobility group 1 DNA binding proteins (HMGB-1). Its expression is upregulated at sites of diverse
pathologies including atherosclerosis and Alzheimer’s disease. In fact RAGE-mediated cellular
stimulation is thought to increase expression of the receptor itself, thereby generating a positive
feedback mechanism and perpetuating the proinflammatory state.97,236,237
Recent studies demonstrate the activation of multiple signal transduction cascades subsequent to
ligand binding, including the family of MAPKs (p38, ERK 1/2, and JNK) and the rho gtpases (cdc42 and
rac).237 Like TLRs and IL-1R, RAGE engagement leads to NFκB activation, suggesting that both receptor
usage and signaling pathways evoke similar responses when cells are activated by PAMPs and DAMPs.
It is currently hypothesized that RAGE–ligand interaction induces a new heightened basal state of
activation. With a superimposed stimulus, cellular perturbation is magnified. Rather than returning to
homeostasis, cellular signal transduction mechanisms favor augmented dysfunction.97,236
Studies have implicated RAGE to be an important receptor during various acute and chronic
inflammatory processes, including tumor biology. RAGE expression and function directly correlated
with tumor growth in RAGE-transfected C6 glioma cells. In a murine tumor model, mice treated with
soluble RAGE, which functions as a decoy, exhibited a reduction in lung metastases, cellular invasion,
and expression of matrix metalloproteinases.237
RAGE has also been identified as a receptor for S100A12, a member of the S100/calgranulin family of
proinflammatory mediators. Endothelial cells cultured with S100A12 displayed RAGE-dependent
expression of VCAM-1 and tissue factor. Mononuclear phagocytes displayed S100A12-RAGE chemotaxis,
expression of tissue factor, and elaborated IL-1 and TNFα. In vivo studies of delayed-type
hypersensitivity demonstrated reduced inflammatory response when mice were treated with anti-RAGE
F(ab′)2, anti-S100 F(ab′)2, or soluble RAGE. Treated animals also displayed reduced NFκB activation
and IL-1 and TNFα expression.237
The angiopathy of diabetes is thought to be consequent to inflammatory processes generated by
elevated glucose concentrations. Hyperglycemia has been demonstrated to activate numerous signaling
cascades. One process that might mediate these effects is through the nonenzymatic formation of
AGEs.97,236,237 AGE-RAGE interactions on endothelium lead to the expression of procoagulant tissue
factor and VCAM-1 and macrophages-released tissue factor. Animals treated with soluble RAGE showed
decreases in atherosclerotic lesion area and number and a marked reduction in lesion complexity. Also,
treated animals had reduced expression of adhesion molecules, tissue factor, MCP-1, and matrix
metalloproteinases.97,236,237
CD91
The immunological properties of HSPs were discovered by their ability to elicit antitumor immunity. It
213
was later discovered that this antigenic specificity was determined by the peptides they chaperoned.
APCs can bind and internalize HSP–peptide complexes derived from virus-infected cells or tumors and
represent them on major histocompatibility MHC class I molecules. In addition, APC engagement of
HSP–peptide complexes induces maturation, the expression of costimulatory molecules, and the
induction and release of cytokines (TNFα, IL-1, IL-12, IL-6, GM-CSF, MIP-1, RANTES, and NO).238,239
CD91 had been identified as a receptor for the serum protein α2 macroglobulin, a natural protease
inhibitor that like HSPs is found across many species. In fact α2 macroglobulin is the evolutionary
precursor of the C3 complement component. By binding pathogen proteases utilized during invasion and
shuttling them for endocytosis, α2 macroglobulin hinders pathogen invasion.238,240
However, such a method of host defense would be ineffective for intracellular pathogens that gain
access by alternative means, such as mimicking host proteins and developing ligands for host receptors.
Hence, another method for signaling danger is necessary. It is currently thought that upon cell death,
HSPs contained within the cell transfer information regarding the infected intracellular environment to
CD91. This large cell surface receptor, complexed with the HSPs, is internalized and delivers antigen to
the classical MHC class I pathway. The MHCs bind and present them to CD8+ T cells. On recognizing
nonself, T cells are induced to proliferate and mediate killing. This mechanism could be generalized to
implicate CD91 and HSP interactions in the recognition of all cellular stress that culminates in injury
and death.240
CD91 was first identified by Binder et al. as the receptor for gp96 and then by Basu et al. as a
common receptor for other HSPs (HSP70, HSP90, and calreticulin).241,242 This large multidomain 600-
kD protein possesses multiple binding sites for at least 32 ligands. The binding of this receptor to many
members of the HSP family has been corroborated by several independent functional and structural
studies.240
Several in vivo studies suggest a physiological relevance for HSP-CD91 interaction. Mice immunized
with tumor-derived gp96–peptide complexes reject a subsequent tumor challenge. If CD91 antiserum is
mixed with the HSP–peptide inoculum, the mice fail to reject the tumors. Srivastava et al. noted that
blocking of CD91 completely inhibits the phenomenon of representation of peptides that are carried or
chaperoned by HSPs, suggesting that not only is CD91 a receptor for HSPs, but it may also be the sole
receptor involved in antigen representing.239,242
Figure 7-12. Autophagy/mitophagy. Autophagy is inhibited by the metabolic growth rheostat mTOR that inhibits autophagy when
ATP and nutrients are plentiful. Sepsis and metabolic stress lead to inhibition of mTOR and initiation of the isolation membrane.
Atg12-ATG5-Atg16L and LC3-II localize to the phagophore to capture selected targets for degradation. Upon completion of
autophagosome formation, the Atg12-Atg5-Atg16L complex dissociates while LC3-II remains on it. The autophagosome ultimately
fuses with the lysosome to form an autolysosome, where its contents are degraded.
HSPs have been shown to chaperone antigenic peptides (tumor, viral, minor histocompatibility
antigens) from all cellular compartments. The family of HSPs thus appear to be a universal mechanism
for antigen capture, and they permit a high-efficiency antigen uptake through a receptor-mediated
mechanism.
Evidence that HSP–peptide–CD91 interactions serve to signal cellular stress is beginning to culminate.
Basu et al. demonstrate that Hsp70, Hsp90, gp96, and calreticulin are released from cells as a result of
necrotic cell death, but not apoptotic cell death.241 Similarly, Melcher reported that tumor cells
undergoing necrotic death are highly immunogenic as compared to those undergoing apoptotic death.243
Actual necrosis may be unnecessary as stressed cells and cancer cells have been reported to express cell
214
surface HSP molecules, which may activate APCs. Li et al. observed that physical contact of tumor cells
artificially engineered to express cell surface HSPs with immature DCs elicits a powerful maturation of
DCs.244
Other HSP Receptors

CD40 was reported as a receptor for Hsp70 when anti-CD40 antibodies were observed to inhibit
macrophage chemokine secretion in response to mycobacterial Hsp70. Subsequently, Becker noted the
association of recombinant GST-tagged CD40 with murine Hsp70.245,246 They further demonstrated
enhanced binding after the APCs were stimulated with LPS. As LPS induces expression of a number of
cell surface molecules, the authors concluded that CD40 mediates recognition and binding of Hsp70.247
CD36 has been implicated as a receptor for gp96. Transfection of CD36 into CD36-negative cells has
been shown to enhance gp96 binding. In addition, CD36−/− macrophages have a 52% reduction in gp96
binding compared with wild-type controls, suggesting that some role for CD36 as an Hsp receptor.247
LOX-1, a member of the same scavenger superfamily as CD91 and CD36 has been postulated to be an
additional receptor for endocytic uptake of Hsp70 and chaperoned peptides by human DCs. Anti-LOX-1
antibodies and LOX-1 ligand-acetylated albumin competed with Hsp70 for binding to DCs.114
Both TLRs and CD14 have been implicated as receptors for HSPs, such as Hsp70.248 Hsp70 stimulates
macrophage IL-12p40 production that is partially abrogated by inhibiting downstream TlR signaling
cascades. In addition, human Hsp60 activated NFκB and TNFα production by 293T cells transfected with
either TLR-2 or TLR-4 and MD-2.249 Hsp60 also activated JNK kinase and IKK kinase signaling and
TNFα production by macrophages, an effect that was partially eliminated by knocking out MyD88 or
TRAF6. Similar functional studies have proposed that CD14 might serve as an Hsp70 receptor in APCs.
All of these studies heavily suggest a role of TLRs or CD14 in HSP binding, although several
investigators call into question the potential for contamination with LPS to be mediating much of these
effects.247
AUTOPHAGY
Autophagy is an ancient cytoplasmic homeostatic process governing cellular biomass quantity, quality,
and distribution through the recycling of cytoplasmic proteins and organelles to support vital functions
during periods of stress (i.e., starvation).250,251 It literally originates from the Greek words auto
meaning “self” and phagein meaning “to eat.” Fundamental for embryological development and survival,
it integrates extensively with apoptosis and may itself function as a form of programmed (type II) cell
death.251–253 Hence, it is not surprising that it is preserved in all eukaryotic organisms, from yeast to
humans.
Macroautophagy is coordinated by specialized autophagy-related proteins (ATGs) that sequester large
protein aggregates, dysfunctional organelles, and even microorganisms and target them for lysosomal
degradation. In the setting of nutrient deprivation, the mechanisms orchestrating this dynamic process
involve the main growth rheostat mammalian target of rapamycin (mTOR) and adenosine
monophosphate (AMP) kinase, a sensor of cellular energy status.251,252,254–258 Prototypically, AMP
kinase, sensing reduced cellular energy (i.e., elevated AMP) inhibits mTOR, a negative regulator of
autophagy, thereby inducing autophagy.252,254,259,260
Autophagy is initiated by complex formation of ULK1 and ULK2, the class III phosphatidylinositol-3-
phosphate kinase VPS34, and ATG14-like protein, ATG14L. This initiates the ATG conjugation cascade in
which ATG5 and ATG12 complex with ATG16L1 to form an isolation membrane around the target (Fig.
7-12). The complex facilitates the addition of a phosphatidylethanolamine group to LC3-1 to form LC3-
II. LC3-II together with other factors leads to elongation and closure of the autophagosome, which is
then targeted for fusion with the lysosome, forming the autolysosome (Fig. 7-12).
Though the quintessential function of autophagy is to digest and recycle portions of the cytoplasm
during starvation, it has recently been described as an important effector arm of immune cells
responding to exogenous (i.e., PAMP: LPS)261,262 and endogenous (DAMP: HMGB1) stimuli.250,259,262–266
It is proposed that competition with microorganisms for nutrients, and thus nutrient deprivation, may
have served as a sign of invading organisms and thereby supported the emergence of eukaryotic
autophagic mechanisms of pathogen elimination. However, a host of other PAMPs and DAMPS and
mediators may induce autophagy. In Mφ, LPS induces autophagy through mechanisms dependent on
TLR4, TRIF, RIP1, and p38 MAPK.261,267 Cytosolic pathogens, such as viruses, can induce autophagy, or
rather xenophagy. DAMPS, such as DNA, ATP, and HMGB1 may also induce autophagy, the later
215
through RAGE. The induction of autophagy by the inflammatory cytokine IL-1β is critical for control of
Mycobacterium tuberculosis. Similarly, TNFα stimulates autophagy in restricting intracellular bacteria. By
contrast, TH2 cytokines such as IL-4 and IL-13 and NO inhibit autophagy.
During innate immunity, autophagy has been shown to be important in the elimination of
intracellular microbes, through LC3-associated phagocytosis and xenophagy. This latter process of
selectively degrading intracellular pathogens involves sequestosome 1–like receptors (SLRs) that
recognize molecular motifs on invading pathogens. These SLRs help to clear microorganisms that gain
entry to the cytoplasm if they escape the defenses that are controlled by conventional PRRs. Microbial
polymers, such as DNA, that are present in the cytoplasm might function as autophagy-inducing PAMPS,
as in the case of M. tuberculosis infections. The critical importance of autophagy to cell survival is
perhaps best made evident by the defenses several microbes (Listeria, Shigella, Legionella) exhibit to
combat autophagy machinery.
Autophagy can assist PRR by delivering cytosolic PAMPs to endosomal TLR (i.e., TLR7) and stimulate
their activity.268–270 Nucleic acid receptors called RIG (retinoic acid inducible gene)-I-like receptors
(RLRs) recognize viral RNA, and induce the production of type I IFN to thwart viral invasion. The
interaction between TLRs and autophagy may also serve to augment antigen presentation by DCs.
Autophagy limits the activation of the inflammasome, a cytoplasmic complex that responds to PAMPs
and DAMPs by inducing the proteolytic processing and secretion of IL-1β and IL-18. It does so by
clearing the cytoplasm of debris, such as damaged or depolarized mitochondria that can function as
endogenous agonists. Inhibition of autophagy leads to the release of the products, such as mitochondrial
DNA and ROS.268–270 Autophagy also affects the secretion of pro- and anti-inflammatory mediators. In
senescent cells, it regulates the secretion of IL-6 and IL-8. It reduces immunoglobulin secretion from
plasma cells, and thus, may be important in negatively regulating antibody production.
During adaptive immunity, autophagy contributes to MHC class II presentation. Classically this is
described in the context of presenting cytoplasmic antigen (e.g., virus or self antigen) to endosomal
receptors, such as TLR7 (see above). Thus, autophagy is implicated in autoimmune disorders such as
autoimmune colitis and Crohn’s disease. The link between autophagy and inflammatory diseases has
also been reported. Polymorphisms in ATG16L1 and IRGM are linked to Crohn’s disease. IRGM
polymorphisms may be a risk factor for SLEs, and rheumatoid arthritis has been associated with
variations in the ATG5 gene. In summary, autophagy influences adaptive immune responses through its
effects of antigen presentation, naïve T cell–repertoire selection, T-cell homeostasis and TH-cell
polarization.268–270
Interestingly, nonimmune cells, such as hepatocytes and renal tubular cells also exhibit TLR signaling
and respond to the stress of sepsis or lipopolysaccharide by inducing autophagy.32,264,271–274 Studies
suggest that these mechanisms are similarly induced in vivo in the early response to sepsis, and regulate
bronchoalveolar cytokine/chemokine production and neutrophil accumulation. Others have shown that
sepsis induces similar AMPK- and mTOR-dependent mechanisms of autophagy in the Mϕ, kidney, and
liver.267,271,275–277 This mechanism may be critically important for cell survival, as it has been shown
that augmenting mTOR- or AMPK-dependent autophagy during CLP sepsis attenuates mitochondrial
injury and reduces acute kidney injury (AKI) (Fig. 7-6).274 In summary, recent data support a
fundamental role of autophagy in nearly every arm of immunity as an antimicrobial effector of
TLR.253,264,265,267,268
Mitophagy, autophagy directed at the removal of damaged mitochondria, is considered to of
particular importance in protecting against organ injury, such as AKI.278 At least two mechanisms are
involved in the sequestration and elimination of defective mitochondria: Atg7 and PINK1/Parkin. Atg7
is an autophagy protein that is required for the initiation of ubiquitin-like conjugation pathways of
autophagy. During erythroid maturation, Atg7 serves a nonredundant role in mitochondrial clearance
through canonical autophagosomal pathways.279,280 Alternatively, PINK1 accumulation at the outer
mitochondrial membrane of dysfunctional mitochondria selectively recruits Parkin, which in turn
promotes their selective degradation by mitophagy.281–284 Conditions that induce mitochondrial
dysfunction and depolarization strongly induce this pathway, which is important for cell survival.285
Indeed, endogenous Parkin production and exogenous Parkin overexpression have been found
cytoprotective in different conditions of stress, including sepsis. Not surprising, due to the potential for
release of cytochrome C and ROS, it is vital that a cell possess a programmatic mechanism for the
elimination of defective mitochondria.
216
THE STRESS RESPONSE
The stress response is the cellular reaction to any perturbation or disruption in equilibrium and serves to
restore homeostasis. Inducers of the stress response include physical stresses (burns, radiation, trauma),
chemical agents and mediators (toxin, heavy metals, cytokines, ROS), infectious agents (bacteria,
viruses, parasites), and allergens. It is often referred to as the heat-shock response after the
identification in the 1960s of the HSPs, a group of genes expressed after exposure to heat.286 However,
subsequent investigations delineated additional cellular proteins that are expressed in response to a
wide variety of insults. Clinically, expression of HSP has been observed under conditions in which
oxygen delivery is compromised, as in hemorrhage or ischemia.287
Activation of the stress response is characterized by both morphologic and metabolic cellular
alterations. Morphologic alterations include the accumulation of unprocessed forms of mRNA in the
nucleolus, and increased numbers of actin microfilaments in the cytoplasm. Changes in cellular
metabolism include a rapid reduction in intracellular ATP levels, most likely correlated with alterations
in the integrity of mitochondria. The stress response is characterized by transient downregulation of
most cellular products and by the upregulation of stress proteins.288 It is the induction of stress proteins
that confers the primary adaptive and protective effects of the stress response.
After expression of stress genes, cells become resistant to subsequent stresses. Members of the stress
protein family include HO (see above); the multiple-drug resistance gene product P-glycoprotein;
ubiquitin, involved in targeting proteins for degradation; scavengers such as superoxide dismutase,
ferritin, and metallothioneins; and the glycolytic enzymes enolase and glyceraldehyde 3-phosphate
dehydrogenase. The most extensively characterized are the HSPs.39
HSPs are molecular chaperones that may either be constitutively expressed or induced upon cellular
stress.289 Classification is based upon their molecular mass and degree of homology. The most
extensively studied is the Hsp70 family, members of which possess a mean molecular mass of 70 kD and
greater than 70% homology. Members of the Hsp70 family bind ATP, and are induced under conditions
of energy depletion and stress. Hsp70 is integral in cellular adaptation to and survival during
environmental stresses. Both Hsp72 and Hsp73 are present in the cytosol and nucleus. The former is
constitutively expressed, whereas, expression of Hsp72 is exclusively induced. In most studies Hsp72 is
used as a marker of HSP induction.39,287,290,291
The Hsp60 family members are also referred to as chaperones. The glucose-regulated protein group of
HSP is induced with glucose starvation, inhibitors of N-glycosylation, and calcium ionophores. The
decrease in glucose content may affect the pool of sugar donors during protein glycosylation. The low–
molecular-weight HSP (molecular masses of 20 to 30 kD) may be important regulatory components of
the actin-based cytoskeleton.287
HSP regulation of transcription occurs through the activation of heat-shock elements in the gene
promoters. Two heat-shock transcriptional factors (HSF) have been identified, HSF1 and HSF2. HSF1
activates transcription of the Hsp72 gene in response to heat, heavy metals, and other inducers of the
stress response. With stimulation, unbound HSF1 oligomerizes, translocates to the nucleus, and binds to
the HSP promoter to activate the transcription of the gene. HSF2 is not activated by the classic inducers
of heat-shock genes, but may be important in controlling the activities of HSP gene expression in the
normal or unstressed cell.39,287,290,291
HSP can play multiple roles in modulating the inflammatory response. A number of conditions such as
rheumatoid arthritis, ARDs, and asthma have been shown to benefit experimentally from increased HSP
expression.286–288,291 Functions of HSP include enhancement of immune responses, thermotolerance,
regulation of apoptosis, hemostasis, and cytoprotection against ROS and other inflammatory mediators.
HSP-CD91 interaction is integral to the processing and representation of antigen by APCs. HSP may
shift the balance between TH1 and TH2 toward an increase in more anti-inflammatory TH2 cells. ROS,
including H2O2, hydroxyl radical, and peroxynitrite, activate HSP synthesis. In the presence of iron, ROS
also induce the oxidation-specific stress proteins HO and ferritin, which afford protection against
oxidative stress by binding iron and preventing it from participating in the Fenton reaction. Mechanisms
of HSP-mediated cytoprotection from the toxic effects of ROS include the maintenance of cellular GSH
levels (Hsp27) and mitochondrial protection (Hsp70). Hence, ROS induce a cytoprotective response that
counteracts their own toxicity. Other inflammatory mediators such as NO have also been shown to
induce expression of HSP.39
HSP may participate in intracellular signaling pathways that modulate the production or function of
inflammatory mediators. For example, Hsp90 has been shown to facilitate signaling that leads to NO
217
formation by eNOS.292 Hsp70 has been reported to prevent apoptosis, which may promote propagation
rather than resolution of inflammation. In addition, the body’s immune response to bacterial and
parasitic stress proteins likely protects the host from infection. The bacterial homologue of Hsp60,
GroEL, is a major target of the mammalian humoral response to bacterial infections. Many activators of
HSF1 are potent inhibitors of the proinflammatory transcription factor NFκB. Aspirin and other NSAIDs
activate HSF while inhibiting NFκB. Therefore, the anti-inflammatory effects associated with the stress
response might be related more to the inhibition of NFκB activation.287,293
218
The Acute-Phase Response
The acute-phase response consequent to trauma or cellular injury is characterized by alterations in
hepatic metabolism; activation of the central nervous system, leading to fever and adaptive behaviors;
altered hematopoiesis; activation of complement and the fibrinolytic and coagulation cascades; and the
release of neuropeptides, kinins, and hormones. It is a rapid, nonspecific response that accompanies
both acute and chronic inflammatory disorders. Many of the processes induced during the acute-phase
response are mediated by cytokines. IL-6, IL-1, and TNFα play particularly central roles.294,295 Though
considered a defense mechanism promoting host survival, aberrant or unregulated production of many
of these inflammatory mediators can be lethal.
Acute-Phase Proteins
An acute-phase protein is defined as a protein whose concentration increases by at least 25% during
inflammation (Table 7-7).295,296 These changes are primarily due to altered hepatic synthesis and
typically occur within approximately 6 hours of the inciting stimulus. The function is to restore
homeostasis: hemostatic functions (fibrinogen), microbicidal and phagocytic functions (complement
components, C-reactive protein [CRP]), antithrombotic properties (plasminogen, protein S), antioxidant
properties (haptoglobin), and antiproteolytic actions (α2 macroglobulin, α1 protease, α1 chymotrypsin).
The negative acute-phase proteins albumin, prealbumin, transferrin, and retinol-binding protein
decrease by at least 25%. Levels of the negative acute-phase proteins, albumin and transferrin, drop
almost immediately after operation and remain depressed for several days. The rapid initial loss of these
proteins is likely due to increased vascular permeability and loss to the extravascular space. The
magnitude of the response is proportional to the severity of the stress. Whereas trauma and burns lead
to significant increases in acute-phase reactants, exercise and psychiatric illness induce more moderate
responses.
The two major acute-phase proteins in humans are CRP and serum amyloid A (SAA). CRP, named
because of its reaction with pneumococcal C-polysaccharide, displays both proinflammatory and anti-
inflammatory effects. It has been shown to activate complement, recognize foreign pathogens, bind
phagocytic cells, and enhance activation of tissue factor, the main initiator of coagulation. CRP can also
inhibit superoxide production by neutrophils and inhibit neutrophil adhesion by decreasing surface
expression of L-selectin. Changes in plasma or serum CRP, although nonspecific, may reflect the
magnitude of an inflammatory process and may aid the differentiation of inflammatory from
noninflammatory conditions. Measurement of CRP is more precise than the erythrocyte sedimentation
rate; the latter largely depends on plasma fibrinogen levels and is influenced by a variety of other,
unrelated factors in the circulation. SAA may promote chemotaxis and adhesion of phagocytes during
inflammation.39
C1 inhibitor is of special interest as an acute-phase protein because of its effects outside of the
complement cascade. This antiprotease inhibits the activity of HF, limiting kinin production and factor
XI production. Thus, enhanced expression of a complement inhibitor protein during acute inflammation
may also influence coagulation, fibrinolysis, and kinin pathways.
Systemic Manifestations of the Acute-Phase Response

Systemic manifestations include neuroendocrine changes, shifts in the hematologic profile, and
metabolic and chemical alterations. The classic neuroendocrine manifestation is fever. IL-1, IL-6, and
TNFα mediate the fever response by resetting the hypothalamic temperature setpoint through the
synthesis of PGE2. The secretion of neuropeptides, such as CRH and AVP, and of hormones, such as
glucagon, insulin, thyroxin, and aldosterone, is also characteristic of the acute-phase response. CRH and
AVP are released by the hypothalamus and increase ACTH and cortisol levels. The rise in plasma cortisol
levels occurs rapidly and may function to inhibit the fever response and cytokine gene expression,
thereby serving a potential negative regulatory function in the acute-phase response. Glucocorticoids
also stimulate macrocortin synthesis, which by inhibiting synthesis of PLA2, limits the availability of
arachidonic acid for prostaglandin synthesis. Glucocorticoids increase the rate of synthesis of certain
acute-phase proteins involved in connective tissue repair and clotting, as well as antioxidants and
antiproteinases. They also may function to counteract the hypoglycemic response to insulin
overproduction during infection or stress.
Other alterations include a prominent leukocytosis, thrombocytosis, and the “anemia of chronic
disease.” Metabolic changes include altered lipid metabolism and negative nitrogen balance. Changes in
219
the chemical and enzymatic profile include increased hepatic production of metallothionein, iNOS, HO,
manganese superoxide dismutase, and glutathione (GSH). Plasma levels of zinc and iron are noted to
drop, whereas copper levels increase slightly. This persists for the duration of inflammation and is likely
due to sequestration induced by IL-6, glucocorticoids, and catecholamines. Low levels of iron and zinc
may confer protective antimicrobial effects because they are essential micronutrients for microbial
growth.39
Mediators of the Acute-Phase Response

Bacterial products such as LPS are probably the most potent activators of tissue macrophages, the
initiators of the acute-phase response. LPS, through its interactions with LBP, CD14, and TLR, induces
macrophage synthesis of ROS, including NO; lipid derivatives (e.g., PGE2, thromboxane A2, and PAF);
and acute-phase cytokines (e.g., TNFα, IL-6). Additional mediators inducing the synthesis of acute-phase
cytokines in the absence of bacterial infection include free radicals, prostaglandins, and the release of
DAMPs from injured tissues.39 Indeed the response to the sterile insult of trauma mirrors much of what
is observed during severe sepsis, a similarity that may be the consequence of substantial overlap in
signaling mechanisms, such as TLR4.
Acute-phase cytokines can be proinflammatory (IL-1, TNFα, IFNγ, IL-8) or anti-inflammatory (IL-10,
IL-4, IL-13, TNFβ). However, it is IL-6 and IL-6-type cytokines that are most critical in the acute-phase
response. IL-6 is the major inducer of acute-phase proteins synthesis and, together with IL-1 and TNFα,
is responsible for the systemic features classically associated with the acute-phase response (fever,
anorexia, leukocytosis, and hormonal changes).39
In addition to the aforementioned cytokines, IFNγ is a potent inducer of complement components.
The anti-inflammatory cytokine TGFβ stimulates synthesis of antiproteases, urokinase, and negative
acute-phase proteins. IL-4 is inhibitory to some acute-phase proteins. Growth factors, including
hepatocyte growth factor and TGFβ are also able to modulate the synthesis of acute-phase proteins.
Glucocorticoids augment the response to cytokines, and insulin attenuates the cytokine-induced rise in
acute-phase proteins.39
Effects of the cytokines are influenced by cytokine receptors, receptor antagonists, and hormones. IL-
1RA competes with IL-1 and attenuates the acute-phase response in vivo. Soluble receptors for IL-1 and
TNFα act as antagonists. In contrast, soluble receptors for IL-6 act as agonists.
Regulation of Acute-Phase Cytokines and Proteins

Several major families of transcription factors participate in the upregulation of acute-phase cytokines
and proteins, the most important being NF-IL-6, AP-1, and NFκB.297 NF-IL6 participates in the
expression of the cytokines IL-1, TNFα, IL-6, and IL-8. Activation through the NFκB is probably the
predominant pathway. The triggering of IL-6 in monocytes in vitro by IFNγ involves a change in the
amount of the phosphorylated transcription factor Sp1, together with the induction and activation of
IFN-regulatory factor.
All known acute-phase proteins are regulated primarily at the transcriptional level. Activation of
TNFα and IL-1 receptors triggers signaling pathways that activate transcription factors AP-1 and NFκB.
Many type I acute-phase proteins genes contain response elements for NFκB, NF-IL6, and AP-1. Acute-
phase protein responses to IL-6 are mediated through the JAK-STAT signal transduction pathway. In
addition, both IL-1 and IL-6 signal transduction mechanisms activate the MAPK pathway that activates
transcription factors NF-IL6, linking the IL-1 and IL-6 pathways.
Reperfusion Injury
Prolonged tissue ischemia produces irreversible injury and cell death. Timely restoration of perfusion
may salvage some tissue, though paradoxically can induce injury as well. Reperfusion injury is the
damage caused by the restoration of blood flow in previously ischemic tissue (i.e., myocardial ischemia,
transplantation, vascular surgery). Injury is the direct consequence of activation of the inflammatory
response, especially complement activation and neutrophil recruitment. Components of the complement
cascade promote tissue damage through the generation of anaphylatoxins and by the formation of the
MAC. Invading neutrophils injure tissue through the generation of ROS and the release of proteolytic
enzymes. Recent evidence points to TLR4 as a sensor of tissue stress, the signal of which is probably
through release of DAMPs from ischemic cells.32
Alterations in the microvascular endothelium are central to the pathophysiologic process of
reperfusion injury. Early loss of constitutive NO production facilitates neutrophil adherence, the
220
upregulation of cell adhesion molecules such as P-selectin, and inhibits vasorelaxation and perfusion.298
Low oxygen tension induces the conversion of xanthine dehydrogenase to xanthine oxidase. Reperfusion
and reoxygenation yield the formation of superoxide anion and H2O2 and induce oxidant injury.
Neutrophils and other cellular effectors are progressively recruited and activated, releasing ROS,
cytokines, and NO, further contributing to increased vascular permeability and tissue injury. PAF
released by neutrophils activates circulating platelets and promotes vascular plugging. Platelets also
release factors that enhance platelet–neutrophil adhesion. Both cell types also release vasoconstricting
agents that can further exacerbate no-reflow. Capillary plugging by neutrophils and platelets can impair
local blood flow and cause the “no-reflow phenomenon.”39
Neutrophils mediate direct toxicity to the surrounding tissue through the elaboration of ROS and
granule contents. Peroxynitrite formed by the reaction of NO and superoxide can contribute directly to
tissue injury during reperfusion. Neutrophil granule proteases such as elastase, collagenase, and
gelatinase alter the vascular permeability and are highly destructive to local tissue. The significance of
the neutrophil in mediating these effects are apparent in neutrophil depletion studies demonstrating
attenuated tissue injury when compared to subjects with normal numbers of neutrophils.299 Animal
studies using blocking monoclonal antibodies to selectins and β2 integrins show improved organ
function ischemia/reperfusion.300
The mechanism by which complement is activated with reperfusion is not completely understood.
Ischemia may alter the cell’s plasma membrane or through the exposure of basement membrane or
subcellular organelle components, creating a complement-activating surface. Alternatively, binding of
natural antibody may lead to induction of these cascades.172 Complement activation has been shown to
occur in the setting of therapeutic thrombolysis. The generation of plasmin-dependent fibrinolytic
agents and plasmin after tissue plasminogen activator administration has been associated with
complement activation.301
Anaphylatoxins are important effectors of complement-mediated injury. They alter vascular
permeability, induce smooth muscle cell contraction, and stimulate the release of histamine from mast
cells and basophils. C3a and C5a are potent chemoattractants especially for neutrophils. C5 can be
activated by an abundance of oxygen free radicals. The subsequent generation of the MAC perturbs the
maintenance of vital ion gradients, induces cell lysis, and facilitates neutrophil recruitment. In addition
it can induce the expression of numerous inflammatory mediators, including cytokines (TNFα, IL-1, IL-
8), ROS, prostaglandins, LTs, and cell surface adhesion molecules.302
Systemic Inflammatory Response Syndrome

The inability of host defenses to control a localized inflammatory process or an unchecked inflammatory
response can result in SIRS. A recent consensus conference defined SIRS as the presence of any two of
the following physiologic parameters: (1) a temperature greater than 38°C or less than 36°C; (2)
leukocytosis (>12,000), leukopenia (<4,000), of more than 10% bands; (3) pulse greater than 90 beats
per minute; (4) tachypnea (respiratory rate greater than 20 or PaCO2 < 32 mm Hg).303 Infection
underlies a significant minority of cases as only a third of patients with SIRS will have a documented
infection and meet the criteria for sepsis. There is a continuum from the development of SIRS to sepsis,
to severe sepsis, septic shock, and MODS.304 The outcome depends on the balance between SIRS and
host compensatory mechanisms. In one prospective study, 26% of patients with SIRS developed sepsis
and 7% died.305
SIRS may be initiated by infectious or noninfectious causes, such as trauma, autoimmune reactions, or
pancreatitis. Gram-negative organisms, rich in LPS, induce a potent inflammatory response mediated
through the CD14/TLR4/MyD88 pathway previously described and account for the majority of
infectious SIRS cases. Gram-positive organisms can generate a similarly impressive degree of
inflammation either through TLR2 or alternative mechanisms. Streptococcal superantigen may induce a
global and nonspecific activation of T cells that culminates in massive systemic elaboration of cytokines
and cardiovascular collapse termed TSS. Trauma, either through tissue injury (HMGB1-RAGE, HSP-
CD91) or the ischemia/reperfusion consequent to hemorrhage can culminate in inflammatory
pathophysiology indistinguishable from that accompanying these other inflammatory states. As the
growing evidence continues to support the promiscuity of TLR and other signaling pathways, we are
replacing the former concept distinct receptor-signaling mechanisms for each stimulus with one that
emphasizes the similarities, overlap and integration. Though there are clearly mechanisms by which
host distinguishes normal self from endogenous (trauma) and exogenous (infection) dangers, there is
considerable overlap, and all stimuli appear to converge upon similar signaling mechanisms in attaining
221
the goal of preserving the host.
The development of SIRS has been described as progressing through three stages: Stage I – local
cytokine production recruits inflammatory cells to the injured site; Stage II – an acute-phase response is
initiated and small quantities of cytokines are released into the circulation to enhance the local
response; and Stage III – homeostasis cannot be reestablished.306 Enhanced levels of CRP, the major
acute-phase protein in humans, occur in SIRS/sepsis, and clinical resolution is preceded by a drop in
CRP levels.
The elaboration of proinflammatory cytokines (IL-1, TNFα, and IL-6) is central to the pathogenesis of
SIRS regardless of the initiating stimulus. Their release triggers increased expression of adhesion
molecules, leukocyte recruitment, and the production of secondary proinflammatory mediators, such as
chemokines. Endotoxin is one of the most powerful triggers of SIRS. LPS activates the complement and
coagulation cascades, induces endothelial cell activation, and increases TNFα and IL-1 synthesis, and the
late release of HMGB1. However, noninfectious tissue injury induces a similar inflammatory response.
LPS, TNFα, and IL-1 also induce increased production of NO by iNOS. PGI2 and arachidonic acid,
together with NO contribute to decreased systemic vascular resistance and hypotension. Autocrine and
paracrine NO production also results in myocardial depression. Increased vascular permeability
promotes extravasation of fluid and edema formation. Activated endothelial cells express tissue factor,
PECAM, and TXA2, which promote a procoagulant local environment that predisposes to microthrombi
formation. Adherent leukocytes further exacerbate organ injury by mechanically impeding
microvascular blood flow and by damaging the endothelial cells and surrounding connective tissue. The
results are end-organ hypoperfusion, inadequate oxygen delivery, initiation of anaerobic metabolism,
and organ failure. The metabolic and nutritional sequelae of this activated cytokine milieu includes
fever, catabolism, cachexia, and altered fat, glucose, and trace mineral metabolism.
SIRS is counteracted by the concomitant induction of an anti-inflammatory response termed the
compensatory anti-inflammatory response syndrome (CARS).306 Many of the proinflammatory
mediators that participate in SIRS modulate the immune function of lymphocytes and mononuclear cells.
Proinflammatory mediators can inhibit their own synthesis or enhance the synthesis of natural
antagonists by negative feedback mechanisms. Thus, at any given time, the clinical manifestation is
SIRS, CARS, or an intermediate, mixed inflammatory response syndrome. The spectrum of features that
characterizes these syndromes has been termed CHAOS (cardiovascular shock, homeostasis, apoptosis,
organ dysfunction, and immune suppression). Studies employing a variety of specific anticytokine
agents have failed to observe an improvement in the outcome of patients with SIRS or sepsis.
Chronic Inflammation
There are no clear boundaries between an acute and a chronic inflammatory response. In general, if the
source of an acute inflammatory process is incompletely eliminated, a state of chronic inflammation
eventually ensues. Chronicity is usually not characterized by the signs classically associated with acute
responses, such as swelling, heat, or redness. Pain is minimal if not absent. Microscopically, a
mononuclear cell infiltrate predominates (lymphocytes, monocytes, plasma cells) with proliferation of
fibroblasts and vascular elements.
Many agents can create a state of chronic inflammation, including persistent infectious agents,
remnants of dead organisms, foreign bodies, and metabolic byproducts. Ultimately, chronicity of
inflammation is a result of the immune response to a persistent antigen. Furthermore, a chronic
inflammatory response can develop in the absence of a preceding acute response, such as infections with
agents of low toxicity such as mycobacterium and treponema. CD4+ T cells and macrophages are the
primary cellular orchestrators of chronic inflammatory response.307 TH1 cell–mediated immune
responses are protective against most microbes and usually result in the elimination of the pathogen. If
the microbe persists, the ongoing TH1 response results in inflammatory tissue injury. Cytokines and
growth factors released by T lymphocytes and macrophages stimulate proliferative responses.
Neutrophils and eosinophils contribute to the release of proteolytic enzymes and oxygen derivatives.
Eosinophilia occurs with chronic parasitic infections and hypersensitivity conditions. Fibroblasts are
actively recruited by chemoattractants such as fibrin, collagens, and cytokines. Local IL-1 stimulates
fibroblast proliferation and collagen production. Irreversible tissue damage can occur through the
replacement of normal parenchyma with fibrous connective tissue. Fibroblasts can release
metalloproteinases that degrade normal tissue, further contributing to tissue destruction. Mast cells are
elevated in chronic conditions and may play a part in cell-mediated immune responses. Inflammatory
cyst formation may occur as a result of epithelial hyperplasia.
222
References
1. Cotran RS. Inflammation: basic principles and clinical correlates. In: Gallin J, S R. Inflammation:
Historical Perspectives. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.
2. Heifets L. Centennial of Metchnikoff’s discovery. J Reticuloendothel Soc. 1982;31(5):381–391.
3. Cotran RS, Kumar V, Robbins T, eds. Robbins Pathologic Basis of Disease. 6th ed. C RS, K V, R T.
Philadelphia, PA: WB Sanders; 1999.
4. Abbas AK, Lichtman AH. Cellular and Molecular Immunology. 5th ed. Philadelphia, PA: Saunders;
2003.
5. Wheeler JG, Abramson JS. The Neutrophil. Oxford: IRL Press at Oxford University Press; 1993.
6. Bainton D. The cells of inflammation: a general view. In: Weissmann G, ed. The Cell Biology of
Inflammation, Vol 2. 1980, New York: Elsevier/North-Holland; 1980.
7. Dancey JT, Deubelbeiss KA, Harker LA, et al. Neutrophil kinetics in man. J Clin Invest
1976;58(3):705–715.
8. Omann GM, Hinshaw DB. Inflammation. In: Greenfield LJ, et al. eds. Surgery: Scientific Principles
and Practice, 2nd ed. Philadelphia, PA: Lippincott-Raven; 1997:130–159.
9. Trowbridge HO, Emling RC, eds. Inflammation: A Review of the Process. Chicago, IL: Quintessence;
1997.
10. Dustin ML, Springer TA. Role of lymphocyte adhesion receptors in transient interactions and cell
locomotion. Annu Rev Immunol 1991;9:27–66.
11. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood 1996;88(9):3259–
3287.
12. Tedder TF, Steeber DA, Chen A, et al. The selectins: vascular adhesion molecules. FASEB J
1995;9(10):866–873.
13. Frenette PS, Wagner DD. Adhesion molecules–part II: blood vessels and blood cells. N Engl J Med
1996;335(1):43–45.
14. Frenette PS, Wagner DD. Adhesion molecules–part 1. N Engl J Med 1996;334(23):1526–1529.
15. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992;69(1):11–25.
16. Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the
inflammatory response. Trends Immunol 2003;24(6):327–334.
17. Vaporciyan AA, DeLisser HM, Yan HC, et al. Involvement of platelet-endothelial cell adhesion
molecule-1 in neutrophil recruitment in vivo. Science 1993;262(5139):1580–1582.
18. Thornhill M, Haskard D. Leukocyte adhesion to endothelium. Blood cell biochemistry. In: Horton
M, ed. Macrophages and Related Cells. Vol 5. New York: Plenum Press; 1993.
19. Rot A. The role of leukocyte chemotaxis in inflammation. In: Whicker J, Evans S, eds. Biochemistry
and Inflammation. Boston, MA: Kluwer Academic; 1992.
20. Wagner JG, Roth RA. Neutrophil migration during endotoxemia. J Leukoc Biol 1999;66(1):10–24.
21. Indik ZK, Park JG, Hunter S, et al. Structure/function relationships of Fc gamma receptors in
phagocytosis. Semin Immunol 1995;7(1):45–54.
22. Ezekowitz R. The mannose receptor and phagocytosis. In: Furth RV, ed. Mononuclear Phagocytes:
Biology of Monocytes and Macrophages. Boston, MA: Kluwer Academic; 1992.
23. Ezekowitz RA, Sim RB, Hill M, et al. Local opsonization by secreted macrophage complement
components. Role of receptors for complement in uptake of zymosan. J Exp Med 1984;159(1):244–
260.
24. Lee WL, Harrison RE, Grinstein S. Phagocytosis by neutrophils. Microbes Infect 2003;5(14):1299–
1306.
25. Zychlinsky A, Weinrauch Y, Weiss J. Introduction: forum in immunology on neutrophils. Microbes
Infect 2003;5(14):1289–1291.
26. Borregaard N, Cowland JB Granules of the human neutrophilic polymorphonuclear leukocyte. Blood
1997;89(10):3503–3521.
27. Faurschou M, Borregaard N. Neutrophil granules and secretory vesicles in inflammation. Microbes
Infect 2003;5(14):1317–1327.
28. Lehrer RI, Ganz T, Selsted ME. Defensins: endogenous antibiotic peptides of animal cells. Cell
223
1991;64(2):229–230.
29. Elsbach P. The bactericidal/permeability-increasing protein (BPI) in antibacterial host defense. J
Leukoc Biol 1998;64(1):14–18.
30. Beamer LJ, Carroll SF, Eisenberg D. The BPI/LBP family of proteins: a structural analysis of
conserved regions. Protein Sci 1998;7(4):906–914.
31. Gabay JE, Scott RW, Campanelli D, et al. Antibiotic proteins of human polymorphonuclear
leukocytes. Proc Natl Acad Sci U S A 1989;86(14):5610–5614.
32. Tsung A, Klune JR, Zhang X, et al. HMGB1 release induced by liver ischemia involves Toll-like
receptor 4 dependent reactive oxygen species production and calcium-mediated signaling. J Exp
Med 2007;204(12):2913–2923.
33. Chapple IL. Reactive oxygen species and antioxidants in inflammatory diseases. J Clin Periodontol
1997;24(5):287–296.
34. Kasahara Y, Iwai K, Yachie A, et al. Involvement of reactive oxygen intermediates in spontaneous
and CD95 (Fas/APO-1)-mediated apoptosis of neutrophils. Blood 1997;89(5):1748–1753.
35. Roos D, van Bruggen R, Meischl C. Oxidative killing of microbes by neutrophils. Microbes Infect
2003;5(14):1307–1315.
36. Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin
system. Free Radic Biol Med 2001;31(11):1287–1312.
37. Winyard PG, Perret D, Harris G, et al. The role of toxic oxygen species in inflammation with special
reference to DNA damage. In: Whicker JT, Evans SW, eds. Biochemistry of Inflammation. Boston,
MA: Kluwer Academic; 1992.
38. Nohl H. Generation of superoxide radicals as byproduct of cellular respiration. Ann Biol Clin (Paris)
1994;52(3):199–204.
39. Schuchert RD, Billiar TR. Inflammation. In: Greenfield LJ, ed. Surgery: Scientific Principles and
Practice. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
40. Menshikova EV, Salama G. Cardiac ischemia oxidizes regulatory thiols on ryanodine receptors:
captopril acts as a reducing agent to improve Ca2 +uptake by ischemic sarcoplasmic reticulum. J
Cardiovasc Pharmacol 2000;36(5):656–668.
41. Szabo C. The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-
reperfusion injury. Shock 1996;6(2):79–88.
42. Warren J, Ward P, Johnson K. Oxygen radicals as mediators of inflammation. In: Hensen PM,
Murphy RC, eds. Handbook of Inflammation. Vol 6. New York: Elsevier Science Publishers BV; 1989.
43. Burg ND, Pillinger MH. The neutrophil: function and regulation in innate and humoral immunity.
Clin Immunol 2001;99(1):7–17.
44. Marenzi G, Assanelli E, Marana I, et al. N-acetylcysteine and contrast-induced nephropathy in
primary angioplasty. N Engl J Med 2006;354(26):2773–2782.
45. Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J
Immunol 2012;189(6):2689–2695.
46. Zawrotniak M, Rapala-Kozik M. Neutrophil extracellular traps (NETs) - formation and implications.
Acta biochimica Polonica 2013;60(3):277–284.
47. Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J
Thromb Haemost 2008;6(3):415–420.
48. Kobayashi SD, Voyich JM, DeLeo FR. Regulation of the neutrophil-mediated inflammatory response
to infection. Microbes Infect 2003;5(14):1337–1344.
49. Burkitt HG, Young B, Heath JW. Wheater’s Functional Histology: A Text and Colour Atlas. 3rd ed.
Edinburgh, UK; Churchill Livingstone; 1993.
50. Ma J, Chen T, Mandelin J, et al. Regulation of macrophage activation. Cell Mol Life Sci
2003;60(11):2334–2346.
51. Ben-Baruch A, Michiel DF, Oppenheim JJ. Signals and receptors involved in recruitment of
inflammatory cells. J Biol Chem 1995;270(20):11703–11706.
52. Kuijpers T, Hakkert B, Knol E, et al. Membrane surface antigen expression on human monocytes:
changes during purification, in vitro activation and transmigration across monolayers of endothelial
cells. In: Furtin RV, ed. Mononuclear Phagocytes: Biology of Monocytes and Macrophages. Boston, MA:
224
Kluwer Academic; 1992.
53. Nathan C, Xie QW. Nitric oxide synthases: roles, tolls, and controls. Cell 1994;78(6):915–918.
54. de Waal Malefyt R, Yssel H, Roncarolo MG, et al. Interleukin-10. Curr Opin Immunol
1992;4(3):314–320.
55. MacMicking J, Xie QW, Nathan C. Nitric oxide and macrophage function. Annu Rev Immunol
1997;15:323–350.
56. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med
2004;255(3):320–331.
57. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science
1999;285(5425):248–251.
58. Griffiths GM, The cell biology of CTL killing. Curr Opin Immunol 1995;7(3):343–348.
59. Romagnani S. Understanding the role of Th1/Th2 cells in infection. Trends Microbiol
1996;4(12):470–473.
60. Mosmann TR, Coffman RL. TH1 and TH2 cells: different patterns of lymphokine secretion lead to
different functional properties. Annu Rev Immunol 1989;7:145–173.
61. Lane PJ, Brocker T. Developmental regulation of dendritic cell function. Curr Opin Immunol
1999;11(3):308–313.
62. Banchereau J, Steinman RM. Dendritic cells and the control of immunity. Nature
1998;392(6673):245–252.
63. Braciale TJ, Morrison LA, Sweetser MT, et al. Antigen presentation pathways to class I and class II
MHC-restricted T lymphocytes. Immunol Rev 1987;98:95–114.
64. Razi-Wolf Z, Freeman GJ, Galvin F, et al. Expression and function of the murine B7 antigen, the
major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A
1992;89(9):4210–4214.
65. Lanzavecchia A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-
restricted T lymphocytes. Annu Rev Immunol 1990;8:773–793.
66. Gumperz JE, Parham P. The enigma of the natural killer cell. Nature 1995;378(6554):245–248.
67. Janeway C, Travers P. Immunobiology: the immune system in health and disease. In: Janeway C,
Travers P, eds. Immunobiology: The Immune System in Health and Disease. 3rd ed. 1997.
68. Surh CD, Sprent J. T-cell apoptosis detected in situ during positive and negative selection in the
thymus. Nature 1994;372(6501):100–103.
69. Zal T, Volkmann A, Stockinger B. Mechanisms of tolerance induction in major histocompatibility
complex class II-restricted T cells specific for a blood-borne self-antigen. J Exp Med
1994;180(6):2089–2099.
70. Picker LJ. Control of lymphocyte homing. Curr Opin Immunol 1994;6(3):394–406.
71. Dustin ML, Springer TA. T-cell receptor cross-linking transiently stimulates adhesiveness through
LFA-1. Nature 1989;341(6243):619–624.
72. Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep
paradigm. Cell 1994;76(2):301–314.
73. Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell 1994;76(2):275–285.
74. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today
1996;17(3):138–146.
75. Jain J, McCaffrey PG, Miner Z, et al. The T-cell transcription factor NFATp is a substrate for
calcineurin and interacts with Fos and Jun. Nature 1993;365(6444):352–355.
76. Lee KP, Harlan DM, June CH. Role of co-stimulation in the host response to infection. In: Gallin JI,
Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 1999.
77. Lin MY, Zal T, Ch’en IL, et al. A pivotal role for the multifunctional calcium/calmodulin-dependent
protein kinase II in T cells: from activation to unresponsiveness. J Immunol 2005;174(9):5583–
5592.
78. Broide DH, Hoffman H, Sriramarao P. Genes that regulate eosinophilic inflammation. Am J Hum
Genet 1999;65(2):302–307.
79. Elsner J, Kapp A. Regulation and modulation of eosinophil effector functions. Allergy
225
1999;54(1):15–26.
80. Weller PF, Bach DS, Austen KF. Biochemical characterization of human eosinophil Charcot-Leyden
crystal protein (lysophospholipase). J Biol Chem 1984;259(24):15100–15105.
81. Giembycz MA, Lindsay MA. Pharmacology of the eosinophil. Pharmacol Rev 1999;51(2):213–340.
82. Slungaard A, Mahoney JR Jr, Thiocyanate is the major substrate for eosinophil peroxidase in
physiologic fluids. Implications for cytotoxicity. J Biol Chem 1991;266(8):4903–4910.
83. Wardlaw AJ, Moqbel R, Kay AB. Eosinophils: biology and role in disease. Adv Immunol
1995;60:151–266.
84. Wedi B, Raap U, Lewrick H, et al. Delayed eosinophil programmed cell death in vitro: a common
feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis. J Allergy Clin Immunol
1997;100(4):536–543.
85. Valent P, Schmidt G, Besemer J, et al. Interleukin-3 is a differentiation factor for human basophils.
Blood 1989;73(7):1763–1769.
86. Nilsson G, Cost J, Metcalfke D. Mast cells and basophils. In: Gallin JI, Snyderman R, eds.
Inflammation: Basic Principles and Clinical Correlates. 3rd ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 1999.
87. Metcalfe DD, Baram D, Mekori YA. Mast cells. Physiol Rev 1997;77(4):1033–1079.
88. Klinger MH, Jelkmann W. Role of blood platelets in infection and inflammation. J Interferon
Cytokine Res 2002;22(9):913–922.
89. Marcus A. Platelets: their role in hemostasis, thrombosis, and inflammation. In : Gallin J,
Snyderman R, eds. Inflammation: Basic Principles and Clinical Correlates. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 1999.
90. Du X, Williams DA. Interleukin-11: review of molecular, cell biology, and clinical use. Blood
1997;89(11):3897–3908.
91. Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation. J
Thromb Haemost 2003;1(9):1897–1905.
92. Serhan CN. Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell-cell
interactions or a therapeutic opportunity? Prostaglandins 1997;53(2): 107–137.
93. Marcus AJ, Safier LB, Ullman HL, et al. Platelet-neutrophil interactions. (12S)-
hydroxyeicosatetraen-1,20-dioic acid: a new eicosanoid synthesized by unstimulated neutrophils
from (12S)-20-dihydroxyeicosatetraenoic acid. J Biol Chem 1988;263(5):2223–2229.
94. Serhan CN, Haeggstrom JZ, Leslie CC. Lipid mediator networks in cell signaling: update and impact
of cytokines. FASEB J 1996;10(10):1147–1158.
95. Colletti LM. Cytokines. In: Greenfield LJ, ed. Surgery: Scientific Principles and Practice. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
96. Thomson A. The Cytokine Handbook. 3rd ed. New York: Academic Press; 1998.
97. Schmidt AM, Yan SD, Yan SF, et al. The biology of the receptor for advanced glycation end
products and its ligands. Biochim Biophys Acta 2000;1498(2–3):99–111.
98. Strieter RM, Lynch JP III, Basha MA, et al. Host responses in mediating sepsis and adult respiratory
distress syndrome. Semin Respir Infect 1990;5(3):233–247.
99. Opal SM, Patrozou E. Translational research in the development of novel sepsis therapeutics:
logical deductive reasoning or mission impossible? Crit Care Med 2009;37(1 suppl):S10–S15.
100. Cerami A. Inflammatory cytokines. Clin Immunol Immunopathol 1992;62(1 Pt 2):S3–S10.
101. Bauss F, Droge W, Mannel DN. Tumor necrosis factor mediates endotoxic effects in mice. Infect
Immun 1987;55(7):1622–1625.
102. Philip R, Epstein LB. Tumour necrosis factor as immunomodulator and mediator of monocyte
cytotoxicity induced by itself, gamma-interferon and interleukin-1. Nature 1986;323(6083):86–89.
103. Adam-Klages S, Schwandner R, Adam D, et al. Distinct adapter proteins mediate acid versus neutral
sphingomyelinase activation through the p55 receptor for tumor necrosis factor. J Leukoc Biol
1998;63(6):678–682.
104. Tartaglia LA, Ayres TM, Wong GH, et al. A novel domain within the 55 kd TNF receptor signals cell
death. Cell 1993;74(5):845–853.
105. Meager A. Cytokine regulation of cellular adhesion molecule expression in inflammation. Cytokine
226
Growth Factor Rev 1999;10(1):27–39.
106. Chen G, Ward MF, Sama AE, et al. Extracellular HMGB1 as a proinflammatory cytokine. J Interferon
Cytokine Res 2004;24(6):329–333.
107. Kokkola R, Andersson A, Mullins G, et al. RAGE is the major receptor for the proinflammatory
activity of HMGB1 in rodent macrophages. Scand J Immunol 2005;61(1):1–9.
108. Tracey KJ, Fong Y, Hesse DG, et al. Anti-cachectin/TNF monoclonal antibodies prevent septic shock
during lethal bacteraemia. Nature 1987;330(6149):662–664.
109. Tracey KJ, Lowry SF, Cerami A. Cachectin/TNF mediates the pathophysiological effects of bacterial
endotoxin/lipopolysaccharide (LPS). Prog Clin Biol Res 1988;272:77–88.
110. Le J, Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping
biological activities. Lab Invest 1987;56(3):234–248.
111. Sims JE, March CJ, Cosman D, et al. cDNA expression cloning of the IL-1 receptor, a member of the
immunoglobulin superfamily. Science 1988;241(4865):585–589.
112. Kuno K, Matsushima K. The IL-1 receptor signaling pathway. J Leukoc Biol 1994;56(5):542–547.
113. Colotta F, Dower SK, Sims JE, et al. The type II ‘decoy’ receptor: a novel regulatory pathway for
interleukin 1. Immunol Today 1994;15(12):562–566.
114. Bevilacqua MP, Schleef RR, Gimbrone MA Jr, et al. Regulation of the fibrinolytic system of
cultured human vascular endothelium by interleukin 1. J Clin Invest 1986;78(2):587–591.
115. Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol 1997;15:675–
705.
116. Bacon K, Baggiolini M, Broxmeyer H, et al. Chemokine/chemokine receptor nomenclature. J
Interferon Cytokine Res 2002;22(10):1067–1068.
117. Bacon KB, Greaves DR, Dairaghi DJ, et al. The expanding universe of C, CX3C, and CC chemokines.
In: Thomson A, ed. The Cytokine Handbook. 3rd ed. New York: Academic Press; 1998.
118. Rollins BJ, Chemokines. Blood 1997;90(3):909–928.
119. Schall TJ, Bacon KB. Chemokines, leukocyte trafficking, and inflammation. Curr Opin Immunol
1994;6(6):865–873.
120. Hebert CA, Vitangcol RV, Baker JB. Scanning mutagenesis of interleukin-8 identifies a cluster of
residues required for receptor binding. J Biol Chem 1991;266(28):18989–18994.
121. Clark-Lewis I, Dewald B, Geiser T, et al. Platelet factor 4 binds to interleukin 8 receptors and
activates neutrophils when its N terminus is modified with Glu-Leu-Arg. Proc Natl Acad Sci U S A
1993;90(8):3574–3577.
122. Clark-Lewis I, Kim KS, Rajarathnam K, et al. Structure-activity relationships of chemokines. J
Leukoc Biol 1995;57(5):703–711.
123. D’Andrea A, Rengaraju M, Valiante NM, et al. Production of natural killer cell stimulatory factor
(interleukin 12) by peripheral blood mononuclear cells. J Exp Med 1992;176(5):1387–1398.
124. Shu U, Kiniwa M, Wu CY, et al. Activated T cells induce interleukin-12 production by monocytes
via CD40-CD40 ligand interaction. Eur J Immunol 1995;25(4):1125–1128.
125. Gauldie J, Richards C, Harnish D, et al. Interferon beta 2/B-cell stimulatory factor type 2 shares
identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase
protein response in liver cells. Proc Natl Acad Sci U S A 1987;84(20):7251–7255.
126. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol 1990;8:253–278.
127. LeMay LG, Otterness IG, Vander AJ, et al. In vivo evidence that the rise in plasma IL 6 following
injection of a fever-inducing dose of LPS is mediated by IL 1 beta. Cytokine 1990;2(3):199–204.
128. Tilg H, Trehu E, Atkins MB, et al. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction
of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood
1994;83(1):113–118.
129. Sunden-Cullberg J, Norrby-Teglund A, Rouhiainen A, et al. Persistent elevation of high mobility
group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med
2005;33(3):564–573.
130. Bonaldi T, Talamo F, Scaffidi P, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to
redirect it towards secretion. EMBO J 2003;22(20):5551–5560.
131. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers
227
inflammation. Nature 2002;418(6894):191–195.
132. Gardella S, Andrei C, Ferrera D, et al. The nuclear protein HMGB1 is secreted by monocytes via a
non-classical, vesicle-mediated secretory pathway. EMBO Rep 2002;3(10):995–1001.
133. Tang D, Shi Y, Kang R, et al. Hydrogen peroxide stimulates macrophages and monocytes to actively
release HMGB1. J Leukoc Biol 2007;81(3):741–747.
134. Zhang X, Wheeler D, Tang Y, et al. Calcium/calmodulin-dependent protein kinase (CaMK) IV
mediates nucleocytoplasmic shuttling and release of HMGB1 during lipopolysaccharide stimulation
of macrophages. J Immunol 2008;181(7):5015–5023.
135. Chen G, Li J, Ochani M, et al. Bacterial endotoxin stimulates macrophages to release HMGB1 partly
through CD14- and TNF-dependent mechanisms. J Leukoc Biol 2004;76(5):994–1001.
136. Fiuza C, Bustin M, Talwar S, et al. Inflammation-promoting activity of HMGB1 on human
microvascular endothelial cells. Blood 2003;101(7):2652–2660.
137. Rouhiainen A, Tumova S, Valmu L, et al. Pivotal advance: analysis of proinflammatory activity of
highly purified eukaryotic recombinant HMGB1 (amphoterin). J Leukoc Biol 2007;81(1):49–58.
138. Andersson U, Tracey KJ. HMGB1 in sepsis. Scand J Infect Dis 2003;35(9):577–584.
139. Andersson U, Wang H, Palmblad K, et al. High mobility group 1 protein (HMG-1) stimulates
proinflammatory cytokine synthesis in human monocytes. J Exp Med 2000;192(4):565–570.
140. Andersson UG, Tracey KJ. HMGB1, a pro-inflammatory cytokine of clinical interest: introduction. J
Intern Med 2004;255(3):318–319.
141. Riedemann NC, Guo RF, Ward PA. Novel strategies for the treatment of sepsis. Nat Med
2003;9(5):517–524.
142. Sama AE, D’Amore J, Ward MF, et al. Bench to bedside: HMGB1-a novel proinflammatory cytokine
and potential therapeutic target for septic patients in the emergency department. Acad Emerg Med
2004;11(8):867–873.
143. Erlandsson Harris H, Andersson U. Mini-review: the nuclear protein HMGB1 as a proinflammatory
mediator. Eur J Immunol 2004;34(6):1503–1512.
144. Rovere-Querini P. Capobianco A, Scaffidi P, et al. HMGB1 is an endogenous immune adjuvant
released by necrotic cells. EMBO Rep 2004;5(8):825–830.
145. Peltz ED, Moore EE, Eckels PC, et al. Hmgb1 is markedly elevated within 6 hours of mechanical
trauma in humans. Shock 2009;32(1):17–22.
146. Ombrellino M, Wang H, Ajemian MS, et al. Increased serum concentrations of high-mobility-group
protein 1 in haemorrhagic shock. Lancet 1999;354(9188):1446–1447.
147. Jiang W, Pisetsky DS. Mechanisms of Disease: the role of high-mobility group protein 1 in the
pathogenesis of inflammatory arthritis. Nat Clin Pract Rheumatol 2007;3(1):52–58.
148. Rifkin IR, Leadbetter EA, Busconi L, et al. Toll-like receptors, endogenous ligands, and systemic
autoimmune disease. Immunol Rev 2005;204:27–42.
149. Foell D, Wittkowski H, Roth J. Mechanisms of disease: a ‘DAMP’ view of inflammatory arthritis.
Nat Clin Pract Rheumatol 2007;3(7):382–390.
150. Taniguchi N, Kawahara K, Yone K, et al. High mobility group box chromosomal protein 1 plays a
role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum
2003;48(4):971–981.
151. Bogdan C. The function of type I interferons in antimicrobial immunity. Curr Opin Immunol
2000;12(4):419–424.
152. De Maeyer E, De Maeyer-Guignard J. Type I interferons. Int Rev Immunol 1998;17(1–4):53–73.
153. Uze G, Lutfalla G, Mogensen KE. Alpha and beta interferons and their receptor and their friends
and relations. J Interferon Cytokine Res 1995;15(1):3–26.
154. Selzman CH, Shames BD, Miller SA, et al. Therapeutic implications of interleukin-10 in surgical
disease. Shock 1998;10(5):309–318.
155. Cassatella MA, Meda L, Bonora S, et al. Interleukin 10 (IL-10) inhibits the release of
proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine
role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by
lipopolysaccharide. J Exp Med 1993;178(6):2207–2211.
156. Neurath MF, Meyer zum Buschenfelde KH. Protective and pathogenic roles of cytokines in
228
inflammatory bowel diseases. J Investig Med 1996;44(9):516–521.
157. Smith KA. Interleukin-2: inception, impact, and implications. Science 1988;240(4856):1169–1176.
158. Smith KA. Lowest dose interleukin-2 immunotherapy. Blood 1993;81(6):1414–1423.
159. Zurawski SM, Vega F Jr, Huyghe B, et al. Receptors for interleukin-13 and interleukin-4 are
complex and share a novel component that functions in signal transduction. EMBO J
1993;12(7):2663–2670.
160. de Waal Malefyt R, Figdor CG, Huijbens R, et al. Effects of IL-13 on phenotype, cytokine
production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by
IFN-gamma or IL-10. J Immunol 1993;151(11):6370–6381.
161. Billiau A, Heremans H, Vermeire K, et al. Immunomodulatory properties of interferon-gamma. An
update. Ann N Y Acad Sci 1998;856:22–32.
162. Boehm U, Klamp T, Groot M, et al. Cellular responses to interferon-gamma. Annu Rev Immunol
1997;15:749–795.
163. Lawrence DA. Transforming growth factor-beta: an overview. Kidney Int Suppl 1995;49:S19–S23.
164. Lawrence DA. Transforming growth factor-beta: a general review. Eur Cytokine Netw
1996;7(3):363–374.
165. Wahl SM. Hunt DA, Wakefield LM, et al. Transforming growth factor type beta induces monocyte
chemotaxis and growth factor production. Proc Natl Acad Sci U S A 1987;84(16):5788–5792.
166. Romani N, Gruner S, Brang D, et al. Proliferating dendritic cell progenitors in human blood. J Exp
Med 1994;180(1):83–93.
167. Crawford J, Ozer H, Stoller R, et al. Reduction by granulocyte colony-stimulating factor of fever
and neutropenia induced by chemotherapy in patients with small-cell lung cancer. N Engl J Med
1991;325(3):164–170.
168. Metcalf D, Nicola NA. Proliferative effects of purified granulocyte colony-stimulating factor (G-
CSF) on normal mouse hemopoietic cells. J Cell Physiol 1983;116(2):198–206.
169. Cooper NR. Biology of the complement system. In: Gallin JI, Snyderman R, eds. Inflammation: Basic
Principles and Clinical Correlates. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.
170. Frank MM, Fries LF. The role of complement in inflammation and phagocytosis. Immunol Today
1991;12(9):322–326.
171. Roitt I, Brostoff J, Male D, eds. Complement. In: Roitt I, Brostoff J, Male D, eds. Immunobiology.
3rd ed. St. Louis, MO: Mosby; 1993.
172. Weiser MR, Williams JP, Moore FD Jr, et al. Reperfusion injury of ischemic skeletal muscle is
mediated by natural antibody and complement. J Exp Med 1996;183(5):2343–2348.
173. Cooper NR. The classical complement pathway: activation and regulation of the first complement
component. Adv Immunol 1985;37:151–216.
174. Matsushita M, Fujita T. Activation of the classical complement pathway by mannose-binding
protein in association with a novel C1s-like serine protease. J Exp Med 1992;176(6):1497–1502.
175. Sim RB, Malhotra R. Interactions of carbohydrates and lectins with complement. Biochem Soc Trans
1994;22(1):106–111.
176. Muller-Eberhard HJ. The membrane attack complex of complement. Annu Rev Immunol
1986;4:503–528.
177. Marnett LJ, Rowlinson SW, Goodwin DC, et al. Arachidonic acid oxygenation by COX-1 and COX-2.
Mechanisms of catalysis and inhibition. J Biol Chem 1999;274(33):22903–22906.
178. Seeds MC, Bass DA. Regulation and metabolism of arachidonic acid. Clin Rev Allergy Immunol
1999;17(1–2):5–26.
179. Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1
and -2. J Biol Chem 1996;271(52):33157–33160.
180. Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science
2001;294(5548):1871–1875.
181. Bulger EM, Maier RV. Lipid mediators in the pathophysiology of critical illness. Crit Care Med
2000;28(4 suppl):N27–N36.
182. Gerritsen ME. Physiological and pathophysiological roles of eicosanoids in the microcirculation.
Cardiovasc Res 1996;32(4):720–732.
229
183. Serhan CN. Inflammation. Signalling the fat controller. Nature 1996;384(6604):23–24.
184. Leff JA. Leukotriene modifiers as novel therapeutics in asthma. Clin Exp Allergy 1998;28(suppl
5):147–153; discussion 171–173.
185. McMahon B, Godson C. Lipoxins: endogenous regulators of inflammation. Am J Physiol Renal Physiol
2004;286(2):F189–F201.
186. Marcus AJ. Transcellular metabolism of eicosanoids. Prog Hemost Thromb 1986;8:127–142.
187. De Caterina R, Sicari R, Giannessi D, et al. Macrophage-specific eicosanoid synthesis inhibition and
lipocortin-1 induction by glucocorticoids. J Appl Physiol 1993;75(6):2368–2375.
188. Snyder F, Fitzgerald V, Blank ML. Biosynthesis of platelet-activating factor and enzyme inhibitors.
Adv Exp Med Biol 1996;416:5–10.
189. Snyder F. Metabolic processing of PAF. Clin Rev Allergy 1994;12(4):309–327.
190. Noguchi K, Matsuzaki T, Shiroma N, et al. Involvement of nitric oxide and eicosanoids in platelet-
activating factor-induced haemodynamic and haematological effects in dogs. Br J Pharmacol
1996;118(4):941–950.
191. Blais C Jr, Marceau F, Rouleau JL, et al. The kallikrein-kininogen-kinin system: lessons from the
quantification of endogenous kinins. Peptides 2000;21(12):1903–1940.
192. Erdos EG. Kinins, the long march–a personal view. Cardiovasc Res 2002;54(3):485–491.
193. Hall JM. Bradykinin receptors: pharmacological properties and biological roles. Pharmacol Ther
1992;56(2):131–190.
194. Schreiber AD. Plasma inhibitors of the Hageman factor dependent pathways. Semin Thromb Hemost
1976;3(1):32–51.
195. Volpe AR. Giardina B, Preziosi P, et al. Biosynthesis of endothelium-derived nitric oxide by
bradykinin as endogenous precursor. Immunopharmacology 1996;33(1–3):287–290.
196. Dell’Italia LJ, Oparil S. Bradykinin in the heart: friend or foe? Circulation 1999;100(23):2305–2307.
197. Tschope C. Gohlke P, Zhu YZ, et al. Antihypertensive and cardioprotective effects after angiotensin-
converting enzyme inhibition: role of kinins. J Card Fail 1997;3(2):133–148.
198. Chikanza IC, Grossman AB. Neuroendocrine immune responses to inflammation: the concept of the
neuroendocrine immune loop. Baillieres Clin Rheumatol 1996;10(2):199–225.
199. Whicker JT, Evans SW. A role for neuropeptides in inflammation. In: Whicker JT, Evans SW, eds.
Biochemistry of Inflammation. Boston, MA: Kluwer Academic; 1992.
200. Delgado M, Munoz-Elias EJ, Gomariz RP, et al. Vasoactive intestinal peptide and pituitary
adenylate cyclase-activating polypeptide enhance IL-10 production by murine macrophages: in vitro
and in vivo studies. J Immunol 1999;162(3):1707–1716.
201. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of
endothelium-derived relaxing factor. Nature 1987;327(6122):524–526.
202. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology.
Pharmacol Rev 1991;43(2):109–142.
203. Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition.
Biochem J 2001;357(Pt 3):593–615.
204. Geller DA, Billiar TR. Molecular biology of nitric oxide synthases. Cancer Metastasis Rev
1998;17(1):7–23.
205. De Vera ME, Taylor BS, Wang Q, et al. Dexamethasone suppresses iNOS gene expression by
upregulating I-kappa B alpha and inhibiting NF-kappa B. Am J Physiol 1997;273(6 Pt 1):G1290–
G1296.
206. Kleinert H, Euchenhofer C, Ihrig-Biedert I, et al. Glucocorticoids inhibit the induction of nitric oxide
synthase II by down-regulating cytokine-induced activity of transcription factor nuclear factor-
kappa B. Mol Pharmacol 1996;49(1):15–21.
207. Titheradge MA. Nitric oxide in septic shock. Biochim Biophys Acta 1999;1411(2–3):437–455.
208. Finkel MS, Oddis CV, Jacob TD, et al. Negative inotropic effects of cytokines on the heart mediated
by nitric oxide. Science 1992;257(5068):387–389.
209. Goodwin DC, Landino LM, Marnett LJ. Effects of nitric oxide and nitric oxide-derived species on
prostaglandin endoperoxide synthase and prostaglandin biosynthesis. FASEB J 1999;13(10):1121–
1136.
230
210. Allione A, Bernabei P, Bosticardo M, et al. Nitric oxide suppresses human T lymphocyte
proliferation through IFN-gamma-dependent and IFN-gamma-independent induction of apoptosis. J
Immunol 1999;163(8):4182–4191.
211. Ou J, Carlos TM, Watkins SC, et al. Differential effects of nonselective nitric oxide synthase (NOS)
and selective inducible NOS inhibition on hepatic necrosis, apoptosis, ICAM-1 expression, and
neutrophil accumulation during endotoxemia. Nitric Oxide 1997;1(5):404–416.
212. Isobe M, Katsuramaki T, Hirata K, et al., Beneficial effects of inducible nitric oxide synthase
inhibitor on reperfusion injury in the pig liver. Transplantation 1999;68(6):803–813.
213. Xia Y, Zweier JL. Superoxide and peroxynitrite generation from inducible nitric oxide synthase in
macrophages. Proc Natl Acad Sci U S A 1997;94(13):6954–6958.
214. Szabo C, Billiar TR. Novel roles of nitric oxide in hemorrhagic shock. Shock 1999;12(1):1–9.
215. Hierholzer C, Harbrecht B, Menezes JM, et al. Essential role of induced nitric oxide in the initiation
of the inflammatory response after hemorrhagic shock. J Exp Med 1998;187(6):917–928.
216. Tzeng E, Kim YM, Pitt BR, et al. Adenoviral transfer of the inducible nitric oxide synthase gene
blocks endothelial cell apoptosis. Surgery 1997;122(2):255–263.
217. Nakahira K, Kim HP, Geng XH, et al. Carbon monoxide differentially inhibits TLR signaling
pathways by regulating ROS-induced trafficking of TLRs to lipid rafts. J Exp Med
2006;203(10):2377–2389.
218. Li T, Zhao B, Wang C, et al. Regulatory effects of hydrogen sulfide on IL-6, IL-8 and IL-10 levels in
the plasma and pulmonary tissue of rats with acute lung injury. Exp Biol Med (Maywood)
2008;233(9):1081–1087.
219. Li J, Zhang G, Cai S, et al. Effect of inhaled hydrogen sulfide on metabolic responses in
anesthetized, paralyzed, and mechanically ventilated piglets. Pediatr Crit Care Med 2008;9(1):110–
112.
220. Mok YY, Atan MS, Ping CY, et al. Role of hydrogen sulphide in haemorrhagic shock in the rat:
protective effect of inhibitors of hydrogen sulphide biosynthesis. Br J Pharmacol 2004;143(7):881–
889.
221. Collin M, Thiemermann C. Hydrogen sulfide and sulfite: novel mediators in the pathophysiology of
shock and inflammation. Shock 2005;24(6):595–596.
222. Zhang H, Zhi L, Moochhala SM, et al. Endogenous hydrogen sulfide regulates leukocyte trafficking
in cecal ligation and puncture-induced sepsis. J Leukoc Biol 2007;82(4):894–905.
223. Zhi L, Ang AD, Zhang H, et al. Hydrogen sulfide induces the synthesis of proinflammatory
cytokines in human monocyte cell line U937 via the ERK-NF-kappaB pathway. J Leukoc Biol
2007;81(5):1322–1332.
224. Oh GS, Pae HO, Lee BS, et al. Hydrogen sulfide inhibits nitric oxide production and nuclear factor-
kappaB via heme oxygenase-1 expression in RAW264.7 macrophages stimulated with
lipopolysaccharide. Free Radic Biol Med 2006;41(1):106–119.
225. Kimbrell DA, Beutler B. The evolution and genetics of innate immunity. Nat Rev Genet
2001;2(4):256–267.
226. Medzhitov R, Janeway C Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev
2000;173:89–97.
227. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol
2007;81(1):1–5.
228. Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature
2004;430(6996):257–263.
229. Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation
cluster. Trends Immunol 2002;23(6):301–304.
230. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice:
mutations in Tlr4 gene. Science 1998;282(5396):2085–2088.
231. Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol 2004;4(7):499–511.
232. Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate Toll-like receptors. Proc Natl
Acad Sci U S A 2005;102(27):9577–9582.
233. Kopp E, Medzhitov R. Recognition of microbial infection by Toll-like receptors. Curr Opin Immunol
2003;15(4):396–401.
231
234. Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat
Immunol 2004;5(10):975–979.
235. Mack KD, Von Goetz M, Lin M, et al. Functional identification of kinases essential for T-cell
activation through a genetic suppression screen. Immunol Lett 2005;96(1):129–145.
236. Schmidt AM, Yan SD, Yan SF, et al. The multiligand receptor RAGE as a progression factor
amplifying immune and inflammatory responses. J Clin Invest 2001;108(7):949–955.
237. Stern D, Yan SD, Yan SF, et al. Receptor for advanced glycation endproducts: a multiligand receptor
magnifying cell stress in diverse pathologic settings. Adv Drug Deliv Rev 2002;54(12):1615–1625.
238. Stebbing J, Bower M, Gazzard B, et al. The common heat shock protein receptor CD91 is up-
regulated on monocytes of advanced melanoma slow progressors. Clin Exp Immunol
2004;138(2):312–316.
239. Binder RJ, Han DK, Srivastava PK. CD91: a receptor for heat shock protein gp96. Nat Immunol
2000;1(2):151–155.
240. Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells:
chaperoning of the innate and adaptive immune responses. Annu Rev Immunol 2002;20:395–425.
241. Basu S. Binder RJ, Suto R, et al. Necrotic but not apoptotic cell death releases heat shock proteins,
which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int
Immunol 2000;12(11):1539–1546.
242. Binder RJ, Srivastava PK. Essential role of CD91 in re-presentation of gp96-chaperoned peptides.
Proc Natl Acad Sci U S A 2004;101(16):6128–6133.
243. Melcher A, Todryk S, Hardwick N, et al. Tumor immunogenicity is determined by the mechanism
of cell death via induction of heat shock protein expression. Nat Med 1998;4(5):581–587.
244. Zheng H, Dai J, Stoilova D, et al. Cell surface targeting of heat shock protein gp96 induces
dendritic cell maturation and antitumor immunity. J Immunol 2001;167(12):6731–6735.
245. Heilmann HP, Doppelfeld E, Fernholz HJ, et al. [Results of radiotherapy of bronchial carcinoma
(author’s transl)]. Dtsch Med Wochenschr 1976;101(43):1557–1562.
246. Becker T, Hartl FU, Wieland F. CD40, an extracellular receptor for binding and uptake of Hsp70-
peptide complexes. J Cell Biol 2002;158(7):1277–1285.
247. Binder RJ, Vatner R, Srivastava P. The heat-shock protein receptors: some answers and more
questions. Tissue Antigens 2004;64(4):442–451.
248. Asea A, Kraeft SK, Kurt-Jones EA, et al. HSP70 stimulates cytokine production through a CD14-
dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med
2000;6(4):435–442.
249. Vabulas RM, Ahmad-Nejad P, da Costa C, et al. Endocytosed HSP60s use toll-like receptor 2 (TLR2)
and TLR4 to activate the toll/interleukin-1 receptor signaling pathway in innate immune cells. J
Biol Chem 2001;276(33):31332–31339.
250. Klionsky DJ. Autophagy. Curr Biol 2005;15(8):R282–R283.
251. Klionsky DJ, Emr SD. Autophagy as a regulated pathway of cellular degradation. Science
2000;290(5497):1717–1721.
252. Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation.
Curr Opin Cell Biol 2009;22(2):124–131.
253. Swanson MS, Molofsky. Autophagy and inflammatory cell death, partners of innate immunity.
Autophagy 2005;1(3):174–176.
254. Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct
phosphorylation of Ulk1. Nat Cell Biol 2011;13(2):132–141.
255. Hoyer-Hansen M, Jaattela M. AMP-activated protein kinase: a universal regulator of autophagy?
Autophagy 2007;3(4):381–383.
256. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet
2009;43:67–93.
257. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ
2005;12(suppl 2):1542–1552.
258. Wang CW, Klionsky DJ. The molecular mechanism of autophagy. Mol Med 2003;9(3–4):65–76.
259. Diaz-Troya S, Pérez-Pérez ME, Florencio FJ, et al. The role of TOR in autophagy regulation from
232
yeast to plants and mammals. Autophagy 2008;4(7):851–865.
260. Meley D, Bauvy C, Houben-Weerts JH, et al. AMP-activated protein kinase and the regulation of
autophagic proteolysis. J Biol Chem 2006;281(46):34870–34879.
261. Xu Y, Jagannath C, Liu XD, et al. Toll-like receptor 4 is a sensor for autophagy associated with
innate immunity. Immunity 2007;27(1):135–144.
262. Xu Y, Liu XD, Gong X, et al. Signaling pathway of autophagy associated with innate immunity.
Autophagy 2008;4(1):110–112.
263. Hoyer-Hansen M, Bastholm L, Szyniarowski P, et al. Control of macroautophagy by calcium,
calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 2007;25(2):193–205.
264. Delgado M, Singh S, De Haro S, et al. Autophagy and pattern recognition receptors in innate
immunity. Immunol Rev 2009;227(1):189–202.
265. Delgado MA, Deretic V. Toll-like receptors in control of immunological autophagy. Cell Death Differ
2009;16(7):976–983.
266. Xu Y, Eissa NT. Autophagy in innate and adaptive immunity. Proc Am Thorac Soc 2010;7(1):22–28.
267. Waltz P, Carchman EH, Young AC, et al. Lipopolysaccaride induces autophagic signaling in
macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy 2011;7(3):315–320.
268. Deretic V. Autophagy in innate and adaptive immunity. Trends Immunol 2005;26(10):523–528.
269. Nakagawa I, Amano A, Mizushima N, et al. Autophagy defends cells against invading group A
Streptococcus. Science 2004;306(5698):1037–1040.
270. Paludan C, Schmid D, Landthaler M, et al. Endogenous MHC class II processing of a viral nuclear
antigen after autophagy. Science 2005;307(5709):593–596.
271. Carchman EH, Rao J, Loughran PA, et al. Heme oxygenase-1 mediated autophagy protects against
hepatocyte cell death and hepatic injury from infection/sepsis. Hepatology 2011;53(6):2053–2062.
272. Wu H, Chen G, Wyburn KR, et al. TLR4 activation mediates kidney ischemia/reperfusion injury. J
Clin Invest 2007;117(10):2847–2859.
273. Carchman EH, Whelan S, Loughran P, et al. Experimental sepsis-induced mitochondrial biogenesis
is dependent on autophagy, TLR4, and TLR9 signaling in liver. FASEB J 2013;27(12):4703–4711.
274. Howell GM, Gomez H, Collage RD, et al. Augmenting autophagy to treat acute kidney injury
during endotoxemia in mice. PloS One 2013;8(7):e69520.
275. Guo L, Stripay JL, Zhang X, et al. CaMKIα regulates AMP kinase-dependent, TORC-1-independent
autophagy during lipopolysaccharide-induced acute lung neutrophilic inflammation. J Immunol
2013;190(7):3620–3628.
276. Evankovich J, Zhang R, Cardinal JS, et al. Calcium/calmodulin-dependent protein kinase IV limits
organ damage in hepatic ischemia/reperfusion injury through induction of autophagy. Am J Physiol
Gastrointest Liver Physiol 2012;303(2):G189–G198.
277. Zhang X, Howell GM, Guo L, et al. CaMKIV-dependent preservation of mTOR expression is
required for autophagy during LPS-induced inflammation and acute kidney injury. J Immunol
2014;193(5):2405–2415.
278. Kimura T, Takabatake Y, Takahashi A, et al. Autophagy protects the proximal tubule from
degeneration and acute ischemic injury. J Am Soc Nephrol 2011;22(5):902–913.
279. Zhang J, Randall MS, Loyd MR, et al. Mitochondrial clearance is regulated by Atg7-dependent and -
independent mechanisms during reticulocyte maturation. Blood 2009;114(1):157–164.
280. Mortensen M, Ferguson DJ, Edelmann M, et al. Loss of autophagy in erythroid cells leads to
defective removal of mitochondria and severe anemia in vivo. Proc Natl Acad Sci U S A
2010;107(2):832–837.
281. Cali T, Ottolini D, Negro A, et al. Enhanced parkin levels favor ER-mitochondria crosstalk and
guarantee Ca(2+) transfer to sustain cell bioenergetics. Biochim Biophys Acta 2013;1832(4):495–
508.
282. Amadoro G, Corsetti V, Florenzano F, et al. Morphological and bioenergetic demands underlying
the mitophagy in post-mitotic neurons: the pink-parkin pathway. Front Aging Neurosci 2014;6:18.
283. Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of
mitochondria. Cell Death Differ 2013;20(1):31–42.
284. Springer W, Kahle PJ. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 2011;7(3):266–
233
278.
285. Wang Y, Nartiss Y, Steipe B, et al. ROS-induced mitochondrial depolarization initiates
PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy 2012;8(10):1462–
1476.
286. Polla BS, Bachelet M, Dall’ava J, et al. Heat shock proteins in inflammation and asthma: Dr Jekyll
or Mr Hyde? Clin Exp Allergy 1998;28(5):527–529.
287. Polla BS, Bachelet M, Elia G, et al. Stress proteins in inflammation. Ann N Y Acad Sci 1998;851:75–
85.
288. Multhoff G, Botzler C. Heat-shock proteins and the immune response. Ann N Y Acad Sci
1998;851:86–93.
289. Perdrizet GA. Heat shock and tissue protection. New Horiz 1995;3(2):312–320.
290. Mathew A, Morimoto RI. Role of the heat-shock response in the life and death of proteins. Ann N Y
Acad Sci 1998;851:99–111.
291. Ribeiro SP, Villar J, Slutsky AS. Induction of the stress response to prevent organ injury. New Horiz
1995;3(2):301–311.
292. Garcia-Cardena G, Fan R, Shah V, et al. Dynamic activation of endothelial nitric oxide synthase by
Hsp90. Nature 1998;392(6678):821–824.
293. Wong HR, Ryan M, Wispe JR. Stress response decreases NF-kappaB nuclear translocation and
increases I-kappaBalpha expression in A549 cells. J Clin Invest 1997;99(10):2423–2428.
294. Moshage H. Cytokines and the hepatic acute phase response. J Pathol 1997;181(3):257–266.
295. Pepys MB, ed. Acute Phase Proteins in the Acute Phase Response. New York: Springer-Verlag; 1989.
296. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J
Med 1999;340(6):448–454.
297. Koj A. Initiation of acute phase response and synthesis of cytokines. Biochim Biophys Acta
1996;1317(2):84–94.
298. Giraldez RR, Panda A, Xia Y, et al. Decreased nitric-oxide synthase activity causes impaired
endothelium-dependent relaxation in the postischemic heart. J Biol Chem 1997;272(34):21420–
21426.
299. Romson JL, Hook BG, Kunkel SL, et al. Reduction of the extent of ischemic myocardial injury by
neutrophil depletion in the dog. Circulation 1983;67(5):1016–1023.
300. Vedder NB, Winn RK, Rice CL, et al. A monoclonal antibody to the adherence-promoting leukocyte
glycoprotein, CD18, reduces organ injury and improves survival from hemorrhagic shock and
resuscitation in rabbits. J Clin Invest 1988;81(3):939–944.
301. Agostoni A, Gardinali M, Frangi D, et al. Activation of complement and kinin systems after
thrombolytic therapy in patients with acute myocardial infarction. A comparison between
streptokinase and recombinant tissue-type plasminogen activator. Circulation 1994;90(6):2666–
2670.
302. Morgan BP. Complement membrane attack on nucleated cells: resistance, recovery and non-lethal
effects. Biochem J 1989;264(1):1–14.
303. Muckart DJ, Bhagwanjee S. American College of Chest Physicians/Society of Critical Care Medicine
Consensus Conference definitions of the systemic inflammatory response syndrome and allied
disorders in relation to critically injured patients. Crit Care Med 1997;25(11):1789–1795.
304. Bone RC. Sepsis, sepsis syndrome, and the systemic inflammatory response syndrome (SIRS).
Gulliver in Laputa. JAMA 1995;273(2):155–156.
305. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory
response syndrome (SIRS). A prospective study. JAMA 1995;273(2):117–123.
306. Davies MG, Hagen PO. Systemic inflammatory response syndrome. Br J Surg 1997;84(7):920–935.
307. Dvorak HF, Galli SJ, Dvorak AM. Cellular and vascular manifestations of cell-mediated immunity.
Hum Pathol 1986;17(2):122–137.
234
Chapter 8
Surgical Infections
Lena M. Napolitano
Key Points
1 Surgical infections include intra-abdominal infections (appendicitis, cholecystitis/cholangitis,

diverticulitis, colitis including C. difficile colitis, pancreatitis, and peritonitis), soft tissue infections
(necrotizing and nonnecrotizing), surgical site infections, and hospital-acquired infections that occur
in surgical patients (pneumonia, central line–associated bloodstream infections [CLABSI], and
catheter-associated urinary tract infections [CAUTI]).
2 Early empiric appropriate broad-spectrum antimicrobial therapy, to cover all potential causative
pathogens, is an important adjunct to source control in the treatment of surgical infections.
Inappropriate antimicrobial therapy is associated with increased mortality.
3 Any of these surgical infections can result in severe sepsis or septic shock.
4 A key concept in surgical infections is “source control,” defined as any physical intervention to
remove or eliminate a focus of invasive infection (drainage, debridement, and device removal) and
to restore optimal anatomic function.
5 Pathogen identification and appropriate deescalation of antimicrobial therapy are of paramount
importance in treatment of surgical infections, as increasing prevalence of multidrug-resistant
pathogens has been identified in both abdominal and skin surgical infections.
6 Complicated intra-abdominal infection (cIAI) extends beyond the hollow viscus of origin into the
peritoneal space and is associated with either abscess formation or peritonitis.
7 Recommendations for specific antimicrobial therapy for cIAI are based on whether the infection is
“community-acquired” or “healthcare-associated.”
8 In patients with intra-abdominal infections who have undergone an adequate source control
procedure, fixed-duration antibiotic therapy for 4 days is noninferior to longer duration
antimicrobial therapy until resolution of physiologic abnormalities, with no difference in surgical
site infection, recurrent intra-abdominal infection, or death.
9 The two surgical procedures indicated for C. difficile colitis treatment include (1) total abdominal
colectomy (for peritonitis, colonic perforation, ischemia, necrosis, toxic megacolon with impending
perforation, septic shock with organ failure) and (2) diverting loop ileostomy and intraoperative
colonic lavage for toxin reduction. The second option is associated with colonic preservation.
10 The initial treatment of infected pancreatic necrosis is percutaneous catheter or endoscopic
(transgastric/transduodenal) drainage with additional drain placement as required.
11 Lack of clinical improvement of necrotizing infected pancreatitis with initial percutaneous drainage
warrants consideration of minimally invasive techniques for pancreatic necrosectomy including
video-assisted retroperitoneal debridement, minimally invasive retroperitoneal pancreatectomy, or
transluminal direct endoscopic necrosectomy.
12 Acute bacterial skin and skin structure infections are defined as bacterial infection of the skin with a
lesion size area of at least 75 cm2 (lesion size measured by the area of redness, edema, or
induration), including cellulitis, wound infection, and abscess.
13 Early operative debridement is the major determinant of outcome in necrotizing soft tissue
infections. Delayed definitive debridement remains the single most important risk factor for death.
INTRODUCTION
1 Surgical infections include intra-abdominal infections (appendicitis, cholecystitis, diverticulitis, colitis,
and pancreatitis), soft tissue infections (necrotizing and nonnecrotizing), surgical site infections (SSIs),
235
and hospital-acquired infections that occur in surgical patients (pneumonia, central line–associated
bloodstream infections [CLABSI], and catheter-associated urinary tract infections [CAUTI]).1
Appropriate therapy of surgical infections to optimize patient outcomes includes four steps: (1) early
diagnosis, (2) early initiation of appropriate empiric broad-spectrum antimicrobial therapy, (3)
adequate source control (surgical or interventional radiologic), and (4) pathogen identification and
appropriate deescalation of antimicrobial therapy (Table 8-1).
The initial management of all surgical infections should include the initiation of early empiric
antimicrobial therapy to cover all potential possible pathogens, since early and appropriate empiric
antibiotic therapy improves patient outcomes (Table 8-2).2 The choice of early empiric antimicrobial
therapy is guided by the specific site of infection, the common pathogens associated with that infection,
and by local and regional antibiograms. The goal of antimicrobial therapy is to achieve antibiotic levels
at the site of the infection that exceed the minimum inhibitory concentration of the microbial pathogens
present.
Early Use of Appropriate Broad-Spectrum Antimicrobial Therapy

2, 3 Early use of appropriate broad-spectrum antimicrobial therapy is an important adjunct to
appropriate surgical management of surgical infections. Numerous studies have confirmed that
inappropriate empiric antibiotics (i.e., antibiotics that do not cover the causative pathogens) are
associated with increased mortality.3 In patients who manifest severe sepsis or septic shock, every hour
delay of antimicrobial therapy is associated with increased mortality.4 The Surviving Sepsis Guidelines
recommendations are listed in Table 8-3.
Table 8-1 Appropriate Therapy of Surgical Infections
Source Control
4 Source control is defined as any physical intervention to remove or eliminate a focus of invasive
infection (drainage, debridement, and device removal) and to restore optimal anatomic function.5 In
surgical infections, antimicrobial agents are used in conjunction with adequate source control of the
initial infection. Adequate source control can be accomplished by either surgical or percutaneous
interventional radiologic techniques. A number of factors have been identified that predict failure of
source control for intra-abdominal infections (Table 8-4).
Pathogen Identification
5 Pathogen identification is extremely important, in part related to increased prevalence of multidrug-
resistant pathogens that are associated with surgical infections. Whenever possible, high-quality
specimens should be obtained from source control procedures for Gram stain and culture in order to
identify causative pathogens and determine antimicrobial susceptibility of the bacterial isolates
identified. This will enable appropriate deescalation of antimicrobial therapy from broad-spectrum
therapy to directed potential single antimicrobial agent therapy.
INTRA-ABDOMINAL INFECTIONS
Classification
6 Complicated intra-abdominal infection (cIAI) extends beyond the hollow viscus of origin into the
peritoneal space and is associated with either abscess formation or peritonitis. “Uncomplicated” intra-
abdominal infection involves intramural inflammation of the gastrointestinal tract and has a substantial
probability of progressing to cIAI if not adequately treated.
Table 8-2 Spectrum of Activity of Specific Antimicrobials for Specific Pathogens
236
Table 8-3 Antimicrobial Therapy, Surviving Sepsis Guidelines 2012
Diagnosis
Patients with cIAI present with abdominal pain and gastrointestinal symptoms. A comprehensive
abdominal physical examination must be performed in these patients. If peritonitis is present, evaluation
for emergent laparotomy without diagnostic studies is considered. If peritonitis is not present, recent
evidence-based guidelines recommend that computed tomography (CT) scan of the abdomen and pelvis
is the diagnostic imaging modality of choice to evaluate for cIAI and its source.6,7
Treatment
7 Early empiric appropriate systemic antimicrobial therapy to cover all potential causative pathogens
and early source control are the mainstays of treatment of cIAIs. In order to select appropriate empiric
antimicrobial agents for use, cIAIs are further classified as “community-acquired” or “healthcare-
associated.”
Community-Acquired Complicated Intra-Abdominal Infection

For patients who have “community-acquired” cIAI, determination of whether the disease is
“mild/moderate (appendicitis, mild diverticulitis)” or “severe (fecal peritonitis, perforated
diverticulitis)” facilitates appropriate antimicrobial treatment (Table 8-5). Patients with “severe”
community-acquired cIAI should have antibiotics that cover Pseudomonas and Enterococcus pathogens,
and both single-agent and combination-agent regimens are available for use. A number of antimicrobials
are no longer recommended for use in community-acquired cIAI:
Table 8-4 Clinical Factors Predicting Failure of “Source Control” for Intra-
Abdominal Infection
237
Ampicillin/sulbactam is not recommended because of high resistance of Escherichia coli to this agent
(B-II)
Cefotetan and clindamycin are not recommended for use because of increasing resistance of the
Bacteroides fragilis group to these agents (B-II)
Because of the availability of less toxic agents demonstrated to be of at least equal efficacy,
aminoglycosides are not recommended for routine use in community-acquired IAI in adults (B-II).
Healthcare-Associated Complicated Intra-Abdominal Infection

For patients with “healthcare-associated” cIAI, separate evidence-based guideline recommendations for
empiric antimicrobial treatment are provided (Algorithm 8-1). Specific antimicrobials are recommended
based on whether the patient and/or institution have high risk for infection with multidrug-resistant
pathogens. Quinolone-resistant E. coli have become common in many communities, and quinolones
should not be used unless hospital antibiograms confirm greater than 90% susceptibility of E. coli to
quinolones. In patients with healthcare-associated cIAI, carbapenems are an excellent single-agent
regimen for empiric treatment.
Table 8-5 Empiric Antimicrobial Treatment of Extrabiliary cIAIs, Community

Acquired
Duration of Antibiotics for Complicated Intra-Abdominal Infection

8 Duration of antibiotics for treatment of cIAI has long been controversial. A recent important
randomized controlled trial examined the efficacy of short-course (4 days) antimicrobial therapy in
patients with intra-abdominal infections who had undergone an adequate source control procedure.
Fixed-duration antibiotic therapy for 4 days was noninferior to longer duration antmicrobial therapy
until resolution of physiologic abnormalities, with no difference in the composite endpoints of SSI,
recurrent intra-abdominal infection, or death.8
SPECIFIC INTRA-ABDOMINAL INFECTIONS

Appendicitis
Appendicitis is common with over 300,000 hospital discharges in the United States per year. Although
appendectomy provides definitive source control for the treatment of acute nonperforated appendicitis,
238
intravenous (IV) antibiotics should be administered preoperatively with a dose repeated
intraoperatively if the surgery is prolonged, a number of controversies in diagnosis and management of
appendicitis persist.9
Antibiotics versus Appendectomy

In patients with uncomplicated appendicitis (nonperforated, no abscess, or phlegmon), appendectomy is
definitive source control. But a number of recent randomized trials have confirmed that acute
nonperforated appendicitis can be treated successfully with antibiotics alone. A meta-analysis of 6
studies with 1,201 patients reported that in patients treated with antibiotics alone, 7 ± 4% failed to
respond and required appendectomy, and acute appendicitis recurred in 14 ± 11%. A normal appendix
was found in 7.3 ± 5.1% of patients at appendectomy. Complications were considerably less likely to
occur with antibiotic treatment than with appendectomy. Major surgical complications included
enterocutaneous fistula and reoperation.10
Algorithm 8-1. Empiric antimicrobial treatment of extrabiliary cIAIs, community acquired versus healthcare associated. (Adapted
from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults
and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt)
2010;11(1):79–109.)
A Cochrane meta-analysis of 5 trials with 901 patients reported that 73.4% of patients who were
treated with antibiotics and 97.4% patients underwent appendectomy were cured within 2 weeks
without major complications (including recurrence) within 1 year.11 Another meta-analysis included
only four trials and reported that efficacy was significantly higher for surgery but rates of perforated
appendicitis were not different, and complication rates were significantly higher for surgery.12
The most recent trial (APPAC) enrolled 530 patients in Finland with uncomplicated appendicitis
confirmed by CT scan and randomized to early appendectomy or antibiotic treatment (ertapenem for 3
days, then oral levofloxacin and metronidazole for 7 days) with 1-year follow-up. In the antibiotic
group, 70 patients (27.3%) underwent appendectomy within 1 year of initial presentation for
appendicitis. Antibiotic treatment did not meet the prespecified criterion for noninferiority compared
239
with appendectomy. But it was notable that 72.7% of patients with uncomplicated appendicitis treated
with antibiotics alone did not require subsequent appendectomy.13,14
The trials published to date were primarily from European countries, used antibiotics not available in
the United States and had minimal use of laparoscopic appendectomy or CT scan for diagnostic
imaging.15 Further high-quality randomized trials are therefore needed to determine which patients are
most likely to benefit from antibiotic therapy alone. Although appendectomy remains the standard
treatment for acute appendicitis, antibiotic treatment alone may be used as an alternative treatment in
patients with contraindication to surgery (or where surgery is high risk).
Laparoscopic versus Open Appendectomy

Appendectomy can be performed by laparoscopic or open approach. A large retrospective review
(2005–2008) of laparoscopic versus open appendectomy using the American College of Surgeons
National Surgical Quality Improvement Program (NSQIP) reported that 76.4% were performed
laparoscopically and 23.6% performed open. Open appendectomy was associated with increased
morbidity, SSI, and mortality.16
A Cochrane review of 67 trials was updated in 2010 and reported that laparoscopic appendectomy
was associated with lower SSI rates but higher intra-abdominal abscess rate. Laparoscopic approach was
associated with shorter hospital length of stay, faster return to normal activity, and decreased
postoperative pain. This review concluded that laparoscopic appendectomy should be considered the
preferred approach where surgical expertise and equipment are available.17
Time to Appendectomy and Perforation Risk

It has long been thought that appendiceal luminal obstruction leads to appendiceal perforation without
timely surgical intervention. This belief led to attempts to decrease time from presentation and
diagnosis of acute appendicitis to operating room start time. With the advent of early appropriate
empiric systemic antimicrobial therapy, this fundamental concept is no longer true. As discussed
previously, in patients with uncomplicated appendicitis, antibiotic treatment alone does not lead to
appendiceal perforation. Furthermore, using data from the Washington State Surgical Care and
Outcomes Assessment Program (SCOAP) with 9,048 adult patients who underwent appendectomy, there
was no association between appendiceal perforation and in-hospital time prior to surgery. This study
confirmed that appendiceal perforation is most commonly a prehospital occurrence, and timing of
surgery should be determined based on all factors relevant to the surgeon and patient.18
Abscess or Phlegmon Management

In patients with periappendiceal abscess or phlegmon, current evidence (mainly retrospective studies)
supports nonoperative management with IV transitioned to oral antibiotics and percutaneous drainage if
possible. A meta-analysis of 19 retrospective studies from 1969 to 2005 reported that nonsurgical
treatment failed in only 7.6% of patients and immediate appendectomy was associated with higher
morbidity. Similar findings were confirmed in a more recent review.19 Routine interval appendectomy
is not recommended since the risk of recurrence is low (7.4%). But either colonoscopy or repeat CT
imaging is recommended due to the risk of a malignant disease (1.2%) or important benign disease
(0.7%) identified during follow-up.20
240
Algorithm 8-2. Biliary infections and algorithm for diagnosis and management. (From Demehri FR, Alam HB. Evidence-based
management of common gallstone-related emergencies. J Intensive Care Med 2016;31(1):3–13.)
Interval Appendectomy after Initial Nonoperative Management

A large retrospective cohort study reported that 3% of patients were initially treated with nonoperative
management. Of these, 15% had an interval appendectomy and the remaining 85% did not. Of the 864
patients that did not undergo interval appendectomy only 39 patients (5%) had recurrence of
appendicitis after a median follow-up of 4 years.21 Routine interval appendectomy after initial
successful nonoperative treatment is therefore not justified and should be abandoned. In a meta-analysis
including 2,771 patients initially treated nonoperatively for appendiceal phlegmon or abscess, 31
patients were found to have a malignant diagnosis and a lower rate of inflammatory bowel disease.
These data highlight the need for follow-up with either CT scan or colonoscopy after successful
nonoperative management.20 Although a retrospective study in pediatric appendicitis reported a 2.8-fold
higher rate of recurrent appendicitis in patients with an appendicolith, this study is limited by small
sample size (n = 96) and a higher overall rate of recurrent appendicitis than all other published
studies.22 See also chapter on Appendiceal Diseases.
Biliary Infections
Biliary infections include acute cholecystitis which may be calculous or acalculous, may include
choledocholithiasis or not, and cholangitis.23 Acute cholecystitis and ascending cholangitis are primary
inflammations of the gallbladder and bile ducts, respectively, which are caused by infection and possible
biliary obstruction.
Acute Cholecystitis
Acute cholecystitis is inflammation of the gallbladder resulting from obstruction of the cystic duct and
subsequent bacterial invasion and overgrowth. Cholelithiasis is the cause of cystic duct obstruction in
more than 90% of cases of acute cholecystitis in the United States. Acalculous cholecystitis is more
common in critically ill patients and the pathophysiology is transmural ischemia. Acalculous
cholecystitis carries higher morbidity and mortality rates than calculous cholecystitis.
The diagnosis of acute cholecystitis is made based on the common constellation of right upper
quadrant tenderness, leukocytosis, and fever. Initial diagnostic imaging is right upper quadrant
ultrasound to evaluate for gallstones, gallbladder wall thickening, and pericholecystic inflammation
(sensitivity 88% to 94%, specificity 78% to 80%). If ultrasound is inconclusive or is discordant with the
241
clinical evaluation, then cholescintigraphy (99mTc-hepatobiliary iminodiacetic acid, HIDA scan) is
recommended and nonvisualization of the gallbladder confirms acute cholecystitis with sensitivity of
96% and specificity of 90% (Algorithm 8-2).24
Early systemic antimicrobial treatment is indicated for acute cholecystitis to cover the causative
pathogens, including aerobic, enteric, gram-negative bacilli (i.e., E. coli, Klebsiella, Enterobacter, and
Proteus), and aerobic gram-positive organisms (i.e., Enterococcus and Streptococcus). Anaerobes are
uncommon, identified in approximately 15% of isolates. Clostridial organisms can be identified in cases
of emphysematous cholecystitis confirmed by identification of gas in the gallbladder wall.
Cholangitis
Cholangitis signs/symptoms include jaundice, fever, right upper quadrant tenderness,
hyperbilirubinemia, and leukocytosis. Ultrasound confirms common bile duct dilation (>7 mm).
Appropriate evidence-based recommendations for diagnosis and treatment from the Tokyo Guidelines
are provided in Tables 8-6 and 8-7. For treatment recommendations, urgent biliary drainage (<24
hours) is indicated when (1) obstructive biliary stones are associated with severe or moderate acute
cholangitis OR (2) mild acute cholangitis is not responding to IV antibiotics and fluid resuscitation.
For patients with biliary infections, specific evidence-based guideline recommendations for
antimicrobial treatment are classified into four patient populations (Table 8-8). For patients undergoing
cholecystectomy for acute cholecystitis with complete source control (i.e., complete cholecystectomy),
antimicrobial therapy should be discontinued within 24 hours of the operation unless there is evidence
of infection outside the wall of the gallbladder. See also chapter on Calculous Biliary Disease.
Table 8-6 Diagnosis of Cholangitis: Tokyo Guidelines 2013
Table 8-7 Treatment of Acute Cholangitis by Severity Classification: Tokyo

Guidelines 2013 Criteria
242
Diverticulitis
Diverticulitis is a common intra-abdominal infection. Its pathophysiology is associated with altered gut
motility, increased luminal pressure, and an altered colonic microenvironment.
Uncomplicated diverticulitis is treated with systemic antibiotics and usually resolves. Antimicrobial
treatment of diverticulitis is the same as for cIAI which is reviewed above. In a cohort study of 2,366
patients hospitalized in the Kaiser Permanente system and followed for 8.9 years, only 13.3% had a first
recurrence and 3.9% had a second recurrence.25
Surgery for acute diverticulitis is indicated for patients who present with peritonitis and/or sepsis or
who do not improve with medical management and/or percutaneous drainage of associated
abscess/infection. Although less than 25% of patients will develop generalized peritonitis after colonic
perforation, it is severe with high mortality. Surgical options include simple colostomy formation in the
setting of profound inflammation (rarely performed), traditional sigmoid resection with colostomy
(Hartmann procedure), and sigmoid resection with a primary colocolonic or colorectal anastomosis with
or without a diverting loop ileostomy. Laparoscopic surgery is preferred to open surgery when
possible.26
Table 8-8 Antimicrobials for Treatment of Biliary Infections
243
Figure 8-1. Hinchey classification scheme. Patients with stage 1 disease have small, confined, pericolic, or mesenteric abscesses,
whereas those with stage 2 disease have larger abscesses, often confined to the pelvis. Stage 3 disease, or perforated diverticulitis,
is present when a peridiverticular abscess has ruptured and caused purulent peritonitis. Rupture of an uninflamed and unobstructed
diverticulum into the free peritoneal cavity with fetal contamination, the so-called free rupture, signifies stage 4 disease and carries
the highest risk of an adverse outcome.
Since recurrence after recovery from an uncomplicated episodes of diverticulitis is rare and two or
more recurrences are not associated with increased risk of complications, elective colectomy following
two episodes of diverticulitis is no longer recommended. Decisions regarding surgical intervention and
colectomy must therefore be based on individual potential risks and benefits of colon resection.27
For patients who require surgical intervention, the specific treatment that is associated with the best
outcome is controversial. Hinchey proposed a practical clinical classification of diverticulitis based on
the severity of peritoneal contamination (Fig. 8-1) identified at operation.28 The modified Hinchey
classification includes Hinchey Ia (confined pericolic inflammation–phlegmon) and Ib (confined pericolic
244
abscess) and considers classification based on radiologic imaging with CT scan as well. Increasing
Hinchey classification is associated with increased mortality. The mortality for patients with Hinchey III
is reported as 6% but increases greatly to 35% for fecal peritonitis (Hinchey IV). A systematic review
comparing surgical treatments for Hinchey III or IV colonic diverticulitis confirmed that primary
resection with anastomosis has a significant advantage with lower mortality compared to Hartmann
procedure. Furthermore, laparoscopic peritoneal lavage with subsequent surgical resection if indicated
had lower surgical morbidity and hospital length of stay compared to the primary resection and
anastomosis group.29 See also chapter on Diverticular Disease.
Figure 8-2. Treatment of initial episode of Clostridium difficile infection.
Clostridium Difficile Colitis

The incidence and severity of Clostridium difficile infection (CDI) has increased, particularly in surgical
patients who have been exposed to prior antimicrobial therapy. There has been a substantial change in
the management of CDI related to the emergence of the NAP1/BI/027 strain which is associated with
higher toxin production and more severe forms of disease. CDI may be associated with mild to
moderate diarrhea or colonic ileus and obstipation to severe colitis.30
Early diagnosis of CDI is imperative. Recommended testing includes two steps, using a glutamine
dehydrogenase assay for the Clostridium difficile antigen, followed by enzyme immunoassay toxin
testing. Polymerase chain reaction (PCR) confirmatory testing is used if the antigen is positive and toxin
is negative.31 Radiologic testing is helpful, and CT may show colonic mucosal edema (thumbprinting or
target sign), ascites, inflammation, and fat stranding and the “accordion sign” which indicates
alternating edematous colonic haustra separated by transverse mucosal ridges filled with enteral
contrast.
Initial management of CDI is cessation of all antibiotics if possible. The 2010 SHEA/IDSA guidelines
have evidence-based recommendations for CDI based on severity of disease (Fig. 8-2).32 Vancomycin
and metronidazole are first-line therapy. Vancomycin is preferred for severe or complicated disease.
Fidaxomicin (a macrocyclic antibiotic with a narrow antimicrobial spectrum against C. difficile,
staphylococci, and enterococci) may be considered for recurrent CDI or where risk of recurrence is high.
A multicenter multinational randomized trial confirmed decreased recurrence rates compared to oral
vancomycin and it is the U.S. Food and Drug Administration (FDA) approved with a recommended
treatment dose of 100 mg po bid.33 Fecal microbiota transplantation is associated with symptom
resolution and may be effective in recurrent CDI, but has no role in primary CDI treatment.
9 CDI may warrant surgical intervention. Surgical consultation should occur very early in the course
245
of disease in patients with severe and complicated CDI. The indications for surgical management of CDI
patients are not clearly defined, but severe disease, worsening clinical condition despite appropriate
treatment, and peritonitis or shock states are all potential indications. The two surgical procedures
indicated for CDI treatment include (1) total abdominal colectomy (for peritonitis, colonic perforation,
ischemia, necrosis, toxic megacolon with impending perforation, septic shock with organ failure) and
(2) diverting loop ileostomy and intraoperative colonic lavage for toxin reduction while preserving the
colon (Fig. 8-3). This new treatment strategy resulted in reduced mortality compared with the historical
population who had undergone total abdominal colectomy (19% vs. 50%), and preservation of the colon
was achieved in 93% of patients.34 No randomized studies have been published to date comparing these
two options.
Pancreatitis
A new classification of acute pancreatitis has been implemented and is based on local disease (whether
pancreatic necrosis is present or not, whether it is sterile or infected) and systemic determinants
(whether organ failure is present or not, whether it is transient or persistent) of severity (Table 8-9).
Early management requires goal-directed fluid resuscitation (with avoidance of over-resuscitation and
abdominal compartment syndrome), assessment of severity of pancreatitis, diagnostic CT imaging to
assess for necrotizing pancreatitis, consideration of endoscopic retrograde cholangiopancreatography
(ERCP) for biliary pancreatitis, and early enteral nutrition support. Antibiotic prophylaxis for severe
acute or necrotizing pancreatitis is not recommended.35
Figure 8-3. Diverting loop ileostomy with antegrade colonic irrigation for CDI. Before surgery is started:
1. Place the patient in lithotomy position with easy access to rectum
2. Place a fluid collection bag (commonly used by urology) under the patient’s rectum for drainage collection
3. Place a rectal drainage tube (large Malecot catheter, large foley catheter, #9 or #10 endotracheal tube, or other large catheter)
4. Have 8 L of warmed polyethylene glycol 3350/electrolyte solution (GoLytely; Braintree Laboratories) available in OR for
intraoperative colonic irrigation, and dulcolax suppository
Intraoperatively:
1. Ensure that the colon is viable and without perforation
2. Create a loop ileostomy (laparoscopic or open)
3. Place a 24-French Malecot catheter into the efferent limb of the ileostomy and advance into the right colon through the
ileocecal valve. Secure to skin with sutures.
4. Infuse 8 L of warmed polyethylene glycol 3350/electrolyte solution (GoLytely; Braintree Laboratories) into the 24-French
Malecot catheter via the efferent limb of the ileostomy
5. Once colonic lavage completed, perform rectal examination to empty rectum, place dulcolax suppository in rectum to
encourage colonic emptying
6. Instill antegrade colonic enema with vancomycin (500 mg in 500 mL) via ileostomy efferent limb, continue postoperatively
(Adapted from Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic lavage. An alternative to total abdominal
colectomy for the treatment of severe, complicated clostridium difficile-associated disease. Ann Surg 2011;254(3):423–429.)
Table 8-9 New International Classification of Acute Pancreatitis: Determinants of

Severity of Acute Pancreatitis by the 2011 World Congress of the
International Association of Pancreatology
246
Necrotizing pancreatitis is high risk for progression to necrotizing infected pancreatitis. Therapeutic
antibiotics are required for treatment of documented infected pancreatic necrosis. Causative pathogens
include gram-negative microbes and an increase in gram-positive organisms has been reported.36
Therefore broad-spectrum IV antimicrobials are recommended.
10 The initial treatment of infected pancreatic necrosis is percutaneous catheter or endoscopic
(transgastric/transduodenal) drainage with a second drain placement as required. The “step-up”
approach consisted of percutaneous drainage followed, if necessary, by minimally invasive
retroperitoneal necrosectomy. The minimally invasive step-up approach, as compared with open
necrosectomy, reduced the rate of the primary composite endpoint (12% vs. 50%, including major
complications [new-onset multiple organ failure or multiple systemic complications, perforation of a
visceral organ or enterocutaneous fistula, or bleeding] or death), but the mortality rate did not differ
significantly between groups (19% vs. 16%).37,38
11 Lack of clinical improvement after these initial procedures warrants consideration of minimally
invasive techniques for pancreatic necrosectomy including video-assisted retroperitoneal debridement
(VARD), minimally invasive retroperitoneal pancreatectomy (MIRP), or transluminal direct endoscopic
necrosectomy (DEN).39 VARD and MIRP use the tract created by percutaneous drainage catheters as a
guide for placement of a laparoscope into the retroperitoneum so that debridement and lavage can be
performed under direct visualization. Open necrosectomy is associated with substantial morbidity, but
to date no randomized trial has documented superiority of either minimally invasive or open surgical
technique. Additional trials are underway to address this (Algorithm 8-3). See also chapter on Acute
Pancreatitis.
SKIN AND SOFT TISSUE INFECTIONS

Skin and soft tissue infections (SSTIs) span a broad spectrum of clinical entities from limited cellulitis to
rapidly progressive necrotizing fasciitis, which may be associated with septic shock or toxic shock
syndrome and associated organ failure.40,41 These SSTIs may result in critical illness and require
management in the intensive care unit (ICU).42,43 Methicillin-resistant Staphylococcus aureus (MRSA) has
emerged as the most common identifiable cause of severe SSTIs, therefore initiation of empiric anti-
MRSA antimicrobials is warranted in all cases of severe SSTIs. In addition, appropriate critical care
management, including fluid resuscitation, organ support, and nutritional support are necessary
components of treatment of severe SSTIs.
The complex interplay of environment, host, and pathogen is important to consider when evaluating
SSTIs and planning therapy. The key to a successful outcome in caring for patients with severe SSTIs is
(1) early diagnosis and differentiation of necrotizing versus nonnecrotizing SSTI, (2) early initiation of
appropriate empiric broad-spectrum antimicrobial therapy with consideration of risk factors for specific
pathogens, (3) “source control,” that is, early aggressive surgical intervention for drainage of abscesses
247
and debridement of necrotizing soft tissue infections (NSTIs), and (4) pathogen identification and
appropriate deescalation of antimicrobial therapy.
Algorithm 8-3. Step-up approach to management of necrotizing infected pancreatitis. (Adapted from Besselink MG, van Santvoort
HC, Nieuwenhuijs, et al.; Dutch Acute Pancreatitis Study Group. Minimally invasive ‘step-up approach’ versus maximal
necrosectomy in patients with acute necrotizing pancreatitis (PANTER trial): design and rationale of a randomized controlled
multicenter trial [ISRCTN13975868]. BMC Surg 2006;6:6.)
Table 8-10 Comparison of Old and New Classification of SSTIs by FDA
Classification of Skin and Soft Tissue Infections

The FDA previously classified SSTIs into two broad categories for the purpose of clinical trials
evaluating new antimicrobials for the treatment of SSTIs: uncomplicated and complicated (Table 8-
10). Uncomplicated SSTIs include superficial infections such as cellulitis, simple abscesses, impetigo,
and furuncles. These infections can be treated by antibiotics and/or surgical incision for drainage of
abscess alone. In contrast, complicated SSTIs include deep soft tissue infections that require significant
surgical intervention, such as infected ulcers, infected burns, and major abscesses, and these patients
also have significant underlying comorbidities, that is, disease states which complicate (and usually
delay) response to treatment. Complicated SSTIs are a significant clinical problem, in part related to the
increasing resistance of infecting bacteria to current antibiotic therapies.
248
Uncomplicated Skin and Soft Tissue Infections
Uncomplicated SSTIs are associated with low risk for life- or limb-threatening infection. These patients
can be treated with empiric antibiotic therapy according to likely pathogen and local resistance
patterns.
Complicated Skin and Soft Tissue Infections

Complicated SSTIs are associated with high risk for life- or limb-threatening infection. In these patients,
it is of paramount importance to initiate appropriate and adequate broad-spectrum initial empiric
antimicrobial therapy with coverage for MRSA and to consider the need for surgical intervention for
abscess drainage or debridement.
Patients with complicated SSTIs require hospitalization for treatment. Specific circumstances that
warrant hospitalization include the presence of tissue necrosis, sepsis, severe pain, altered mental status,
immunocompromised state, and organ failure (respiratory, renal, hepatic). SSTIs can lead to serious
potentially life-threatening local and systemic complications. The infections can progress rapidly and
early recognition and proper medical and surgical management is cornerstone of therapy.
12 In October 2013, the FDA changed the SSTI terminology and issued final guidance for the
treatment of acute bacterial skin and skin structure infections (ABSSSI).44 This guidance defined ABSSSI
as cellulitis, erysipelas, wound infection, and major cutaneous abscess. An ABSSSI is defined as a
bacterial infection of the skin with a lesion size area of at least 75 cm2 (lesion size measured by the area
of redness, edema, or induration). The minimum area of involvement of 75 cm2 is chosen to select
patients with acute bacterial skin infections for which a reliable control drug treatment effect can be
estimated for the conduct of new antimicrobial treatment trials. While the FDA generally requires two
phase III trials to support approval of drugs to treat ABSSSI, this guidance stated that a single phase III
study that is supported by additional independent evidence may suffice.
Patients with the following infection types can be enrolled in ABSSSI clinical trials:
Cellulitis/erysipelas: A diffuse skin infection characterized by spreading areas of redness, edema,
and/or induration
Wound infection: An infection characterized by purulent drainage from a wound with surrounding
redness, edema, and/or induration
Major cutaneous abscess: An infection characterized by a collection of pus within the dermis or
deeper that is accompanied by redness, edema, and/or induration
Unfortunately, this new guidance does not address less serious skin infections, such as impetigo and
minor cutaneous abscess, or more serious infections needing more complex treatment regimens, such as
infections resulting from animal or human bites, NSTIs, diabetic foot infection, decubitus ulcer infection,
myonecrosis, osteomyelitis, and ecthyma gangrenosum.
Early Diagnosis and Differentiation of Necrotizing versus Nonnecrotizing SSTI

Another classification for SSTIs that is commonly used is the differentiation of NSTIs from
nonnecrotizing infections. This differentiation is critical since necrotizing infections warrant prompt
aggressive surgical debridement. Clinical clues to the diagnosis of NSTIs are listed in Table 8-3. The
differentiation of necrotizing infections from nonnecrotizing infections is critical to achieving adequate
surgical therapy.45 A clear approach to these infections must allow rapid identification and treatment of
NSTIs because they are limb threatening and life threatening.
When clinical “hard clinical signs” (bullae, crepitus, gas on x-ray, hypotension with SBP <90 mm Hg,
or skin necrosis) of NSTI are present, establishing the diagnosis of NSTI is not difficult. However, hard
signs of NSTIs are often absent on presentation, thus potentially delaying diagnosis and surgical
intervention. Studies have documented that less than 50% of patients with a definitive diagnosis of NSTI
presented with “hard clinical signs” of NSTI.46 Admission of white blood cell count >15,400 × 109/L
and/or serum sodium <135 mEq/L was documented to help differentiate NSTI from non-NSTI and
aided in early diagnosis.47,48 The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score is
also helpful as a laboratory aid in distinguishing necrotizing from nonnecrotizing SSTIs (see NSTI
section below). In retrospective studies CT scan has been shown to have a negative predictive value of
100% and a positive predictive value of 76% in diagnosing NSTI.49
If there is any question regarding the possible diagnosis of an NSTI, it is imperative to proceed with
surgical intervention and to be certain that the surgical incision is continued down to the fascial and
muscle level to make a definitive diagnosis.
249
Early Initiation of Appropriate Empiric Broad-Spectrum Antimicrobial Therapy with Anti-
MRSA Coverage and Consideration of Risk Factors for Specific Pathogens
Antimicrobial therapy is an essential element in the management of severe SSTIs. As in all serious life-
threatening infections, it is important to initiate early and appropriate empiric antimicrobial therapy.
It is well established that prompt appropriate treatment of hospitalized infections reduces mortality.2
Similar findings were reported in studies of patients with ventilator-associated pneumonia 50 and
sepsis.51 A study of ICU patients found that the higher mortality rate associated with inappropriate
initial therapy is still observed when antibiotics are switched from an inappropriate to an appropriate
treatment.52
Furthermore, appropriate and timely antibiotic therapy improves treatment outcomes for SSTIs
caused by MRSA.53 In a study of 492 patients with community-onset MRSA SSTIs, 95% of episodes
treated with an active antibiotic within 48 hours were treated successfully, compared with an 87% rate
of successful treatment in patients who did not receive an active antibiotic. In logistic regression
analysis, failure to initiate active antimicrobial therapy within 48 hours of presentation was the only
independent predictor of treatment failure. Similarly, in a study of patients admitted to the hospital
with MRSA sterile-site infection, multivariate analysis found inappropriate antimicrobial treatment to be
an independent risk factor for hospital mortality.54
An empiric treatment algorithm for SSTI directed against community-associated MRSA (CA-MRSA) in
the emergency department that promotes both the use of antibiotics likely active against CA-MRSA and
early incision and drainage of abscesses was examined. Clinical failure occurred in only 3% of cases
treated according to the algorithm, compared with 62% of those not treated according to the algorithm.
Furthermore, among cases that underwent immediate incision and drainage, initial treatment with
antibiotics active in vitro against the MRSA isolate was associated with a decreased clinical failure rate
when compared to those treated with inactive antibiotics (0% vs. 67%).55
Empiric antibiotic therapy should be initiated in all patients with SSTIs. IV broad-spectrum
antimicrobial therapy should be initiated when an infection is severe or progresses rapidly, when there
are signs of systemic illness, when the patient has comorbidities or is immunosuppressed, for very old
or young patients, when an abscess cannot be completely drained, and when the infection does not
respond to incision and drainage.56
Timely initiation of antimicrobial therapy is also important in the treatment of severe SSTIs,
particularly if associated with septic shock. In a study of 2,731 adult patients with septic shock, a strong
relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted.4
Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of
documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in
antimicrobial administration over the ensuing 6 hours was associated with an average decrease in
survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital
mortality rate was significantly increased relative to receiving therapy within the first hour. In
multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and
therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest
predictor of outcome. Interestingly, only 50% of septic shock patients received effective antimicrobial
therapy within 6 hours of documented hypotension.
Necrotizing Soft Tissue Infections

NSTIs are aggressive soft tissue infections that cause widespread necrosis, and can include necrotizing
cellulitis, fasciitis, and myositis/myonecrosis.57,58 Establishing the diagnosis of NSTI can be the main
challenge in treating patients with NSTI, and knowledge of all available tools is key for early and
accurate diagnosis.59 There have been a number of recent advances in the definition, pathogenesis,
diagnostic criteria, and treatment of NSTIs.60,61
Patients with NSTIs require prompt aggressive surgical debridement, appropriate IV antibiotics, and
intensive support. Despite aggressive treatment, their mortality and morbidity rates remain high, with
some series reporting mortality rates of 25% to 35%.62 A high index of suspicion should be used in
conjunction with laboratory and imaging studies to establish the diagnosis as rapidly as possible.
Successful treatment requires early, aggressive surgical debridement of all necrotic tissue, appropriate
broad-spectrum systemic antibiotic therapy, and supportive care (fluid resuscitation, organ and critical
care support) to maintain oxygenation and tissue perfusion. Delayed definitive debridement remains the
single most important risk factor for death. Early operative debridement is the major determinant of
outcome in NSTIs.
250
A recent single-institution series of 166 patients documented that the overall mortality rate was 17%
and limb loss occurred in 26% of patients with extremity involvement.63 Independent predictors of
mortality included white blood cell count greater than 30,000 × 103/μL, creatinine level greater than 2
mg/dL, and heart disease at hospital admission. Independent predictors of limb loss included heart
disease and shock (systolic blood pressure <90 mm Hg) at hospital admission. Clostridial infection was
an independent predictor for both limb loss and mortality and was highly associated with IV drug use
and a high rate of leukocytosis on hospital admission.
A 30-day postoperative mortality risk calculator for NSTI was developed using the NSQIP which
identified seven independent variables that correlated with mortality: age older than 60 years,
functional status, requiring dialysis, American Society of Anesthesiologists (ASA) class 4 or higher,
emergent surgery, septic shock, and low platelet count. The receiver operating characteristic area was
0.85, which indicated a strong predictive model that can aid physicians in the decision-making
process.64
13 Early operative debridement is the major determinant of outcome in NSTIs. However, early
recognition of NSTIs is difficult clinically. A novel diagnostic scoring system for distinguishing NSTIs
from other severe soft tissue infections based on laboratory tests routinely performed for the evaluation
of severe SSTIs is called the LRINEC score (Table 8-11).65 The LRINEC score was initially developed in a
retrospective observational study including 145 patients with necrotizing fasciitis and 309 patients with
severe cellulitis or abscesses admitted to the 2 tertiary care hospitals. The cutoff value for the LRINEC
score was 6 points with a positive predictive value of 92% and negative predictive value of 96%. The
LRINEC score is a robust score capable of detecting clinically early cases of necrotizing fasciitis. The
variables used are routinely measured to assess severe soft tissue infections. Patients with a LRINEC
score of ≥6 should be carefully evaluated for the presence of necrotizing fasciitis.
Table 8-11 The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) Score
Since the initial development of the LRINEC score, a number of other cohort studies have validated its
utility in the diagnosis of NSTIs. A multicenter study in 229 patients with NSTIs from 2002 to 2005
reported an overall mortality rate of 16% and amputation rate of 26%. This study also documented that
a LRINEC score ≥6 was associated with a higher rate of both mortality and amputation.66
Diagnostic Imaging in Necrotizing Soft Tissue Infections

NSTIs necessitate prompt aggressive surgical debridement for satisfactory treatment in addition to
antimicrobial therapy. Because of the rapidly progressive and potentially fatal outcome of this
condition, if imaging cannot be performed expeditiously, delaying treatment is not justified. Plain film
findings may reveal extensive soft tissue gas. CT examination can reveal asymmetric thickening of deep
fascia in association with gas, and associated abscesses may also be present. MR imaging can also assist
in the diagnosis of NSTIs.67 MR imaging has been documented to effectively differentiate between
necrotizing and nonnecrotizing infections of the lower extremity and other areas of the body, but should
not delay prompt surgical intervention in NSTIs management.68–70
251
Microbiology of Necrotizing Soft Tissue Infections
Necrotizing fasciitis and myonecrosis are typically caused by infection with group A streptococcus
(GAS), Clostridium perfringens, or, most commonly, aerobic and anaerobic organisms as part of a
polymicrobial infection that may include S. aureus. In case series, CA-MRSA has recently been described
as a predominantly monomicrobial cause of necrotizing fasciitis.71,72 A retrospective review of patients
presenting with necrotizing fasciitis indicated that MRSA was the most common pathogen, accounting
for one-third of the organisms isolated.73
NSTIs have been classified into two types, either polymicrobial (type I) or monomicrobial (type II).
Polymicrobial infections are more common, due to both aerobic and anaerobic organisms, and
commonly occur in the trunk and perineum. NSTIs that are monomicrobial in origin commonly occur in
the limbs and are typically caused by infection with GAS, C. perfringens, or S. aureus. NSTIs are
categorized into these two specific types based on the microbiologic etiology of the infection, and this
classification does impact on the specific antimicrobial agents required for treatment of these NSTIs.
Increasingly, MRSA has been identified as the causative microbe in NSTIs, but a separate category for
this NSTI does not currently exist.74–78 Given this finding, anti-MRSA empiric antimicrobial therapy
should be initiated in all patients with NSTIs and pathogen-directed antimicrobial therapy considered
once tissue culture results are available.
Uncommon microbiologic causes of NSTIs and primary sepsis include Vibrio and Aeromonas species,
virulent gram-negative bacteria, and members of the Vibrionaceae family that thrive in aquatic
environments.79 These NSTIs are likely to occur in patients with hepatic disease, diabetes, and
immunocompromised conditions.80 These organisms are found in warm sea waters and are often present
in raw oysters, shellfish, and other seafood. The diagnosis of vibrio NSTIs should be suspected when a
patient has the appropriate clinical findings and a history of contact with seawater or raw seafood.81
Early fasciotomy and culture-directed antimicrobial therapy should be aggressively performed in those
patients with hypotensive shock, leukopenia, severe hypoalbuminemia, and underlying chronic illness,
especially a combination of hepatic dysfunction and diabetes mellitus. The rates of amputation and
mortality are very high in these patients, and early definitive management is of paramount
importance.82–84 A study of 125 patients identified that a LRINEC score of 2 or greater and the presence
of hemorrhagic bullous/blistering lesions in patients with Vibrio vulnificus SSTI are associated with an
12-fold increased risk for the presence of NSTI and necrotizing fasciitis.85
Pyomyositis
Myositis is a rare infection that may lead to serious and potentially life-threatening local and systemic
complications.86 The infection can progress rapidly, and early recognition and proper medical and
surgical management is therefore the cornerstone of therapy. With the increasing prevalence of
community-associated MRSA as a pathogen in severe SSTIs, pyomyositis is more common than in past
years.87,88 Myositis often occurs in muscle sites that have been compromised by injury, ischemia,
malignancy, or surgery. The predominant pathogens are S. aureus, GAS, gram-negative aerobic and
facultative bacilli, and the indigenous aerobic and anaerobic cutaneous and mucous membranes local
microflora.
CT scan imaging is a rapid and sensitive diagnostic test and commonly demonstrates diffuse
enlargement of the involved muscle and may demonstrate the presence of fluid or gas collections within
the muscle suggesting the presence of abscesses. MRI is more sensitive in showing early inflammatory
changes prior to development of abscesses in myositis.89 Emergency surgical exploration is warranted in
order to define the nature of the infective process which is accomplished by direct examination of the
involved muscles. Surgical intervention is required to perform appropriate abscess drainage and
debridement and also to evaluate for necrotizing myositis. Fasciotomies and extremity amputation are
sometimes necessary.
SURGICAL SITE INFECTIONS

Epidemiology
SSI is the leading nosocomial infection among surgical patients and the second most common
nosocomial infection overall. In the United States, greater than 40 million inpatient and outpatient
surgical procedures are performed each year and 2% to 5% are complicated by SSIs. SSIs result in
increased length of stay (7 days) and additional cost ($400 to $2,600 per infection; total $130 to $845
252
million per year).90–93 Among the four healthcare-associated infections (pneumonia, SSI, urinary tract
infection, and bloodstream infection), SSIs are the second most common healthcare-associated infection,
accounting for 17% of all healthcare-associated infections among hospitalized patients. A similar rate
was obtained from the National Healthcare Safety Network (NHSN) hospitals reporting data in 2006–
2008 (15,862 SSI following 830,748 operative procedures, with an overall rate of nearly 2%).94
Definitions
SSIs are defined in three specific categories by the Centers for Disease Control and Prevention (CDC),
including superficial incisional SSI, deep incisional SSI, and organ/space SSI (Fig. 8-4, Table 8-12),
dependent on the depth of the infection at the surgical incision site. In addition, the SSI must occur
within 30 days after the operative procedure if no implant is left in place or within 1 year if implant is
in place and the infection appears to be related to the operative procedure. More specific criteria
regarding these definitions are available in the CDC Guideline for Prevention of Surgical Site
Infection.95
Risk Factors for Surgical Site Infection

SSI risk is strongly associated with wound classification, with low risk for SSI in clean and clean-
contaminated wound classes, and high risk for SSI in contaminated and dirty–infected wound classes.
Three independent variables have been shown to be associated with SSI risk, initially developed by the
National Nosocomial Infections Surveillance System (NNIS). The NHSN was established in 2005 to
integrate and supersede three legacy surveillance systems at the CDC: the NNIS system, the Dialysis
Surveillance network (DSN), and the National Surveillance System for Healthcare Workers (NaSH).
Similar to the NNIS system, NHSN facilities voluntarily report their healthcare-associated infection
surveillance data for aggregation into a single national database.
The NHSN SSI Risk Index includes an ASA score greater than 2, classification of wound as
contaminated or dirty, and prolonged duration of operation.96,97 Although the risk of infection increases
within the wound classification, it has been shown to be also dependent within each wound class on the
NNIS classification.
Table 8-12 CDC/NHSN Classification of Surgical Site Infections (SSIs)
253
Figure 8-4. Surgical site infection (SSI) definitions by CDC.
Cross-section of the abdominal depicted.
Superficial incisional SSI involves only the skin and subcutaneous tissue layer of the incision
Deep incisional SSI involves deep soft tissues (e.g., fascia and muscle layers) of the incision
Organ/space SSI involves any part of the body, excluding the skin incision, fascia or muscle layers, that is opened or manipulated
during the operative procedure (e.g., intra-abdominal abscess or thoracic empyema)
Basic SSI Risk Index

The index used in NHSN assigns surgical patients into categories based on the presence of three major
risk factors:
1. Operation lasting more than the duration cut point hours, where the duration cut point is the
approximate 75th percentile of the duration of surgery in minutes for the operative procedure.
2. Contaminated (class 3) or dirty/infected (class 4) wound class.
3. ASA classification of 3, 4, or 5.
The patient’s SSI risk category is simply the number of these factors present at the time of the
operation.
The laparoscopic surgical approach is associated with decreased SSI incidence, and a modified risk
index (category 1 when procedure was performed with a laparoscope) has been created to address this
approach.
Additional patient-specific risk factors for SSI have also been identified that are not included in this
risk index, including the presence of anemia, blood transfusion intraoperatively, and colonization with
resistant pathogens.97,98 This SSI Risk Index warrants reevaluation for the future, particularly with
regard to resistant pathogens and other patient-specific risk factors that are not modifiable prior to
surgical intervention. It is of paramount importance to include an SSI risk assessment in all future
clinical trials where SSI is a primary outcome measure.
Surgical Site Infection Prevention

Preventive measures for SSI include antimicrobial prophylaxis, sterilization methods, proper ventilation
of operating rooms, use of barriers, no shaving, clipping if hair removal is required, proper surgical skin
preparation and surgical techniques, maintenance of normothermia, glycemic control, and the provision
of supplemental oxygen.93 The National Surgical Infection Prevention (SIP) project was initiated as the
first component of the Surgical Care Improvement Project (SCIP). Initiated in 2003, the SCIP
partnership sought to substantially reduce surgical mortality and morbidity through collaborative
efforts.
Despite evidence of effectiveness of preoperative antimicrobials for SSI prevention and the
publication of guidelines for antimicrobial prophylaxis, it was recognized that use was often suboptimal.
As part of the SIP initiative, three SIP performance measures were developed:
SIP-1: Antibiotic timing: Proportion of patients in whom IV antimicrobial prophylaxis is initiated
within 1 hour before incision
SIP-2: Antibiotic selection: Proportion of patients are given prophylactic antimicrobials consistent with
published guidelines
254
SIP-3: Antibiotic discontinuation within 24 hours: Proportion of patients whose antimicrobial
prophylaxis is discontinued within 24 hours after surgery
Numerous studies document that antimicrobial prophylaxis for SSI is most effective when provided 30
to 60 minutes prior to the initial surgical incision, allowing adequate blood and tissue concentrations at
the time of skin incision. Risk of SSI increases when antimicrobial prophylaxis is given too early (more
than 2 hours prior to skin incision) or too late (after skin incision). In a recent study of 4,472 patients,
SSI risk increased incrementally as the interval of time between antibiotic infusion and the surgical
incision increased. These data from a large multicenter collaborative study confirmed lower SSI risk
when surgical antimicrobial prophylaxis with cephalosporins and other antibiotics with short infusion
times were given within 30 minutes prior to surgical incision.99
In addition, the correct antimicrobial must be administered to cover the potential causative
pathogens, dependent on the surgical procedure performed. The SCIP pocket card (Table 8-13) provides
a list of the recommended preoperative antimicrobials for specific surgical procedures. The recent
publication of the “Clinical practice guidelines for antimicrobial prophylaxis in surgery” by the
American Society of Health-System Pharmacists, Infectious Diseases Society of America, Surgical
Infection Society, and Society for Healthcare Epidemiology of America provide evidence-based national
recommendations.100
The first report of the National SIP Project baseline results from a systematic random sample of
34,133 medicare inpatients undergoing surgery in US hospitals in 2001 documented that only 55.7% of
patients received a dose of parenteral antimicrobial prophylaxis within 1 hour before surgical incision.
Antimicrobial agents consistent with published guidelines were administered to 92.6% of patients and
antimicrobial prophylaxis was discontinued within 24 hours of surgery end time for only 40.7% of
patients. Interestingly, only 28% of these surgical patients had compliance with all three of these
performance measures.101
Table 8-13 Recommended Preoperative Antimicrobials for Specific Surgical

Procedures
We have truly made remarkable progress in the United States with appropriate perioperative
antimicrobial prophylaxis since that initial published report. Compliance with SIP-1 measure (antibiotics
within 60 minutes prior to incision) increased from 55.7% to 91.6%; compliance with SIP-2 measure
(guideline antibiotics) increased from 92.6% to 95.8%; and compliance with SIP-3 (antibiotics
discontinued) increased from 40.7% to 87.7%.
Additional Strategies for Surgical Site Infection Prevention

Surgical Hand Antisepsis
Surgical hand antisepsis, to destroy bacteria, is routinely carried out before undertaking invasive
procedures. A recent review of 10 trials confirmed that alcohol rubs used in preparation for surgery by
the surgical team are as effective as aqueous scrubbing in SSI prevention. There is no evidence to
255
suggest that any particular alcohol rub is better than another. Evidence from four studies suggests that
chlorhexidine gluconate–based aqueous scrubs are more effective than povidone iodine–based aqueous
scrubs in terms of the numbers of bacterial colony–forming units on the hands.102
Chlorhexidine as Skin Surgical Site Preparation

Preoperative skin antisepsis of the surgical site is performed to reduce the risk of SSI by removal of skin
microorganisms. A review of six randomized controlled trials identified significant heterogeneity and
the trial results could not be pooled. There was no evidence of a benefit in four trials associated with
the use of iodophor-impregnated drapes.103 More recent studies have documented that chlorhexidine
provided superior skin decontamination compared to povidone-iodine.104–107 The most recent Cochrane
systematic review found evidence that preoperative skin preparation with 0.5% chlorhexidine in alcohol
was associated with lower SSI rates following clean surgery than alcohol-based povidone-iodine
paint.108
Appropriate Hair Removal

The preparation of the surgical site has traditionally included the routine removal of body hair,
however, some studies have suggested that this is deleterious. A Cochrane systematic review of 11
randomized clinical trials, and 3 trials (n = 3,193) comparing shaving with clipping, found that there
were statistically more SSIs with shaving than clipping. If it is necessary to remove hair, clipping results
in fewer SSIs than shaving using a razor.109
Normothermia Maintenance During Surgery

Perioperative hypothermia is common and adversely affects clinical outcomes. The primary beneficial
effects of warming are mediated through increased blood flow and oxygen tension at the tissue level.
Hypothermia may facilitate SSI in two ways. First, sufficient intraoperative hypothermia triggers
thermoregulatory vasoconstriction. Second, considerable evidence indicates that mild core hypothermia
directly impairs immune function including T-cell–mediated antibody production and nonspecific
oxidative bacterial killing by neutrophils. Randomized controlled trials have documented that
perioperative warming is associated with a significant reduction in SSI and this simple SSI preventive
strategy should be implemented in all surgical patients.110–112
Normoglycemia Maintenance During Surgery

Perioperative hyperglycemia has been associated with increased SSIs and previous recommendations
have been to treat glucose levels above 200 mg/dL. Recent studies have questioned the optimal
glycemic control regimen to prevent SSIs. A recent Cochrane Database systematic review included five
randomized controlled clinical trials with a total of 773 patients randomized. Due to heterogeneity in
patient populations, perioperative period, glycemic target, route of insulin administration, and
definitions of outcome measures, combination of the results of the five trials into a meta-analysis was
not appropriate. The authors concluded that there is insufficient evidence to support strict glycemic
control in the intra- and postoperative period among surgical patients for the prevention of SSIs.113 A
Cochrane review of 12 trials that randomized diabetic patients to intensive or conventional glycemic
control perioperatively concluded that no significant differences were identified in patients with
diabetes mellitus. However, posthoc analysis indicated that intensive glycemic control was associated
with greater incidence of hypoglycemia episodes.114
There are no randomized trials evaluating immediate preoperative glycemic control in any setting or
intra/postoperative glycemic control in non-ICU patients. High-quality evidence for strict glycemic
control in the intra- and/or postoperative period among surgical ICU patients, cardiac and noncardiac,
to reduce SSIs, independent of other potential benefits, is also lacking. Further large, adequately
powered, well-designed randomized trials are necessary to identify the ideal target for perioperative
glycemic control in patients at high risk for SSIs. Future trials should report all nosocomial infections as
well as SSIs. Given the heterogeneity seen in the included trials, it would appear that trials should be
targeted at very specific populations and attempts to draw broader conclusions should not be made. At
present, we should strive at least to maintain blood glucose <200 mg/dL in the perioperative period in
our surgical patients.
Supplemental Oxygen in Perioperative Period

Several randomized controlled trials have been conducted to assess the benefit of perioperative
supplemental oxygen in SSI reduction, yet meta-analyses have arrived at different conclusions.115–117 On
256
careful review, a number of problems with the conduct of these trials are noted: (1) SSI definition was
not consistent with CDC definitions; (2) the interval for assessment of SSI was variable, ranging from 15
to 30 days; (3) SSI was captured retrospectively in some studies and was not always a primary outcome
measure; (4) no assessment of the patient’s individual risk factors for SSI was performed; (5) no control
of perioperative antibiotic prophylaxis timing or selection was performed; and (6) there was variable
provision of high FiO2 supplemental oxygen in each of the studies.118
The first institutional priority should be to universally implement all the evidence-based practices that
reduce SSIs. The “SSI Bundle” from the Institute for Healthcare Improvement includes (1) appropriate
use of antibiotics, (2) appropriate hair removal, (3) perioperative glucose control, and (4) perioperative
normothermia.119 The additional provision of increased inspired oxygen concentrations should be
considered as an additional quality improvement measure, particularly in institutions with high SSI
rates. A collaborative of 44 hospitals implemented the SSI preventive strategies discussed above and
documented a significant reduction in the SSI rate, from 2.3% to 1.7%, representing a 27% reduction
from the first to the last 3 months of the 1-year project.120 Finally, prospective SSI surveillance,
including postdischarge surveillance, should be instituted to obtain accurate information regarding
institutional SSI rates.121
Surgical Site Infection and Colorectal Surgery

Surgical care bundles have been documented to be effective in reducing SSIs in patients undergoing
colorectal surgery and therefore should be implemented.122 Surgeons have held a long-standing belief
that mechanical bowel preparation is an efficient strategy to reduce SSI and anastomotic leak rates
following elective colorectal surgery. Recent systematic reviews have found that there is no statistically
significant evidence that patients benefit from mechanical bowel preparation either in SSI or
anastomotic leak rates.123 In contrast, the use of nonabsorbable enteral antimicrobials covering aerobic
and anaerobic colonic bacteria, in addition to IV preoperative antibiotics, is associated with a significant
reduction in SSI by at least 75%.124–126
Treatment of Surgical Site Infection

Once superficial or deep incisional SSI is diagnosed, “pathogen identification” is of paramount
importance. In years past, the surgical incision was opened and dressing changes were initiated with no
culture of the surgical site obtained. In today’s era of multidrug-resistant pathogens, a Gram stain and
culture of the surgical site should always be obtained in order to determine the optimal antimicrobial
therapy that is required for SSI treatment.
SSI treatment includes four strategies for successful treatment: (1) early empiric antimicrobial
therapy; (2) decision-making regarding whether the surgical site should be opened; (3) pathogen
identification; and (4) deescalation of antimicrobial therapy once culture results are available.
For organ/space SSI, “source control” and “pathogen identification” are both high priorities in order
to achieve successful treatment. In the case of intra-abdominal abscess, source control can be provided
by either interventional radiology percutaneous drainage or open surgical drainage of the abscess.
Abscess fluid should be sent for Gram stain and culture, and empiric antimicrobial treatment should be
deescalated once culture results are available.
Current Challenges in Surgical Site Infection

There are a number of growing challenges in SSI, including resistant pathogens, our increasingly elderly
population, more patients with chronic diseases or immunocompromised states undergoing surgery, and
increasing patients undergoing surgery for solid organ transplantation and placement of prosthetic
devices. MRSA was reported to be the most common cause of SSI in vascular surgery patients (n = 772
over a 2-year period) in 2004.127,128 MRSA has emerged as the leading cause of postoperative infection
in vascular surgery patients, and is associated with substantial morbidity, increased hospital length of
stay, and higher incidences of amputation and graft removal.
Comparison of the causative pathogens for SSI in US hospitals documents that S. aureus increased
from 22.5% (1986–2003) to 30% (2006–2007), with MRSA now the leading causative pathogen,
comprising 49.2% of all isolates.128,129 In a study of 8,302 patients readmitted to US hospitals with
culture-confirmed SSI from 2003 to 2007, it was noted that the proportion of infections due to MRSA
significantly increased from 16.1% to 20.6% and was associated with higher mortality rates, longer
length of stay, and higher hospital costs.130 Based on this important finding, some have strongly
advocated for active screening for nasal carriage of MRSA prior to elective surgery with modification of
257
antimicrobials for SSI prevention based on those results.131–133 Eradication of MRSA before surgery
appears to lower SSI rates due to MRSA and is recommended.134,135 In contrast, a prospective
interventional cohort study that employed a universal rapid MRSA admission screening strategy among
21,754 surgical patients at a Swiss teaching hospital reported that nosocomial MRSA infection, including
SSI, did not decrease, but relatively low rates of MRSA infection were present at the start of this
study.136
An “MRSA bundle” has been developed including five components:
1. MRSA nasal screening of patients upon admission, transfer, and discharge using PCR;
2. contact isolation of positive patients;
3. standardized hand hygiene;
4. cultural transformation campaign with staff and leadership engagement through positive deviance;
and
5. ongoing monitoring of process and outcome measures.
Implementation of the MRSA bundle was associated with a significant decrease in MRSA transmission
from 5.8 to 3.0 per 1,000 bed-days, significant reduction in MRSA nosocomial infections (2.0 to 1.0 per
1,000 bed-days), and a significant decrease in overall SSIs, with a 65% reduction in orthopedic MRSA
SSIs and a 1% decrease in cardiac MRSA SSIs.137
The advent of CA-MRSA138,139 has also significantly impacted SSI. Recent studies document that CA-
MRSA is replacing traditional healthcare-associated or nosocomial MRSA strains in SSI among
inpatients.140 A report from a large community hospital in St. Louis, MO, examined the rates of SSI due
to S. aureus in a total of 122,040 surgical procedures in an earlier period (2003–2006) versus later
period (2006–2007). MRSA was identified as the SSI pathogen in 40% of all inpatients in both time
periods. Interestingly, the percentage of clindamycin-susceptible MRSA (distinguishing CA-MRSA) as an
SSI causative pathogen for inpatients rose from 9% in the early period to 19% in the later period. This
increase in the rate of CA-MRSA SSI was observed only among inpatients, not among ambulatory
patients. Similarly, CA-MRSA has emerged as a leading cause of healthcare-associated infections among
patients with prosthetic joint SSIs.141
The use of perioperative intranasal mupirocin for SSI prevention, particularly in patients with MRSA
nasal colonization, remains controversial. Reviews of multiple clinical trials documented that no
reduction in SSI was seen in general surgery or cardiac surgery patients; however, in nongeneral
surgery patients the use of mupirocin was associated with a reduction in SSI.134,135,142
References
1. Napolitano LM. Perspectives in surgical infections: what does the future hold? Surg Infect (Larchmt)
2010;11(2):111–123.
2. Kollef MH, Sherman G, Ward S, et al. Inadequate antimicrobial treatment of infections: a risk factor
for hospital mortality among critically ill patients. Chest 1999;115:462–474.
3. Marquet K, Liesenborgs A, Bergs J, et al. Incidence and outcome of inappropriate in-hospital
empiric antibiotics for severe infection: a systematic review and meta-analysis. Crit Care
2015;19:63.
4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective
antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med
2006;34:1589–1596.
5. Marshall JC. Principles of source control in the early management of sepsis. Curr Infect Dis Rep
2010;12(5):345–353.
6. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-
abdominal infection in adults and children: guidelines by the Surgical Infection Society and the
Infectious Diseases Society of America. Surg Infect (Larchmt) 2010;11(1):79–109.
7. Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-
abdominal infection in adults and children: guidelines by the Surgical Infection Society and the
Infectious Diseases Society of America. Clin Infect Dis 2010;50(2):133–164.
8. Sawyer RG, Claridge JA, Nathens AB, et al. Trial of short-course antimicrobial therapy for
intraabdominal infection. N Engl J Med 2015; 372(21):1996–2005.
258
9. Wray CJ, Kao LS, Millas SG, et al. Acute appendicitis: controversies in diagnosis and management.
Curr Probl Surg 2013;50(2):54–86.
10. Liu K, Fogg L. Use of antibiotics alone for treatment of uncomplicated acute appendicitis: a
systematic review and meta-analysis. Surgery 2011; 150(4):673–683.
11. Wilms IM, de Hoog DE, de Visser DC, et al. Appendectomy versus antibiotic treatment for acute
appendicitis. Cochrane Database Syst Rev 2011;(11):CD008359.
12. Ansaloni L, Catena F, Coccolini F, et al. Surgery versus conservative antibiotic treatment in acute
appendicitis: a systematic review and meta-analysis of randomized controlled trials. Dig Surg
2011;28(3):210–221.
13. Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for treatment of
uncomplicated acute appendicitis: the APPAC randomized clinical trial. JAMA 2015;313(23):2340–
2348.
14. Livingston E, Vons C. Treating appendicitis without surgery. JAMA 2015;313(23):2327–2328.
15. Kao LS, Boone D, Mason RJ; Evidence-Based Reviews in Surgery Group. Antibiotics vs
appendectomy for uncomplicated acute appendicitis. J Am Coll Surg 2013;216(3):501–505.
16. Ingraham AM, Cohen ME, Bilimoria KY, et al. Comparison of outcomes after laparoscopic versus
open appendectomy for acute appendicitis at 222 ACS NSQIP hospitals. Surgery 2010;148:625–635;
discussion 635–637.
17. Sauerland S, Jaschinski T, Neugebauer EA. Laparoscopic versus open surgery for suspected
appendicitis. Cochrane Database Syst Rev 2010;10:CD001546.
18. Drake FT, Mottey NE, Farrokhi ET, et al. Time to appendectomy and risk of perforation in acute
appendicitis. JAMA Surg 2014;149(8):837–844.
19. Simillis C, Symeonides P, Shorthouse AJ, et al. A meta-analysis comparing conservative treatment
versus acute appendectomy for complicated appendicitis (abscess or phlegmon). Surgery
2010;147:818–829.
20. Andersson RE, Petzold MG. Nonsurgical treatment of appendiceal abscess or phlegmon: a
systematic review and meta-analysis. Ann Surg 2007;246(5):741–748.
21. Kaminski A, Liu IL, Applebaum H, et al. Routine interval appendectomy is not justified after initial
nonoperative treatment of acute appendicitis. Arch Surg 2005;140:897–901.
22. Ein SH, Langer JC, Daneman A. Nonoperative management of pediatric ruptured appendix with
inflammatory mass or abscess: presence of an appendicolith predicts recurrent appendicitis. J
PediatrSurg 2005;40:1612–1615.
23. Demehri FR, Alam HB. Evidence-based management of common gallstone-related emergencies. J
Intensive Care Med 2016;31(1):3–13.
24. Kiewiet JJ, Leeuwenburgh MM, Bipat S, et al. A systematic review and meta-analysis of diagnostic
performance of imaging in acute cholecystitis. Radiology 2012;264(3):708–720.
25. Broderick-Villa G, Burchette RJ, Collins JC, et al. Hospitalization for acute diverticulitis does not
mandate routine elective colectomy. Arch Surg 2005;140(6):576–581.
26. Morris AM, Regenbogen SE, Hardiman KM, et al. Sigmoid diverticulitis: a systematic review. JAMA
2014;311(3):287–297.
27. Regenbogen SE, Hardiman KM, Hendren S, et al. Surgery for diverticulitis in the 21st century: a
systematic review. JAMA Surg 2014;149(3):292–303.
28. Hinchey EJ, Schaal PG, Richards GK. Treatment of perforated diverticular disease of the colon. Adv
Surg 1978;12:85–109.
29. Cirocchi R, Trastulli S, Desiderio J, et al. Treatment of Hinchey stage III–IV diverticulitis: a
systematic review and meta-analysis. Int J Colorectal Dis 2013;28(4):447–457.
30. To KB, Napolitano LM. Clostridium difficile infection: update on diagnosis, epidemiology, and
treatment strategies. Surg Infect (Larchmt) 2014;15(5):490–502.
31. Bagdasarian N, Rao K, Malani PN. Diagnosis and treatment of Clostridium difficile in adults: a
systematic review. JAMA 2015;313(4):398–408.
32. Cohen SH, Gerding DN, Johnson S, et al.; Society for Healthcare Epidemiology of America;
Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection
in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the
infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431–455.
259
33. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with
Clostridium difficile in Europe, Canada, and the USA: a double-blind, noninferiority, randomised
controlled trial. Lancet Infect Dis 2012;12:281–289.
34. Neal MD, Alverdy JC, Hall DE, et al. Diverting loop ileostomy and colonic lavage: an alternative to
total abdominal colectomy for the treatment of severe, complicated Clostridium difficile associated
disease. Ann Surg 2011;254:423–427; discussion 423–429.
35. Rosenberg A, Steensma EA, Napolitano LM. Necrotizing pancreatitis: new definitions and a new era
in surgical management. Surg Infect (Larchmt) 2015;16(1):1–13.
36. De Waele JJ, Rello J, Anzueto A, et al. Infections and use of antibiotics in patients admitted for
severe acute pancreatitis: data from the EPIC II study. Surg Infect 2014;15:394–398.
37. van Santvoort HC, Besselink MG, Bakker OJ, et al. A stepup approach or open necrosectomy for
necrotizing pancreatitis. N Engl J Med 2010;362:1491–1502.
38. Warshaw AL. Improving the treatment of necrotizing pancreatitis—a step up. N Engl J Med
2010;362:1535–1537.
39. van Brunschot S, Fockens P, Bakker OJ, et al. Endoscopic transluminal necrosectomy in necrotising
pancreatitis: a systematic review. Surg Endosc 2014;28:1425–1438.
40. Napolitano LM. Introduction: the diagnosis and treatment of skin and soft tissue infections (SSTIs).
Surg Infect (Larchmt) 2008;9(suppl 1):s1.
41. DiNubile MJ, Lipsky BA. Complicated infections of skin and skin structures: when the infection is
more than skin deep. J Antimicrob Chemother 2004;53(suppl 2):ii37–ii50.
42. Vinh DC, Embil JM. Severe skin and soft tissue infections and associated critical illness. Curr Infect
Dis Rep 2007;9(5):415–421.
43. Napolitano LM. Severe soft tissue infections. Infect Dis Clin North Am 2009;23(3):571–591.
44.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071185.pd
45. May AK. Skin and soft tissue infections. Surg Clin North Am 2009;89(2):403–420.
46. Chan T, Yaghoubian A, Rosing D, et al. Low sensitivity of physical examination findings in
necrotizing soft tissue infection is improved with laboratory values: a prospective study. Am J Surg
2008;196(6):926–930; discussion 930.
47. Wall DB, deVirgilio C, Black S, et al. Objective criteria may assist in distinguishing necrotizing
fasciitis from non-necrotizing soft tissue infection. Am J Surg 2000;179(11):17–21.
48. Wall DB, Klein SR, Black S, et al. A simple model to help distinguish necrotizing fasciitis from non-
necrotizing soft tissue infections. J Am Coll Surg 2000;191(3):227–231.
49. Zacharias N, Velmahos GC, Salama A, et al. Diagnosis of necrotizing soft tissue infections by
computed tomography. Arch Surg 2010;145(5):452–455.
50. Iregui M, Ward S, Sherman G, et al. Clinical importance of delays in the initiation of appropriate
antibiotic treatment for ventilator-associated pneumonia. Chest 2002;122:262–268.
51. Garnacho-Montero J. Impact of adequate empirical antibiotic therapy on the outcome of patients
admitted to the intensive care unit with sepsis. Crit Care Med 2003;31:2742–2751.
52. Alvarez-Lerma F; the ICU-Acquired Pneumonia Study Group. Modification of empiric antibiotic
treatment in patients with pneumonia acquired in the intensive care unit. Intensive Care Med
1996;22:387–394.
53. Ruhe JJ, Smith N, Bradsher RW, et al. Community-onset methicillin-resistant Staphylococcus aureus
skin and soft-tissue infections: impact of antimicrobial therapy on outcome. Clin Infect Dis
2007;44:777–784.
54. Schramm GE, Johnson JA, Doherty JA, et al. Methicillin-resistant Staphylococcus aureus sterile-site
infection: the importance of appropriate initial antimicrobial treatment. Crit Care Med
2006;34(8):2069–2074.
55. Chuck EA, Frazee BW, Lambert L, et al. The benefit of empiric treatment for MRSA. J Emerg Med
2010;38(5):567–571.
56. Gorwitz RJ, Jernigan DB, Powers JH, et al. Participants in the CDC-Convened Experts’ Meeting on
Management of MRSA in the Community. Strategies for clinical management of MRSA in the
community: summary of an experts’ meeting convened by the Centers for Disease Control and
Prevention. 2006. Available at: http://www.cdc.gov/mrsa/pdf/mrsa-strategies-expmtgsummary-
260
2006.pdf
57. Sarkar B, Napolitano LM. Necrotizing soft tissue infections. Minerva Chir 2010;65(3):347–362.
58. Sarani B, Strong M, Pascual J, et al. Necrotizing fasciitis: current concepts and review of the
literature. J Am Coll Surg 2009;208(2):279–288.
59. Anaya DA, Dellinger EP. Necrotizing soft-tissue infection: diagnosis and management. Clin Infect Dis
2007;44(5):705–710.
60. Cainzos M, Gonzalez-Rodriguez FJ. Necrotizing soft tissue infections. Curr Opin Crit Care
2007;13(4):433–439.
61. Yilmazlar T, Ozturk E, Alsoy A, et al. Necrotizing soft tissue infections: APACHE II score,
dissemination, and survival. World J Surg 2007;31(9):1858–1862.
62. Cuschieri J. Necrotizing soft tissue infection. Surg Infect (Larchmt) 2008; 9(6):559–562.
63. Anaya DA, McMahon K, Nathens AB, et al. Predictors of mortality and limb loss in necrotizing soft
tissue infections. Arch Surg 2005;140:151–157.
64. Faraklas I, Stoddard GJ, Neumayer LA, et al. Development and validation of a necrotizing soft-
tissue infection mortality risk calculator using NSQIP. J Am Coll Surg 2013;217(1):153–160.e3;
65. Wong CH, Khin LW, Heng KS, et al. The LRINEC (Laboratory Risk Indicator for Necrotizing
Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections. Crit
Care Med 2004;32(7):1535–1541.
66. Su YC, Chen HW, Hong YC, et al. Laboratory risk indicator for necrotizing fasciitis score and the
outcomes. ANZ J Surg 2008;78(11):968–972.
67. Struk DW, Munk PL, Lee MJ, et al. Imaging of soft tissue infections. Radiol Clin North Am
2001;39(2):277–303.
68. Brothers TE, Tagge DU, Stutley JE, et al. Magnetic resonance imaging differentiates between
necrotizing and non-necrotizing fasciitis of the lower extremity. J Am Coll Surg 1998;187:416–421.
69. Malghem J, Lecouvet FE, Omoumi P, et al. Necrotizing fasciitis: contribution and limitations of
diagnostic imaging. Joint Bone Spine 2013;80(2):146–154.
70. Kim KT, Kim YJ, Won Lee J, et al. Can necrotizing infectious fasciitis be differentiated from
nonnecrotizing infectious fasciitis with MR imaging? Radiology 2011;259(3):816–824.
71. Wong CH, Chang HC, Pasupathy S, et al. Necrotizing fasciitis: clinical presentation, microbiology,
and determinants of mortality. J Bone Joint Surg Am 2003;85(8):1454–1460.
72. McHenry CR, Piotrowski JJ, Petrinic D, et al. Determinants of mortality for necrotizing soft-tissue
infections. Ann Surg 1995;221(5):558–565.
73. Elhabash S, Lee L, Farrow B, et al. Characteristics and microbiology of patients presenting with
necrotizing fasciitis. Presented at the Association of VA Surgeons 31st Annual Meeting. Little Rock:
Arkansas; May 10–12, 2007.
74. Lee TC, Carrick MM, Scott BG, et al. Incidence and clinical characteristics of MRSA necrotizing
fasciitis in a large urban hospital. Am J Surg 2007; 194(6):809–812.
75. Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-
associated MRSA in Los Angeles. N Engl J Med 2005;352(14):1445–1453.
76. Young LM, Price CS. Community-acquired MRSA emerging as an important cause of necrotizing
fasciitis. Surg Infect (Larchmt) 2008;9(4):469–474.
77. Olsen RJ, Burns KM, Chen L, et al. Severe necrotizing fasciitis in a human immunodeficiency virus-
positive patient caused by MRSA. J Clin Microbiol 2008;46(3):1144–1147.
78. Dehority W, Wang E, Vernon PS, et al. Community-associated MRSA necrotizing fasciitis in a
neonate. Pediatr Infect Dis J 2006;25(11):1080–1081.
79. Tsai YH, Hsu RW, Huang TJ, et al. Necrotizing soft tissue infections and sepsis caused by Vibrio
vulnificus compared with those caused by Aeromonas species. J Bone Joint Surg Am
2007;89(3):631–636.
80. Tsai YH, Hsu RW, Huang KC, et al. Systemic Vibrio infection presenting as necrotizing fasciitis and
sepsis. A series of 13 cases. J Bone Joint Surg Am 2004;86(11):2497–2502.
81. Minnaganti VR, Patel PJ, Iancu D, et al. Necrotizing fasciitis caused by Aeromonas hydrophila.
Heart Lung 2000;29(4):306–368.
261
82. Vibrio vulnificus infection: diagnosis and treatment. Am Fam Physician 2007;76(4):539–544.
83. Tsai YH, Huang TJ, Hsu RW, et al. Necrotizing soft tissue infections and primary sepsis caused by
Vibrio vulnificus and Vibrio cholerae non-O1. J Trauma 2009;66(3):899–905.
84. Kuo YL, Shieh SJ, Chiu HY, et al. Necrotizing fasciitis caused by Vibrio vulnificus: epidemiology,
clinical findings, treatment and prevention. Eur J Clin Microbiol Infect Dis 2007;26(11):785–792.
85. Chao WN, Tsai SJ, Tsai CF, et al. The Laboratory Risk Indicator for Necrotizing Fasciitis score for
discernment of necrotizing fasciitis originated from Vibrio vulnificus infections. J Trauma Acute
Care Surg 2012; 73(6):1576–1582.
86. Brook I. Microbiology and management of myositis. Int Orthop 2004;28(5):257–260.
87. Ruiz ME, Yohannes S, Wladyka CG. Pyomyositis caused by methicillin-resistant Staphylococcus
aureus. N Engl J Med 2005;352(14):1488–1489.
88. Woodward JF, Sengupta DJ, Cookson BT, et al. Disseminated community-acquired USA300
methicillin-resistant Staphylococcus aureus pyomyositis and septic pulmonary emboli in an
immunocompetent adult. Surg Infect (Larchmt) 2010;11(1):59–63.
89. Garcia J. MRI in inflammatory myopathies. Skeletal Radiol 2000;29:425–438.
90. Napolitano LM. Severe soft tissue infections. Infect Dis Clin North Am 2009;23(3):571–591.
91. Wilson MA. Skin and soft tissue infections: impact of resistant gram-positive bacteria. Am J Surg
2003;186(5A):35S–41S.
92. Barie PS, Eachempati SR. Surgical site infections. Surg Clin North Am 2005;1115–1135.
93. Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection,
1999. Hospital Infection Control Practices Advisory Committee. Infect Control Hosp Epidemiol
1999;20:250–278.
94. Klevens RM, Edward JR, Richards CL Jr, et al. Estimating health care-associated infections and
deaths in U.S. hospitals, 2002. Public Health Rep 2007;122:160–166.
95. http://www.cdc.gov/ncidod/dhqp/pdf/guidelines/SSI.pdf
96. National Nosocomial Infections Surveillance (NNIS) system report, data summary from January
1992–June 2001, issued August 2001. Am J Infect Control 2001;29:404–421.
97. Campbell DA Jr, Henderson WG, Englesbe MJ, et al. Surgical site infection prevention: the
importance of operative duration and blood transfusion, results of the first American College of
Surgeons National Surgical Quality Improvement Program Best Practices Initiative. J Am Coll Surg
2008; 207:810–820.
98. Malone DL, Genuit T, Tracy JK, et al. Surgical site infections: reanalysis of risk factors. J Surg Res
2002;103(1):89–95.
99. Steinberg JP, Braun BI, Hellinger WC, et al. Trial to Reduce Antimicrobial Prophylaxis Errors
(TRAPE) Study Group. Timing of antimicrobial prophylaxis and the risk of surgical site infections:
results from the Trial to Reduce Antimicrobial Prophylaxis Errors. Ann Surg 2009;250(1):10–16.
100. Bratzler DW, Dellinger EP, Olsen KM, et al. American Society of Health-System Pharmacists
(ASHP); Infectious Diseases Society of America (IDSA); Surgical Infection Society (SIS); Society for
Healthcare Epidemiology of America (SHEA). Clinical practice guidelines for antimicrobial
prophylaxis in surgery. Surg Infect (Larchmt) 2013;14(1):73–156.
101. Bratzler DW, Houck PM, Richards C, et al. Use of antimicrobial prophylaxis for major surgery:
baseline results from the National Surgical Infection Prevention Project. Arch Surg 2005;140:174–
182.
102. Tanner J, Swarbrook S, Stuart J. Surgical hand antisepsis to reduce surgical site infection. Cochrane
Database Syst Rev 2008;(1):CD004288.
103. Edwards PS, Lipp A, Holmes A. Preoperative skin antiseptics for preventing surgical wound
infections after clean surgery. Cochrane Database Syst Rev 2004;(3):CD003949.
104. Darouiche RO, Wall MJ Jr, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for
surgical-site antisepsis. N Engl J Med 2010;362(1):18–26.
105. Bibbo C, Patel DV, Gehrmann RM, et al. Chlorhexidine provides superior skin decontamination in
foot and ankle surgery: a prospective randomized study. Clin Orthop Related Res 2005;438:204–208.
106. Saltzman MD, Nuber GW, Gryzlo SM, et al. Efficacy of surgical preparation solutions in shoulder
surgery. J Bone Joint Surg Am 2009;91(8):1949–1953.
262
107. Sidhwa F, Itani KM. Skin preparation before surgery: options and evidence. Surg Infect (Larchmt)
2015;16(1):14–23.
108. Dumville JC, McFarlane E, Edwards P, et al. Preoperative skin antiseptics for preventing surgical
wound infections after clean surgery. Cochrane Database Syst Rev. 2015;4:CD003949.
109. Tanner J, Woodings D, Moncaster K. Preoperative hair removal to reduce surgical site infection.
Cochrane Database Syst Rev 2006;(2):CD004122.
110. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-
wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N
Engl J Med 1996; 334:1209–1215.
111. Melling AC, Ali B, Scott EM, et al. Effects of preoperative warming on the incidence of wound
infection after clean surgery: a randomized controlled trial. Lancet 2001;358(9285):976–980.
112. Wong PF, Kumar S, Bohra A, et al. Randomized clinical trial of perioperative systemic warming in
major elective abdominal surgery. Br J Surg 2007;94(4):421–426.
113. Kao LS, Meeks D, Moyer VA, et al. Peri-operative glycaemic control regimens for preventing
surgical site infections in adults. Cochrane Database Syst Rev 2009;(3):CD006806.
114. Buchleitner AM, Martínez-Alonso M, Hernández M, et al. Perioperative glycaemic control for
diabetic patients undergoing surgery. Cochrane Database Syst Rev 2012;9:CD007315.
115. Qadan M, Akça O, Mahid SS, et al. Perioperative supplemental oxygen therapy and surgical site
infection: a meta-analysis of randomized controlled trials. Arch Surg 2009;144(4):359–366.
116. Brar MS, Brar SS, Dixon E. Perioperative supplemental oxygen in colorectal patients: a meta-
analysis. J Surg Res 2011;166(2):227–235.
117. Al-Niaimi A, Safdar N. Supplemental perioperative oxygen for reducing surgical site infection: a
meta-analysis. J Eval Clin Pract 2009;15(2):360–365.
118. Napolitano LM. Invited critique. Arch Surg 2009;144(4):366–367. For: Qadan M, Akca O, Mahid SS,
et al. Perioperative supplemental oxygen therapy and surgical site infection: a meta-analysis of
randomized controlled trials. Arch Surg 2009;144(4):359–366.
119. Prevent surgical site infections. Institute for Healthcare Improvement Web site. Available at:
http://www.ihi.org/IHI/Programs/Campaign/SSI.htm
120. Dellinger EP, Hausmann SM, Bratzler DW, et al. Hospitals collaborate to decrease surgical site
infections. Am J Surg 2005;190:9–15.
121. Manniën J, Wille JC, Snoeren RL, et al. Impact of postdischarge surveillance on surgical site
infection rates for several surgical procedures: results from the nosocomial surveillance network in
the Netherlands. Infect Control Hosp Epidemiol 2006;27(8):809–816.
122. Tanner J, Padley W, Assadian O, et al. Do surgical care bundles reduce the risk of surgical site
infections in patients undergoing colorectal surgery? A systematic review and cohort meta-analysis
of 8,515 patients. Surgery 2015;158(1):66–77.
123. Guenga KK, Matos D, Wille-Jorgensen P. Mechanical bowel preparation for elective colorectal
surgery. Cochrane Database Syst Rev 2009;(1):CD001544.
124. Nelson RL, Glenny AM, Song F. Antimicrobial prophylaxis for colorectal surgery. Cochrane Database
Syst Rev 2009;(1):CD001181.
125. Morris MS, Graham LA, Chu DI, et al. Oral antibiotic bowel preparation significantly reduces
surgical site infection rates and readmission rates in elective colorectal surgery. Ann Surg
2015;261(6):1034–1040.
126. Cannon JA, Altom LK, Deierhoi RJ, et al. Preoperative oral antibiotics reduce surgical site infection
following elective colorectal resections. Dis Colon Rectum 2012;55(11):1160–1166.
127. Taylor M, Napolitano L. Methicillin-resistant Staphylococcus aureus infections in vascular surgery:
increasing prevalence. Surg Infect 2004;5:180–187.
128. Gaynes R, Edwards JR; National Nosocomial Infections Surveillance System. Overview of
nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005;41(6):848–854.
129. Hidron AI, Edwards JR, Patel J, et al.; National Healthcare Safety Network Team; Participating
National Healthcare Safety Network Facilities. NHSN annual update: antimicrobial-resistant
pathogens associated with healthcare-associated infections: annual summary of data reported to the
National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007.
Infect Control Hosp Epidemiol 2008;29:996–1011.
263
130. Weigelt JA, Lipsky BA, Tabak YP, et al. Surgical site infections: causative pathogens and associated
outcomes. Am J Infect Control 2010;38(2):112–120.
131. Morange-Saussier V, Giraudeau B, van der Mee N, et al. Nasal carriage of MRSA in vascular
surgery. Ann Vasc Surg 2006;20(6):767–772.
132. Schelenz S, Tucker D, Georgeu C, et al. Significant reduction of endemic MRSA acquisition and
infection in cardiothoracic patients by means of an enhanced targeted infection control programme.
J Hosp Infect 2005;60(2):104–110.
133. Jog S, Cunningham R, Cooper S, et al. Impact of preoperative screening for MRSA by real-time PCR
in patients undergoing cardiac surgery. J Hosp Infect 2008;69(2):124–130.
134. Trautmann M, Stecher J, Hemmer W, et al. Intranasal mupirocin prophylaxis in elective surgery: a
review of published studies. Chemotherapy 2008;54(1):9–16.
135. Van Rijen M, Bonten M, Wenzel R, et al. Mupirocin ointment for preventing Staphylococcus aureus
infections in nasal carriers. Cochrane Database Syst Rev 2008;(4):CD006216.
136. Harbath S, Fankhauser C, Schrenzel J, et al. Universal screening for MRSA at hospital admission
and nosocomial infection in surgical patients. JAMA 2008;299(10):1149–1157.
137. Awad SS, Palacio CH, Subramanian A, et al. Implementation of a methicillin-resistant
Staphylococcus aureus (MRSA) prevention bundle results in decreased MRSA surgical site
infections. Am J Surg 2009;198:607–610.
138. Popovich KF, Weinstein RA, Hota B. Are community-associated MRSA strains replacing traditional
nosocomial MRSA strains? Clin Infect Dis 2008;46(6):787–794.
139. Klevens RM, Morrison MA, Nadle J, et al. Active Bacterial Core Surveillance (ABCs) MRSA
Investigators. Invasive MRSA infections in the United States. JAMA 2007;298(15):1763–1771.
140. Manian FA, Griesnauer S. Community-associated MRSA is replacing traditional healthcare-
associated strains in surgical site infections among inpatients. Clin Infect Dis 2008;47(3):434–435.
141. Kourbatova EV, Halvosa JS, King MD, et al. Emergence of community-associated MRSA USA 300
clone as a cause of healthcare-associated infections among patients with prosthetic joint infections.
Am J Infect Control 2005;33(7):385–391.
142. Kallen AJ, Wilson CT, Larson RJ. Perioperative intranasal mupirocin for the prevention of surgical
site infections: systematic review of the literature and meta-analysis. Infect Control Hosp Epidemiol
2005;26(12):916–922.
264
Chapter 9
Shock
Joseph Cuschieri and Darren Bowe
Key Points
1 Shock is the clinical syndrome that results from inadequate tissue perfusion from numerous causes:
hypovolemic, cardiogenic, extracardiac obstructive, and distributive.
2 Hypovolemic shock due to ongoing blood and/or plasma loss leads to progressive cardiovascular
deterioration, ultimate hypotension, oliguria, confusion, irreversible cell injury, and death.
3 Cardiogenic shock results in decreased tissue perfusion due to intrinsic pump failure.
4 Extracardiac obstructive shock attenuates cardiac pump function due to external compression of
inflow and outflow (tamponade, tension pneumothorax, etc.).
5 Septic and traumatic shock, forms of distributive shock, are systemic inflammatory responses to
infection or tissue injury with cellular breakdown, producing severe hypotension requiring massive
volume resuscitation and high risk of multiple organ failure and death.
6 Complications of an episode of shock include ischemia–reperfusion injury from oxidant stress;
potential secondary immunosuppression with enhanced nosocomial infection risk; hypothermia and
coagulopathy; and multiple organ failure syndrome, including abdominal compartment syndrome
(ACS).
7 Treatment of shock requires goal-directed volume resuscitation with treatment of the underlying
etiology and careful monitoring of adequacy of end-organ perfusion to avoid under- and
overresuscitation.
1 The current accepted concept of shock was first described in 1929 by Walter B. Cannon1 as inadequate
blood flow that results in cellular hypoxia. Persistence of cellular hypoxia results in dysfunction at both
cellular and organ levels. Although shock can result from a number of etiologies, it was Blalock who
first described the four major causes we still refer to today, which are hematogenic, neurogenic,
cardiogenic, and vasogenic.2
Prior to this, the concept of shock was not understood since the nature and purpose of the heart and
circulatory system were either unknown or misunderstood. Galen was the first to explore the purpose of
the heart and circulatory system. He proposed that the arteries carried blood, not air, as previously
thought, away from the heart. However, he incorrectly believed that arterial blood within the
circulatory system subsequently dissolved in the body to release nutrients. Blood returning to the heart
was not due to recirculation, but rather was rapidly remanufactured by the liver. Additionally, since
much of his dissection work was carried out in frogs, he concluded falsely that the heart had only two
chambers and blood passed from the right to left chamber through invisible pores in the septum.3
These conclusions remained unchallenged for nearly 1,500 years until Vesalius, in the 17th century.
Through a series of dissections, he demonstrated that blood did not flow directly from the right to left
ventricle. Although he provided elaborate drawings of the body’s network of blood vessels, he did not
anticipate that blood circulated through the body and was unable to discern the heart’s purpose. Shortly
thereafter, Harvey moved beyond anatomy and studied physiology; he discovered the closed nature of
the circulation and concluded that the heart was the main pumping mechanism. Although the
microscope had not yet been invented, he proposed the existence of capillaries that connect the arterial
and venous system.3
Due to this improved understanding of the circulatory system, the condition of shock due to blood
loss and other etiologies were carefully being observed and explored. During the 18th century, military
surgeons such as Henri le Dran (1740) noted that injured soldiers left unattended for several hours
suddenly deteriorated as if there had been a secousse (jolt) to the system, which probably led to use of
the word “shock.”1 Surgeons began to notice that even when a wounded extremity was amputated, the
physiologic effects of the injury often continued, and shock was increasingly recognized as a distinct
265
systemic syndrome from the wound itself.3
Eventually, Cannon and then Blalock described our current concept of shock and its attributed
systemic effects. In fact, Blalock was the first to recognize the third-space fluid loss that follows shock
resuscitation that is greater than the quantity of initial blood loss.4 As a result, therapy began to focus
not only on restoring intravascular volume but also on replacing fluid lost to the interstitium with a
balanced salt solution. Investigators then became increasingly intrigued by the fact that, at some point,
shock becomes irreversible and is no longer responsive to further volume resuscitation. As stated more
than 60 years ago by Wiggers, “at a certain stage adequate circulation cannot be restored by merely
filling the system, as one does an automobile radiator.”5 At some point, as had been observed multiple
times previously, the initiating event (e.g., wound, infection, cardiac dysfunction) is no longer the
primary threat. Other “unknown” factors sustain the shock state, blood pressure cannot be restored,
improvements are only transient, and death occurs shortly thereafter due to progressive organ
dysfunction.
The current concept of shock has led to a reclassification into four distinct groups – hypovolemic,
cardiogenic, extracardiac obstructive, and distributive – that may occur independent of each other, or
more characteristically synergistic with each other.6 Early recognition and prompt treatment are
essential to modern treatment. If delayed, uncorrected hypovolemia and critical oxygen delivery deficits
occur that lead to irreversible shock. However, it is believed that future therapies will move beyond
simple recognition and fluid resuscitation. Thus, investigators are increasingly looking to gain an
understanding of the chain of events that occur, which lead to organ damage and irreversibility. This
chapter describes these events, discusses the therapeutic approaches utilized in current management,
and offers a brief perspective on what may lie ahead in the future.
EVALUATION OF SHOCK
Shock is easily recognized by even the most inexperienced caregiver after the compensatory
mechanisms have been overcome (Table 9-1). However, it is more difficult to recognize the patient in
compensated shock, who presents with vital signs that are almost normal. It is critically important to
the patient’s ultimate outcome that recognition and treatment of shock occur before decompensation.
The clinical assessment must be guided by the knowledge that the severity of symptoms and signs of
shock vary between patients and the type of shock present. The patient is evaluated based on clinical
appearance, hemodynamic measurements, physiologic responses, and biochemical analyses.
Early during various shock states, vasoconstriction frequently causes the skin to be cool leading to
poor capillary refill. However, this must be contrasted to shock states induced by either neurogenic or
septic states in which vasodilation is present causing the skin to be warm, with good capillary refill.
Common to the various shock states is the presence of hyperventilation, a compensatory response due
to progressive metabolic acidosis. As shock progresses, mental status changes occur, and decreased
cerebral blood flow and increased catecholamine stimulation may lead to anxiety and restlessness. With
continued shock, lethargy may result. True coma, however, seldom results due to shock alone, unless
coincident complete cardiovascular collapse occurs, and is usually associated with other conditions such
as direct brain injury or severe hypoxia.7 This includes evaluation of the rate and character of the pulse;
the blood pressure; and, in some cases, the central venous pressure (CVP), pulmonary artery pressure,
pulse pressure variation (PPV), and echocardiography.8
The hemodynamic assessment should include evaluation of the rate and character of the pulse; the
blood pressure; and, in some cases, the CVP, pulmonary artery pressure, and PPV.8 Tachycardia is a
normal response to volume loss but also to pain, anxiety, and fear, all of which are commonly present.
Assessment of the pulse may be helpful in determining the proper diagnosis. Because of the body’s
ability to compensate for hypovolemia, changes in blood pressure do not occur reliably until nearly 30%
of blood volume has been lost. However, the pulse pressure usually narrows, even in compensated
shock, because of the effects of vasoconstriction on the diastolic blood pressure. Importantly, the CVP
reflects the adequacy of and not the true blood volume, and the state of the venous tone. Changes in
CVP in response to treatment or from continuing hemorrhage are more revealing than a solitary
measurement. However, this concept remains debatable. Because of the misuse or overuse of pulmonary
artery catheters (PACs), routine placement no longer occurs and has been associated with increased
morbidity.9 As a result, invasive monitoring using PPV, and noninvasive measures such as
echocardiography have become more commonly used.10
An indirect but extremely valuable measure of perfusion and volume status is urine output. A urinary
266
catheter should be inserted in every patient being evaluated for shock. Hourly urine output should be
0.5 to 1 mL/kg for adult patients, at least 1 mL/kg for most pediatric patients, and 1 to 2 mL/kg for
patients younger than 2 years of age. Lack of adequate urine output in the setting of previous normal
kidney function should cause the caregiver to be highly concerned about the continued presence of
inadequate perfusion and cellular hypoxia.
Although each of the physical examination components are important in the identification of shock,
used alone these factors can fail to diagnose compensated shock. As a result, biochemical markers are
used as a means to identify shock in its early stages. Biochemical analysis of shock is based on the shift
from aerobic to anaerobic metabolism in underperfused tissues. This shift is marked by the production
of lactate that can, in turn, be measured serially. Resuscitation of shock results in a decrease in serum
lactate levels, and the time required to normalize serum lactate levels appears to be an important
prognostic factor for survival.11–15
Another biochemical marker useful in the resuscitation of shock is the base deficit. This is defined as
the amount of a fixed base (or acid) that must be added to an aliquot of blood to restore the pH to 7.40.
Base deficit values have been categorized as normal (2 to –2), mild (–3 to –5), moderate (–6 to –9), and
severe (>–10). Changes in base deficit toward normal with volume infusion can be used to judge the
efficacy of resuscitation.16–18 Base deficit has been shown to be superior to pH values in assessing the
normalization of acidosis after shock resuscitation, and the time required for normalization of base
deficit has perhaps even greater prognostic significance than that of lactate.16,19
Table 9-1 Shock Recognition
The biochemical changes associated with the hypoperfusion of shock occur even with compensation.
Because of the potential difficulties in diagnosing compensated shock, an arterial and/or venous blood
gas analysis including base deficit and lactate should be obtained for every patient suspected of being in
shock. Additionally, any patient with a lactate of ≥4 mmol/L or base deficit of ≥6 mEq/L should be
considered to be in shock until proven otherwise.17,20,21
Future Measures: Although each of these factors can be used to characterize shock, no single
measurement has been determined to be optimal or when used singly to be always accurate for
identification and treatment of shock. Currently, other measurements are being investigated that
demonstrate promise. These markers include measurements of central and mixed venous oxygen
saturations, end-diastolic cardiac volume indices, and specific noninvasive end-organ tissue oxygen
saturations.22–28
TYPES OF SHOCK
Although several different classifications for shock have been described, the most widely accepted
classification of shock was proposed by Weil and Shubin in 1971.6 This classification divides the shock
syndrome into four distinct categories (Table 9-2). Despite this separation, however, there is
considerable overlap between the categories, with some patients presenting with more than one factor
267
at the same time. Given this overlap, it is helpful to evaluate the hemodynamic pattern in order to
elucidate the etiology and manage the patient (Table 9-3).
Hypovolemic Shock
2 Hypovolemic shock is the form of shock most commonly encountered in surgical practice (Table 9-2).
The essential feature is a reduction in intravascular volume to a level that prevents the heart from being
able to pump sufficient blood to vital organ systems. Substantial blood (>20% circulating volume) or
plasma (via soft tissue, enteric sequestration, gastrointestinal, urinary, or other insensible losses) losses
are required to produce this syndrome.
The signs and symptoms of shock vary with both the severity and duration of fluid loss. A review of
the Advanced Trauma Life Support classification system of the American College of Surgeons is useful to
comprehend the manifestations and physiologic changes associated with hemorrhagic shock in adults.29
Blood volume is estimated at 7% of ideal body weight, or approximately 4,900 mL in a 70-kg patient
(Table 9-4).
Class I: Mild hemorrhage, up to 15% of total blood volume. This condition is exemplified by voluntary
blood donation. In the supine position, there are no measurable changes in heart or respiratory rates,
blood pressure, or pulse pressure. Capillary refill is normal. This degree of hemorrhage requires little or
no treatment, and blood volume is restored within 24 hours by transcapillary refill and the other
compensatory methods.
Class II: Loss of 15% to 30% of blood volume (800 to 1,500 mL). Clinical symptoms include
tachycardia and tachypnea. The systolic blood pressure may be only slightly decreased, especially in the
supine position, but the pulse pressure is narrowed (because of the diastolic increase from adrenergic
discharge). Urine output is reduced only slightly (20 to 30 mL/hr). Mental status changes (e.g., anxiety)
are frequently present. Capillary refill is usually delayed. Patients with class II hemorrhage usually can
be resuscitated with crystalloid solutions, but some may require blood transfusion.
Class III: Loss of 30% to 40% of blood volume (up to 2,000 mL). Patients with class III hemorrhage
present with inadequate perfusion that is obvious; marked tachycardia and tachypnea; cool, clammy
extremities with significantly delayed capillary refill; hypotension; and significant changes in mental
status (e.g., confusion, combativeness). Class III hemorrhage represents the smallest volume of blood
loss that consistently produces a decrease in systolic blood pressure. The resuscitation of these patients
frequently requires blood transfusion in addition to administration of crystalloids.
Class IV: Loss of more than 40% of blood volume (more than 2,000 mL), representing life-threatening
hemorrhage. Symptoms include marked tachycardia, a significantly depressed systolic blood pressure,
and narrowed pulse pressure or unobtainable diastolic pressure. The mental status is depressed and the
skin is cold and pale. Urine output is negligible. These patients require immediate transfusion for
resuscitation and frequently require immediate surgical or other (e.g., angiographic embolization)
intervention.
In practice, individual susceptibility to blood loss varies greatly and is affected by age, pregnancy,
pre-existing disease, prescription and nonprescription medications (e.g., beta blockers), adequacy of
compensatory mechanisms, and other factors that are poorly characterized. Presence of these factors
should lead the caregiver to consider early use of invasive monitoring as an adjunct to appropriate fluid
resuscitation.
Hypovolemia due to plasma losses may also lead to hypovolemic shock. The clinical findings of
hemorrhagic shock are typically present, but significant differences do exist. Hemoconcentration,
elevated blood urea nitrogen (BUN) and creatinine, and hypernatremia are typical of acute plasma
and/or free water losses and are not necessarily present in other forms of shock. Appropriate evaluation
of preload and urine output should be followed, with specific considerations for unique electrolyte
abnormalities associated with specific plasma and fluid losses (e.g., gastric vs. colonic losses).
Cardiogenic Shock
3 The clinical definition of cardiogenic shock is decreased cardiac output with tissue hypoperfusion,
despite presence of adequate intravascular volume. It is caused by a primary problem with the cardiac
muscle, electrical conduction system, or valves. The most common cause is anterior wall myocardial
infarction, although in surgical patients it is often precipitated by pulmonary embolus, myocardial
contusion, or pulmonary hypertension.
Distinguishing cardiogenic shock from other shock etiologies is occasionally difficult. It is not
uncommon to see combined cardiogenic and traumatic shock in the elderly patient, with one often being
268
the precipitating event for the other. The hallmarks of the hemodynamic and neuroendocrine response
to systemic hypoperfusion from other causes are also typical of cardiogenic shock. Eliciting a history of
pre-existing cardiac disease, and physical findings such as pulmonary rales, cardiac murmurs, an S3
gallop, and jugular venous distention may be helpful. An electrocardiogram may detect significant
ischemia or other pathology. A chest radiograph may reveal bilateral pulmonary infiltrates typical of
cardiogenic edema, and cardio-specific serum tests (troponin I and creatine phosphokinase [CPK]) may
indicate myocardial damage.
Manifestations of cardiogenic shock develop as a consequence of failure of peripheral perfusion, the
associated adrenergic response, and the inability of the heart to accommodate blood returning from the
lungs and the periphery. In the absence of sepsis or tissue injury, however, there is not usually an
associated increase in the metabolic needs of the peripheral tissues. Sympathetic-mediated constriction
of the peripheral vasculature attempts to maintain central blood pressure and perfusion of cerebral and
coronary circulations. The clinical findings of cardiogenic shock may thus be similar to those of
hypovolemic shock because both involve induction of the adrenosympathetic response.
Table 9-2 Classification System and Causes of Shock
Diminished or ineffective contractile activity of the right or left side of the heart allows blood to
accumulate in the respective venous circulations. Shock from an acute left ventricular myocardial infarct
269
occurs when more than 40% of the left ventricle is involved and may be present in approximately 20%
of Q-wave infarcts.30 Shock from an acute right ventricular myocardial infarct, on the other hand, is
rare and only occurs in approximately 10% of all inferior wall infarcts.31 Not only does the diagnosis of
each infarct vary, but also the treatment and support vary significantly.
Table 9-3 Hemodynamic Patterns in Shock
In any patient in shock, especially in those with compromised cardiac function, consideration should
be given to the institution of mechanical ventilation. The work of breathing can be considerable,
especially for the patient in a state of agitation or distress. Oxygen needs are decreased through
intubation and mechanical ventilation. In this manner, the patient can be comfortably sedated with a
secure airway; the work of breathing is undertaken by the ventilator, and gas exchange can be
optimized. If there is a tenuous balance between myocardial oxygen needs and availability, the balance
can thus be shifted in the patient’s favor.
Like other forms of shock, cardiogenic shock tends to be self-perpetuating. Myocardial perfusion
depends on the pressure gradient between the coronary artery and the left ventricle and the duration of
diastole. Both are compromised by the hypotension and tachycardia that characterizes this condition.
High-volume fluid resuscitation, sometimes necessary for treatment of other forms of shock, is poorly
tolerated and likely to be detrimental to an individual with the compromised myocardial function of
cardiogenic shock.
Extracardiac Obstructive Shock

4 A subset of patients with cardiogenic shock do not have intrinsic cardiac disease but have pump
failure due to extrinsic compression that limits diastolic filling and cardiac output. Cardiac tamponade,
tension pneumothorax, diaphragmatic herniation of abdominal viscera, mediastinal hematoma, and,
occasionally, positive-pressure mechanical ventilation may all precipitate cardiogenic shock by exerting
constricting pressure on the myocardium. The key to diagnosis and appropriate therapy is the physical
examination, supplemented by use of appropriate diagnostic modalities.
The classic physical findings of cardiac tamponade, Beck triad, are hypotension, muffled heart sounds,
and jugular venous distention. Unfortunately, these nonspecific clinical findings are seldom present
together. Elevated jugular venous pressure, noted by either physical examination or measurement of
CVP, although not specific for cardiac compression, is usually present. Pulsus paradoxus can be useful
for the diagnosis of cardiac tamponade. Although it may be caused by other conditions, it is virtually
always present in patients with tamponade.
Given the difficulty in evaluation of these patients, especially in combination with other shock states,
early diagnostic evaluation, both invasive and noninvasive, of cardiac function is warranted. Recent
guidelines suggest that any patient with concern for primary or secondary cardiac dysfunction should
undergo early ultrasound evaluation. This early evaluation not only evaluates the primary cardiac
function but also can lead to the early diagnosis and management of secondary causes of cardiac
dysfunction including cardiac tamponade and pulmonary embolism.
Table 9-4 Classification of Hemorrhagic Shock
270
Table 9-5 Systemic Inflammatory Response Syndrome
Distributive Shock
Distributive shock occurs in a state of inappropriate oxygen utilization associated with the systemic
inflammatory response syndrome (SIRS). Classically, SIRS is triggered by sepsis, but SIRS is associated
with other immune processes including trauma, pancreatitis, and other types of tissue injuries.
However, other types of distributive disturbances can occur unrelated to inflammation that may be
directly due to loss of vascular tone from spinal cord injury, endocrine dysfunction, or anaphylaxis.
Septic Shock
5 Septic shock is defined as a SIRS response to infection in conjunction with arterial hypotension,
despite adequate fluid resuscitation.32 It occurs when bacterial products interact with cells of the
immune system, leading to elaboration of mediators that cause circulatory disturbances and direct and
indirect cell damage leading to the clinical manifestations of SIRS (Table 9-5).33 Hemodynamic changes
are defined as early (warm or hyperdynamic) or late (cold or hypodynamic). These stages are primarily
characterized by the degree of ventricular contractility and peripheral vasomotor impairment present,
but can be misclassified if not appropriately evaluated. Early septic shock is distinguished by peripheral
vasodilation, flushed and warm extremities, and a compensatory elevation in cardiac output. Although
an increase in venous capacitance diminishes venous return to the heart, cardiac output is maintained
via tachycardia and the decrease in afterload due to systemic vasodilation.
Late septic shock is characterized by impaired myocardial contractility due to local and systemic
release of cardiac depressants, worsening peripheral perfusion, vasoconstriction, extremity mottling,
oliguria, and hypotension. Peripheral oxygen utilization may be severely impaired by bacterial toxins,
such as lipopolysaccharide (LPS) and the inflammatory products of the host’s own immune response,
resulting in metabolic dysfunction and acidosis despite a high systemic oxygen delivery. This
inappropriate oxygen utilization and systemic shunting lead not only to confusion regarding the
adequacy of resuscitation but also to progressive cell death. Together, both systemic hypoperfusion and
the altered tissue metabolism create a vicious cycle that propagates the inflammatory response initiated
in reaction to the initial infectious challenge leading to progressive cellular injury.
Due to both volume deficits and cardiovascular dysfunction, persistent perfusion deficits are common
and contribute significantly to multiple organ failure and mortality. In fact, the fluid volume required
for treatment may exceed that required for treatment of other forms of shock due to persistent
microvascular endothelial capillary leak. As a result of this profound leak, interstitial and total-body
fluid balances become extreme, leading to the potential development of marked hypoxia and the
abdominal compartment syndrome (ACS).
Although appropriate early resuscitation and cardiovascular support are essential to the treatment of
271
septic shock, as important are early infection source control and appropriate administration of
antimicrobials. In fact, numerous investigators have demonstrated that even a few hours delay in
initiation of antimicrobial therapy is associated with a significant increase in mortality.34
Traumatic Shock
The major contributor to shock after injury is hypovolemia due to hemorrhage. Even when hemorrhage
ceases or is controlled, patients can continue to suffer loss of plasma volume into the interstitium of
injured tissues and develop progressive hypovolemic shock. In addition, tissue injury evokes a broader
pathophysiologic immunoinflammatory response and a potentially more devastating degree of shock
than that produced by hypovolemia alone.
The degree to which direct tissue injury and an inflammatory response participate in the development
and progression of traumatic shock distinguishes it from purely hypovolemic shock. Thus, traumatic
shock results from direct tissue or bony injury, resulting in not only hypovolemia caused by fluid and
blood loss but also an immunologic and neuroendocrine response to tissue destruction and
devitalization. This combined insult complicates what might otherwise be straightforward hemorrhagic
shock by inducing a systemic response that utilizes many of the inflammatory mediators present in
septic shock.35 These mediators propagate and intensify the effects of the initial hypovolemia and make
subsequent multiple organ failure far more likely than occurs with hypovolemic shock alone.
Although this condition can lead to increased fluid requirements, common problems associated with
this condition such as rhabdomyolysis should be aggressively evaluated and treated with optimal
resuscitation.36 In addition, common patient characteristics are known to alter traumatic shock
resuscitation, in particular, morbid obesity that can result in delayed correction of metabolic acidosis
and increased risk for organ dysfunction.37
Thus, initial management of the seriously injured requires the assurance of an airway, breathing, and
circulation; later management requires appropriate volume resuscitation and control of ongoing losses.
Control of hemorrhage is a major concern and demands priority over attention to other injuries. After
resuscitation and control of volume losses, efforts become necessary to minimize the potentially lethal
postshock sequelae, including acute respiratory distress syndrome (ARDS) and multiple organ
dysfunction syndrome (MODS).
Neurogenic Shock
Neurogenic shock is defined as failure of the nervous system to provide effective peripheral vascular
resistance, resulting in inadequate end-organ perfusion. Warm, flushed, flaccid extremities; paraplegia;
confusion; oliguria; and hypotension are the classic clinical findings. Injury to the proximal spinal cord,
with interruption of the autonomic sympathetic vasomotor pathways, disrupts basal vasoconstrictor
tone to peripheral veins and arterioles. Profound vasodilation of all microvascular beds below the level
of cord injury diminishes venous return to the heart, reduces cardiac output, and precipitates
hypotension. Injuries at or above the fourth thoracic vertebrae may disrupt sympathetic enervation to
the heart, resulting in significant bradycardia and severe decompensation.
Similar to the initial therapy for shock resulting from hypovolemia, treatment of the relative
hypovolemia due to vasodilation of neurogenic shock requires intravenous volume resuscitation.
Restoration of the pathologically expanded intravascular space improves preload and cardiac output and
may reverse hypotension. However, maintenance of adequate hemodynamics often requires vasopressor
support in an effort to avoid the administration of excessive fluids. CVP monitoring to assess cardiac
preload should be considered as a means of determining adequate and nonexcessive filling pressures, as
loss of vasomotor capacity within the pulmonary circulation predisposes these patients to pulmonary
edema. As spinal cord injury is often associated with other traumatic injuries, the diagnosis of isolated
neurogenic shock must be a process of exclusion.
This condition should not be confused with spinal shock. Spinal shock is defined as a loss of sensation
accompanied by motor paralysis with initial loss but gradual recovery of spinal reflexes following spinal
cord injury. The reflexes caudal to the spinal cord injury are hyporeflexic or absent, while those rostral
are unaffected. No circulatory compromise is associated with this condition; thus, it should not be
considered a shock state.
Hypoadrenal Shock
The role of adrenocortical hormones in providing resistance to shock is well recognized. The reduction
in effective blood volume and changes in blood chemistry that occur after adrenalectomy are similar to
272
those of shock and hemorrhage. Adrenalectomized animals have markedly diminished tolerance to both
trauma and hypovolemia. Adrenal cortical hormones also play a key role in maintaining normal
capillary tone and permeability. In recent years, the concept of functional or relative adrenal
insufficiency has received increasing attention as a cause of unrecognized shock and hypoperfusion.
Most critically ill patients have elevated cortisol levels, but some have low concentrations in relation to
the degree of stress imposed by their disease. Administration of physiologic doses of steroids to correct
this insufficiency may result in stabilization of hemodynamics and possible survival benefits.38
However, the concept of routine administration of physiologic doses of steroids has been questioned;
thus, routine and indiscriminate use is not recommended.39
Diagnosis of hypoadrenal shock is difficult, as classic signs of Addison disease are absent. The only
clinical clues may be unexplained hypotension and refractory response to high-dose vasopressors. An
isolated serum cortisol level is difficult to interpret because the range of values observed in critically ill
patients varies considerably. A cortisol level below 15 μg/dL suggests a high likelihood of adrenal
insufficiency, whereas a value above 35 μg/dL suggests adequate adrenal function.40 The
adrenocorticotropic hormone (ACTH) stimulation test may be used to identify hypoadrenal patients
when the diagnosis is unclear, but the utility of this test, particularly with an elevated baseline value, is
of questionable utility.
The utility of the ACTH stimulation test is especially questionable in patients with persistent evidence
of shock and elevated baseline levels of cortisol above 35 μg/dL. These patients actually demonstrate
evidence of inadequate systemic cortisol utilization with a significant risk of morality, and thus may
actually benefit from systemic administration of physiologic concentrations of corticosteroids.41
Although hypoadrenal shock may complicate various types of shock, there is conflicting evidence to
support the use of supplemental corticosteroids in patients with septic shock if there is biochemical
evidence of hypoadrenalism. Thus, supplemental corticosteroids should be used with extreme caution
until further evidence is available.32,41
Physiologic Response to Hypovolemia

Common to each shock state is usually an initial decrease in circulating intravascular volume. This
reduction is due directly to fluid loss or secondarily to fluid redistribution. This reduction in circulating
fluid volume initiates both a rapid and sustained compensatory response. Within minutes, a rapid
compensatory response occurs primarily due to adrenergic output. Sustained responses, in contrast,
occur slower and result in intravascular fluid reabsorption and renal conservation of water and
electrolytes (Algorithm 9-1).
Rapid Response
Hypovolemia results in the initial secretion of epinephrine and norepinephrine from the adrenal gland
due to decreased afferent impulses from arterial baroreceptors. Catecholamine release is acute and
limited to the first 24 hours following the onset of hypovolemia. This results in vasoconstriction,
tachycardia, and increased myocardial contractility. Adrenergic-induced vasoconstriction of the systemic
capacitance of small veins and venules shifts blood back to the central venous circulation, thus
increasing right-sided filling pressures. Left-sided filling and pressure are augmented by pulmonary
vasoconstriction. Concomitantly, vasoconstriction occurs in the skin, kidneys, and viscera, effectively
shunting blood to the heart and brain. Adrenergic-induced vasoconstriction increases cardiac filling and
causes increased contractility and reflex tachycardia, all of which combine to increase stroke volume
and cardiac output.
273
Algorithm 9-1. Neurohormonal response to hypovolemia. CNS, central nervous system; ACTH, adrenocorticotropic hormone; AVP,
arginine vasopressin.
Adrenergic-mediated vasoconstriction affects arterioles, pre- and postcapillary sphincters, and small
veins and venules. Due to this specific vasoconstriction, decreased hydrostatic pressure distal to the
precapillary sphincter occurs that leads to reabsorption of interstitial fluid (water, sodium [Na+], and
chloride [Cl−]) into the vascular space. This functions to restore circulating blood volume and is known
as transcapillary refill.42
Sustained Response
Sustained compensatory responses include the release of vasoactive hormones and fluid shifts from the
interstitium and the intracellular space to the intravascular compartment. Decreased renal blood flow,
increased adrenergic activity, and compositional changes in tubular fluid lead to the secretion of renin
from the juxtaglomerular complex. Renin results in increased formation and release of angiotensin I by
the liver. Circulating angiotensin I is rapidly converted to angiotensin II by the lungs and is the most
potent known arterial and arteriolar vasoconstrictor. Angiotensin II also stimulates the release of
pituitary ACTH. Increased circulating levels of both angiotensin II and ACTH result in increased
secretion of aldosterone. As a result, reabsorption of Na+ in the distal renal tubules in exchange for
potassium (K+) and hydrogen ions occurs.
Additionally, due to hypovolemia and increased serum osmolarity, reduced stimulation of arterial
baroreceptors occurs, leading to the release of arginine vasopressin (AVP), also known as antidiuretic
hormone (ADH). This hormone not only functions as a potent vasoconstrictor but also causes increased
reabsorption of water by increasing water permeability and passive Na+ transport in the distal renal
tubule. The overall net effect of aldosterone and AVP is to decrease glomerular filtration and increase
salt and water tubular reabsorption in an effort to replace circulating intravascular volume deficits.
Finally, the increased release of the stress hormones (epinephrine, ACTH, cortisol, and glucagon)
leads to glycogenolysis, lipolysis, and protein catabolism, causing a negative nitrogen balance and high
extracellular concentration of glucose due to decreased insulin release and resistance. This leads to
increased glucose utilization by insulin-independent tissues such as the brain and heart. In addition to
glucose, products of anaerobic metabolism from hypoperfused cells accumulate in the extracellular
compartment, inducing hyperosmolarity. This extracellular hyperosmolarity draws water from the
intracellular space, increasing interstitial osmotic pressure, which in turn drives water, Na+, and Cl−
across the capillary endothelium into the vascular space.
ORGAN-SPECIFIC COMPENSATORY RESPONSES TO SHOCK

Cardiac and Microvascular Response
274
Cardiovascular physiology is profoundly affected by shock (Table 9-3). Reduced stroke volume is caused
by an absolute or relative loss of preload. Intrinsic neuroendocrine and renal compensatory responses,
along with additional intravenous fluid, are needed to increase ventricular end-diastolic volume.
Restoration of adequate preload alone is often sufficient to return cardiac output to levels required to
overcome peripheral perfusion deficits. However, some cases are complicated by acquired myocardial
contractility derangements. Contractile function under these conditions is less a function of preload and
more related to intrinsic myocardial dysfunction.
A defining characteristic of shock is compromise of microvascular perfusion. Far from being a passive
conduit, the microvasculature actively participates in the response to shock. Arteriolar vessels are
innervated by sympathetic nerves, as are small veins and venules. The vasoconstriction of hypovolemic
shock and the vasodilation of septic and neurogenic shock are a result of these autonomic responses.
The majority of the circulating blood volume resides in the venous system, and normal physiologic
compensation mechanisms rely on this venous blood pool as an autotransfusion reservoir. Collapse of
underperfused veins passively propels blood toward the heart, while α-adrenergic venoconstriction
actively mobilizes the venous pool. Profound peripheral vasoconstriction via α-adrenergic, vasopressin,
angiotensin II, and endothelin-1 stimulation of arteriolar and precapillary smooth muscle sphincters
selectively diminishes perfusion to dermal, renal, muscle, and, significantly, splanchnic vascular beds to
preserve perfusion of critical central organs, primarily the central nervous system (CNS) and
myocardium.43
The capillary endothelial monolayer maintains a semipermeable barrier between the intra- and
extraluminal spaces and is compromised by shock.44 Circulating inflammatory mediators and byproducts
of infection (LPS, thrombin, tumor necrosis factor alpha [TNF-α], interleukin [IL]-1, nitric oxide, and
endothelin-1) generated in response to traumatic or septic shock have been shown to induce and sustain
endothelial capillary leak. Although the exact mechanisms of endothelial monolayer dysfunction are
unclear, the only available therapies to reverse microvascular decompensation are timely restoration of
peripheral perfusion, rapid elimination of infectious and necrotic tissue, and pharmacologic and
mechanical support of cardiopulmonary function.45–46
Neuroendocrine Response
The neuroendocrine reaction to shock consists of involuntary responses by the hypothalamus, autonomic
nervous system, and secretory endocrine glands and is directed toward restoration of tissue perfusion
and a redirected utilization of metabolic substrates. The autonomic response is initially triggered by
hypoxia, hypotension, or hypovolemia detected by aortic and carotid baroreceptors and chemoreceptors
(Algorithm 9-2). Subsequently, sympathetic vasoconstriction of specific vascular beds, induced by direct
synaptic release of norepinephrine, results in redistribution of circulating blood volume from tissue of
low metabolic activity to more metabolically demanding organs. Cardiac output, diminished by loss of
preload, is augmented by inhibition of cardiac vagal activity and a resulting reflex tachycardia.
Circulating epinephrine and norepinephrine alter several aspects of glucose utilization, availability,
and metabolism. The hyperglycemia of stress results from catecholamine-induced glycogenolysis,
gluconeogenesis, and decreased pancreatic insulin release. Simultaneously, hypothalamic stimulation of
the anterior pituitary induces release of ACTH, which in turn prompts cortisol and aldosterone release
by the adrenal cortex. Elevated serum cortisol contributes to postinjury hyperglycemia by increasing
gluconeogenesis, enhancing lipolysis, and diminishing peripheral utilization of glucose and amino acids.
The pancreatic response is characterized by a decrease in insulin release and an increase in glucagon
secretion, which further stimulates hepatic gluconeogenesis. The combined actions of catecholamines,
cortisol, and glucagon are synergistic and create a shock-related hyperglycemia that is often refractory
to insulin treatment.
Renal juxtaglomerular secretion of renin in response toadrenergic stimulation and renal
hypoperfusion triggers the formation of angiotensin I in the liver, which is subsequently converted to
angiotensin II by the lungs. Angiotensin II, a potent vasoconstrictor, augments shock-induced
catecholamine-mediated peripheral and splanchnic vasoconstriction and stimulates aldosterone release
from the adrenal cortex. Renal tubular reabsorption of sodium in response to elevated circulating
aldosterone creates highly concentrated, low-volume urine. Vasopressin secretion by the posterior
pituitary similarly contributes to compensatory restoration and maintenance of intravascular volume by
promoting water reabsorption by the renal distal tubules and by causing peripheral and splanchnic
vasoconstriction. A major result is a prolonged severe hypoperfusion of the splanchnic vascular bed,
further augmenting the deleterious host response.
275
Algorithm 9-2. Shock resuscitation algorithm. ATLS, advanced trauma life support; ACLS, advanced cardiac life support; SBP,
systolic blood pressure; CVP, central venous pressure; HCT, hematocrit; VS, vital signs; TTE, transthoracic echocardiography; PAC,
pulmonary artery catheter; CI, cardiac index; MAP, mean arterial pressure.
Immunoinflammatory Response
Many shock-inducing events, particularly those associated with septic or traumatic shock,
simultaneously trigger a massive systemic inflammatory response. Although inflammatory mediators
(TNF-α, ILs, chemokines, etc.) play an integral role in the recovery of local tissue to trauma and
infection, an uncontrolled systemic inflammatory response contributes to organ failure.
Immunologically active cells involved in the systemic inflammatory response include nucleated blood
cells (monocytes, polymorphonuclear leukocytes [PMNs]) and platelets, microvascular endothelial cells,
and tissue macrophages. These cells generate and secrete scores of signal-amplifying inflammatory
mediators ranging in complexity from individual molecules (nitric oxide) to large multisubunit,
extensively modified proteins (TNF-α, IL-1, etc.). Even transient systemic elevation of any of these
mediators has profound physiologic consequences.
Local tissue destruction, microbial contamination, and infection similarly activate the coagulation
cascade and induce platelet aggregation and release of numerous platelet-, endothelial-, and clot-derived
vasoactive mediators. Persistent, profound, and recurring microvascular hypoperfusion of the splanchnic
and other organs likewise causes local tissue ischemia, parenchymal cell injury, microvascular
coagulation, activation of inflammatory cells, and release of inflammatory mediators. Circulating
monocyte, lymphocyte, and PMN adherence to activated endothelium results in extraluminal
transmigration of these inflammatory cells into tissues remote from the area of injury. This
hyperdynamic immunologic response, with continued generation of proinflammatory mediators, is
responsible for the progression of SIRS toward MODS.47–50
Regulation of the systemic inflammatory response has been an active area of shock research for
several decades. Elimination of particular inflammatory mediators from the systemic circulation, or
inhibition of particular cell–cell interactions in experimental animal systems, has been shown to
improve outcomes after shock resuscitation.51–55 However, to date, all efforts to regulate the SIRS
response with therapeutic elimination or supplementation of specific proinflammatory and anti-
inflammatory mediators have proven ineffective or even harmful in humans. This lack of efficacy may
relate to inadequacy of current animal models of shock, sepsis, and organ failure or to inadequate
276
understanding of the full spectrum and interactive nature of key elements that regulate this syndrome.
Unfortunately, the network of inflammatory mediators and affected cells is so complex and redundant
that no single agent is likely to be effective at interrupting this response. As a result, there is probably
no single common pathway likely to respond to a “silver bullet” approach.
Pulmonary Response
The lung is the organ system most sensitive to systemic insult and injury and is frequently the first
organ to fail in the progression to MODS. ARDS represents a high-mortality form of pulmonary
insufficiency that is often precipitated by sepsis or traumatic shock. It is triggered and perpetuated by
the numerous inflammatory mediators created in the hypoperfused microvasculature elsewhere in the
body.51–56
Interstitial edema and subsequent reduced compliance result in diminished tidal volume and
tachypnea, compromising gas exchange. Surfactant abnormalities contribute to alveolar collapse,
resulting in loss of functional residual capacity (FRC) and the onset of pulmonary insufficiency. The
pulmonary microvascular response mirrors the systemic response, with angiotensin and α-adrenergic–
induced vasoconstriction creating significant elevations of pulmonary vascular resistance, further
straining the heart. Pulmonary parenchymal injury may be propagated by excessive positive-pressure
ventilation generated by alveolar overdistention in particular, further contributing to alveolar damage.
No specific measures are available to reverse the ARDS process; therefore, aggressive management of
predisposing conditions is most appropriate. Once ARDS has become fully developed, treatment
involves intensive supportive care while minimizing iatrogenic insults. As a result, early utilization of
lung-protective strategies may diminish progressive ventilator-induced lung injury and improve
outcome.57
Renal Response
Direct sympathetic-induced renal vasoconstriction increases afferent arteriole resistance in response to
shock. This effect is reinforced by elevated circulating angiotensin II and catecholamines. The resulting
decrease in renal blood flow and glomerular filtration rate (GFR), along with elevated circulating
aldosterone and vasopressin (ADH), produce oliguria and prerenal azotemia. Acute tubular necrosis
(ATN) may result from prolonged decreases in renal cortical blood flow, as well as from toxins
generated during sepsis. Oliguric renal failure, like the pulmonary insufficiency of ARDS, is a common
component of MODS.
Distinguishing low urine output due to oliguric renal failure from the oliguria of decreased renal
perfusion pressure can be aided by analyzing urine sodium and osmolality. Renal hypoperfusion usually
results in urine sodium of less than 20 mEq/L with an osmolality of greater than 400 mOsm/kg,
whereas acute tubular injury impairs sodium reabsorption and is associated with a low urinary
osmolality. A fractional excretion of sodium of less than 1% may also help determine whether the cause
is renal or prerenal.
Early detection of abnormal kidney function is critical to prevent progression to renal injury.
Abnormal renal function can be detected as a decline in creatinine clearance. The correlation between a
creatinine clearance based on a 24-hour collection and a sample collected over a shorter interval is poor.
However, the 24-hour value represents an average value over that time. A sample obtained over a
shorter period may reflect the time in question and allow timely recognition and treatment of renal
dysfunction.
Hepatic Response
Ischemic injury to liver is not apparent early during shock. However, the liver plays an important role
in the regulation of shock and subsequent tissue injury through both the release of acute-phase reactants
and lack of clearance of potential toxic agents. As shock continues, hepatic necrosis occurs, leading to
the release of aspartate aminotransferase and alanine aminotransferase. Continued shock results in
attenuated synthesis of coagulation factors, albumin and prealbumin. Although progressive ischemia can
occur, leading to complete loss of glycogen stores and marked hypoglycemia, this condition is rare
without pre-existing liver disease, significant direct liver injury, or hepatic artery occlusion.
Genetic Regulation of the Response to Shock

Individuals vary considerably in their susceptibility to shock and in their ability to recover from its
consequences. Recently, unique host-specific responses have been identified as important determinants
277
of the outcome of sepsis and septic shock. Genetic predispositions in an individual’s
immunoinflammatory response may dictate whether infection is adequately or inadequately countered.
These differences in response may be partially explained by single nucleotide polymorphisms (SNPs) in
the genetic sequences for various inflammatory mediators. These subtle nucleotide variations may affect
the transcription or translation of associated genes or the secretion or function of the corresponding
proteins.
The recognition that genetic background may regulate the response to severe sepsis and septic shock
has led to the identification of an array of genetic markers associated with enhanced risk of septic
mortality. These SNPs are in genes encoding proteins involved in pathogen recognition (toll-like
receptors 2, 4, and 5; CD14; and mannose-binding lectin), cytokine expression (TNF-α, IL-1, IL-6, and
IL-10), and several other genes involved in mediating and controlling the innate immune response and
the inflammatory cascade.58,59
Investigation into genetic polymorphisms should provide important insights into the pathophysiology
of shock. SNP identification leading to early diagnosis of individuals at risk of developing or dying from
the complications of shock may allow therapies to become more preemptive and effectively targeted.
LOSS OF COMPENSATORY RESPONSES TO SHOCK

If shock is prolonged, the arteriolar and precapillary sphincters become refractory and relax, while the
postcapillary sphincter remains in spasm. Therefore, the capillary hydrostatic pressure increases, and
Na+, Cl−, and water are moved into the interstitium, leading to depletion of intravascular volume.
Cellular membrane function is also impaired with prolonged shock. The normal negative membrane
potential approaches neutrality, leading to increased permeability and interstitial flooding by K+. This
is caused, at least in part, by a decrease in the normal function of the adenosine triphosphate–dependent
Na+-K+ membrane pump that is a result of cellular hypoxia. The loss of the membrane potential
difference leads to cellular swelling due to an intracellular influx of Na+ and fluid.
In addition to these cellular effects, severe and prolonged shock results in the development of
progressive organ dysfunction. Although the mechanisms responsible are incompletely understood, it
appears that the vital organs, in particular the lung early on, are limited in their ability to protect
themselves during shock. As a result, direct endothelial injury occurs, resulting in leakage of various
inflammatory mediators, which in turn results in accumulation of interstitial fluid and subsequent
reduction in nutrient and gaseous diffusion. This condition, along with progressive microcirculatory
thrombosis, is responsible for the late organ dysfunction characteristic of uncompensated shock.
COMPLICATIONS OF SHOCK
Ischemia–Reperfusion Injury
Inadequate microvasculature flow results in activation of leukocytes and converts local endothelial cells
to a proinflammatory, prothrombotic phenotype. On reperfusion, the reintroduction of oxygen prompts
these cells to generate superoxide anion, hydroxyl radicals, and hydrogen peroxide, further injuring
local tissue. Microvascular endothelial adherence, monolayer transmigration, and local oxidative burst
by activated neutrophils, along with the profound loss of endothelial monolayer integrity (i.e.,
microvascular capillary leak), contribute to massive interstitial edema after reperfusion. Although all
tissues are sensitive to varying degrees, ischemia–reperfusion injury appears to be most detrimental to
the pulmonary vasculature and the splanchnic circulations. Pulmonary interstitial edema and alveolar
fluid accumulation are associated with the development of ARDS, whereas extensive visceral edema
may contribute to development of ACS and mesenteric ischemia.
Second-hit Phenomena
Patients who have been successfully resuscitated from shock are at risk for what is referred to as the
second-hit phenomenon. A single episode of severe or prolonged shock may precipitate organ failure,
but, in addition, the initial insult may “prime” the inflammatory response, resulting in an augmented or
prolonged response to a subsequent insult such as an infection, a second episode of blood loss, or major
surgery.60 For example, after the primary event, circulating neutrophils demonstrate enhanced
superoxide anion production, increased endothelial cell adherence, augmented cytokine response, and
278
increased cytotoxicity. Not only do circulating innate immune cells demonstrate this priming effect, but
tissue-fixed cells, in particular the macrophage, demonstrate altered phagocytosis and augmented
cytokine release.61 This dysfunctional response leads to not only diminished microbial clearance and
enhanced risk of nosocomial infection but also increased host tissue injury and subsequent development
of MODS.
Multiple Organ Dysfunction Syndrome

6 MODS rarely develops as a result of isolated cardiogenic or neurogenic shock but is most often
precipitated by septic and traumatic shock complicated by second-hit events such as repeated episodes
of hypovolemia, subsequent infection, or repeated blood transfusions. Similarly, the presence of an
unresolved inflammatory focus (such as devitalized necrotic tissue), undrained bodily fluids, or
unresolved regional perfusion deficits can be the primary causes for the persistence of SIRS and the
transition to MODS.
The effects of shock, resuscitation, and reperfusion and the subsequent development of MODS appear
to depend on changes in the splanchnic and pulmonary microcirculations. These vascular beds appear to
be major sites of the activation and subsequent immunoinflammatory mediator production that is
responsible for the SIRS response. As splanchnic microcirculatory flow decreases in response to
homeostatic vasoconstrictive responses during hypovolemia, excessive and prolonged hypoperfusion of
the gut results in extensive microvascular injury and subsequent activation of endothelium, neutrophils,
and macrophages. In addition, mucosal barrier disruption permits translocation of bacteria and bacterial
toxins to circulate and reach the large tissue-fixed macrophage population in the liver. Extensive
activation of the Kupffer cells in the liver results in the release of inflammatory mediators that cause
distant organ injury through the systemic activation of other immune cells.
Not only is a proinflammatory phase of SIRS present, but there is also a compensatory anti-
inflammatory phase of the SIRS response that is evolutionarily designed to counter the locally generated
hyperimmune response and check systemic spread of proinflammatory mediators. If the compensatory
anti-inflammatory response syndrome (CARS) results in excessive immunosuppression, it may contribute
to susceptibility to primary and secondary infections that can then lead to organ failure.62
Numerous clinical trials utilizing proinflammatory and anti-inflammatory mediators as therapeutic
interventions have been conducted. Unfortunately, few therapeutic agents designed to counter immune
dysfunction have had significant impact on the prevention and treatment of MODS. Although studies are
planned and undergoing, no study has demonstrated a sustained impact to date. Several potential
targets, including interferon, have been suggested but this theoretical benefit may prove incorrect as so
many other targets have in the past.63
Abdominal Compartment Syndrome

ACS is a highly morbid complication of reperfusion injury to the splanchnic viscera. This syndrome
appears to be increasingly prominent due to aggressive resuscitation techniques that enable salvage of
profoundly hypotensive and hypovolemic patients. Splanchnic ischemia and reperfusion result in
extensive visceral capillary leak and interstitial edema of the bowel. Excessive volume resuscitation
during this phase leads to grossly edematous viscera within the closed space of the abdomen, which
dramatically increases intra-abdominal pressure, and compromises intra-abdominal organ function,
increases renovascular resistance, limits diaphragmatic excursion, and may decrease cardiac output and
elevate intracranial pressure. The clinical hallmarks of ACS are a distended and tense abdomen,
diminished tidal volume, pulmonary edema, decreased cardiac output, oliguria, and elevated urinary
bladder pressure. Presence of all or a major part of this syndrome should prompt consideration of an
urgent operative laparotomy to decompress the abdomen and treat by leaving the abdomen open.
Hypothermia
Hypothermia (core temperature <35°C) is common during shock. In addition to immobilization, both
prehospital and postadmission exposure can lead to conductive, convective, and evaporative heat loss,
which should all be minimized. In addition, the administration of room temperature intravenous fluids
and of cold-stored blood also contributes to hypothermia.64 Hypothermia increases fluid requirements
and independently increases acute mortality rates.65
As the core temperature decreases, the rate of oxygen consumption also decreases, to approximately
50% of normal at 28°C. The decrease in oxygen consumption is accompanied by increased production of
acid metabolites. A leftward shift in the oxyhemoglobin dissociation curve also occurs with hypothermia
279
but is partially compensated by the acidosis. CNS effects progress from confusion and loss of manual
dexterity to obtundation and frank coma as the core temperature decreases from 35°C to 26.5°C. The
heart rate decreases to approximately half of baseline at 28°C, with a concomitant decrease in cardiac
output. All cardiac electrical conduction intervals are prolonged, consistent with the changes in heart
rate, and both atrioventricular dissociation and refractory ventricular fibrillation occur at 28°C. Other
potential physiologic effects include ileus and pancreatitis (from cold enzyme activation) at
temperatures lower than 35°C.
Compensatory responses to hypothermia include increased excretion of catecholamines, resulting in
doubling of the basal metabolic rate, and increased production of thyroid hormones, further increasing
the basal metabolic rate to five times baseline. Shivering can increase heat production as well, but it
represents a significant energy expenditure and has been shown to be inhibited during episodes of
hypotension or hypoxemia.66 Compensatory responses to hypothermia are lost at temperatures below
30°C or 31°C, and a state of complete poikilothermy is reached.
The treatment for hypothermia is rewarming. The core temperature should be obtained on admission
of the trauma patient. Patients whose core temperatures are 33°C to 35°C can be treated with passive
rewarming, warm blankets, and hot packs. Patients with core temperatures lower than 33°C require
active rewarming. If the patient is unconscious, airway control should first be obtained. Because severe
hypothermia causes vasoconstriction, noninvasive blood pressure measurements may not be feasible or
accurate, and an arterial line should be placed for monitoring and blood gas sampling. The inspired gas
through the ventilator should be heated to 41°C and fully saturated with water vapor to increase heat
conductance in the lung. The intravenous fluids should also be warmed. Commercially available rapid
infusion systems with countercurrent heating elements should be used. For extreme hypothermia,
continuous mechanical arteriovenous rewarming can be performed for both circulatory support and
rewarming. Recently developed microtechnology permits core rewarming by percutaneous placement of
countercurrent warming coils directly in the inferior vena cava (IVC). Finally, other warming methods
include lavage of heated saline through nasogastric and thoracostomy tubes as well as peritoneal lavage,
but are not as effective.
Coagulopathy
Coagulopathy is a frequent problem complicating shock, especially in those patients who have received
large volumes of crystalloid solution and blood for resuscitation. Although this problem is incompletely
understood, it is clear that coagulation defects during shock are multifactorial. The presence of shock,
the fluid volume required for resuscitation, the presence of hypothermia, and pre-existing diseases all
influence the likelihood and severity of coagulopathy.67
A major factor in coagulopathy is usually due to the dilutional thrombocytopenia that occurs after
massive volume resuscitation. Although bleeding times can be prolonged with platelet counts less than
100,000 cells/mL, platelet counts of 50,000 cells/mL or greater are usually adequate for surgical
hemostasis. Dilutional thrombocytopenia becomes more likely with infusions of more than one blood
volume. Each unit of platelets administered increases the platelet count by 10,000 to 15,000 cells/mL.
Control of surgically remediable hemorrhage is prudent before platelet transfusion to prevent the loss of
the transfused platelets.
Dilution of other coagulation factors also plays a role in development of coagulopathy. Factors V and
VIII are the most labile in banked blood, but levels of less than 10% of normal for factors VII, X, XI, XII,
and XIII are all associated with abnormalities in hemostasis, as demonstrated by prolonged partial
thromboplastin time and prothrombin time. Fresh-frozen plasma can be administered as a source of all
the soluble coagulation factors. The administration of cryoprecipitate may be necessary as a
concentrated source of factor VIII and fibrinogen, particularly if adequate hemostasis is not obtained
with the use of fresh-frozen plasma. Recent support has emerged for the use of recombinant activated
factor VIIa. Although developed initially for use in hemophiliacs who developed inhibitors to factor
VIII, anecdotal evidence has suggested that recombinant activated factor VIIa may serve to quickly
reverse hemorrhage-induced coagulopathy.68 However, the use of factor VIIa is associated with
significant complications including pulmonary embolism, myocardial infarction, and stroke and thus is
no longer considered an optimal way to reverse hemorrhage-induced coagulopathy.69 Other agents have
demonstrated promise in rapidly reversing coagulopathy, such as tranexamic acid for massive
hemorrhage-induced coagulopathy and prothrombin concentrates for rapid reversal of
anticoagulants.70–71
Finally, evidence has suggested that coagulopathy and hemorrhage can be minimized following
280
massive blood loss if early aggressive use of fresh-frozen plasma is administered. Military data
demonstrate that significant early coagulopathy is present after massive injury, even before blood
component therapy is begun. Both civilian and military experience with a 1:1 ratio of packed red blood
cells to fresh-frozen plasma has been associated with reduced mortality.72–74 However, this practice has
been associated with an increase in the development of ARDS and organ dysfunction due to poorly
defined mechanisms.75 Thus, generalization of this data to all patients with hemorrhage other than the
massively injured should be performed with caution as demonstrated in the PROPRR study.76
TREATMENT
Fluid Therapy
Early investigators of hemorrhagic shock noted that decreased CVP and a reduction in total-body
oxygen delivery (DO2) were key early findings. If the decrease in oxygen delivery was severe or
prolonged, a reduction in total-body oxygen consumption ensued. After adequate fluid resuscitation,
oxygen delivery and consumption increased above the baseline value for several hours, as if the body
was paying back an “oxygen debt.” Failure of the patient to achieve this hyperdynamic response to
resuscitation was almost always fatal. Because early death from shock appeared to be explained by the
dynamics of oxygen delivery and utilization, therapy focused on restoring hemodynamics and oxygen
transport with fluid and inotropes.
The provision of additional fluid beyond the amount of blood loss was associated with improved
survival in both clinical and experimental studies of hemorrhagic shock, leading to widespread
acceptance of aggressive fluid infusion. However, some researchers have recently described a significant
increase in mortality associated with crystalloid overresuscitation and have postulated that excessive
fluid administration increases the clinical risk of ARDS, MODS, increased intracranial pressure, and
ACS.77–79 Because massive volumes of fluid are only provided to patients with severe shock, it is unclear
if it is the excessive fluid or the associated underlying shock that increases the risk of ARDS, organ
failure, or death after massive fluid resuscitation.
A minimum of two large-bore (14- to 16-gauge) intravenous catheters should be established in adults.
Isotonic fluid is then infused at the same time as blood is obtained for arterial blood gas analysis,
screening, and typing. Fluid can be infused up to 200 mL/min through a 14-gauge catheter and up to
220 mL/min through a 7-French catheter. A fluid challenge of 10 to 25 mL/kg is administered to the
hypotensive patient and the response is assessed (i.e., 2,000 mL or 40% of blood volume of a 70-kg
man). This therapeutic challenge is an effective trial in determining the amount of pre-existing or
continuing volume loss. If the blood pressure returns to normal and is stabilized, the volume loss was
relatively small, and the only treatment required may be infusion of isotonic fluid.
If the increase in blood pressure is transient after fluid bolus, then hemorrhage or continued fluid
losses are severe and ongoing. Additional crystalloid is administered, and the need for blood transfusion
is assessed. Patients who continue to require large amounts of fluid and blood to support perfusion
usually have ongoing hemorrhage and require surgical intervention. No response or a minimal response
to apparently adequate infusions of crystalloid solution and blood indicates exsanguinating hemorrhage
and the need for urgent surgery.
Crystalloids
Balanced salt solutions are the most commonly used resuscitative fluids, and their use to restore
extracellular volume significantly decreases the transfusion requirement after hemorrhagic shock.
Lactated Ringer solution is isotonic, readily available, and inexpensive. It rapidly replaces the depleted
interstitial fluid compartment and does not aggravate any pre-existing electrolyte abnormalities.
Previous investigations have shown that administration of lactated Ringer solution does not lead to
aggravation of the lactic acidosis that is present in shock.80 In fact, animal models have demonstrated
that the use of blood plus lactated Ringer solution results in a more rapid return to normal lactate and
pH than dose-shed blood alone. As volume and perfusion are restored, lactate is mobilized and
metabolized to bicarbonate in a single pass through the liver. In fact, mild metabolic alkalosis may
occur 1 or 2 days after large-volume resuscitations with lactated Ringer solution. Normal saline solution
is also effective for resuscitation of hypovolemic patients. Concerns about inducing hypernatremic,
hyperchloremic metabolic acidosis with massive resuscitation volumes remain but appear of less
relevance by further investigation with normal saline and the hypertonic saline solutions.
281
Recently several investigations have raised concerns about the proinflammatory effects of
resuscitation with lactated Ringer solution. Some commercially available lactated Ringer solutions
contain racemic lactate that is made of equal concentrations of D(−)- and L(−)-isomers of lactate. The
D(−)-isomer has been demonstrated in vitro to result in enhanced production of reactive oxygen species
by neutrophils and inflammatory gene expression by leukocytes.81–82 In addition, increased apoptosis in
both the small intestine and the liver was seen after resuscitation from hemorrhage with lactated Ringer
solution but not with hypertonic solutions or blood resuscitation.83 These findings, however, are not
consistent and do not appear dissimilar from saline resuscitation in other animal models.84 Thus, further
investigations are required to determine the overall inflammatory effect of crystalloid resuscitation and
extent of D(−)-isomer use in current commercial fluids.
Colloids
Colloids have the theoretic advantages of increasing the colloid oncotic pressure and requiring smaller
volumes for resuscitation than crystalloids.85 Colloids commonly used for volume expansion in
hypovolemia include albumin, dextran 70, dextran 40, and hydroxyethyl starch. Although each has
unique individual characteristics, currently there is little justification for the routine addition of colloids
to balanced salt solutions for volume replacement during shock. In fact routine use of colloid such as
hydroxyethyl starch may be associated with increased risk of mortality without any benefit.86
Albumin solutions have been used during resuscitation to increase colloid oncotic pressure and,
hypothetically, to protect the lung from interstitial edema; however, there is a relatively rapid flux of
albumin across the pulmonary capillary membranes and relatively rapid clearance through the
pulmonary lymphatics. In fact, colloid albumin infusion has been demonstrated to prolong the
resuscitation phase and delay postresuscitation diuresis. Additionally, albumin may serve to depress
circulating immunoglobulin levels and suppress albumin synthesis.
Dextran 40 and dextran 70 are polysaccharides with molecular weights of 40 and 70 kD, respectively.
Dextran 40 (10%) is hyperoncotic and initially exerts a volume-expanding effect. However, because of
its lower molecular weight, it is more rapidly excreted. Thus, dextran 40 is commonly used in cases of
peripheral vascular disease and hyperviscosity syndromes. Dextran 70, conversely, is provided as a 6%
solution and does not exert a hyperoncotic effect. The volume expansion is somewhat greater than the
amount infused, and because of its large molecular size the effect is maintained for up to 48 hours. The
dextran preparations, however, cause decreased platelet adhesiveness and decreased factor VIII activity.
They also carry an incidence of allergic reaction of up to 5% and anaphylaxis of 0.6%.85,87
Hydroxyethyl starch is an amylopectin with volume-expanding effects for approximately 36 hours. It
has side effects similar to those of dextran, but with less frequency. The incidence of anaphylaxis is
0.006%. A new hydroxyethyl starch, pentastarch, has a lower molecular weight and fewer hydroxyethyl
groups than hydroxyethyl starch. Pentastarch has a shorter duration of action (2.5 hours) and has been
reported to have even fewer side effects.87–88
The controversy regarding use of crystalloids versus colloids in resuscitation has not been resolved.
Both types of solutions can restore circulating volume. The effects of the solutions on pulmonary
function are at issue and are summarized as follows: (a) the use of crystalloid solutions decreases
plasma oncotic pressure, thereby leading to lung edema at lower microvascular pressures; and (b)
colloids given in the face of pulmonary injury can extravasate, promoting edema because of the reduced
plasma interstitial oncotic gradient. In fact, a previous meta-analysis of colloid versus crystalloid
resuscitation after hemorrhagic shock demonstrated a higher mortality rate among the colloid-
resuscitated patients, partly because of pulmonary complications.89 Therefore, since colloid infusion has
not demonstrated a significant benefit over crystalloid resuscitation alone, it is not currently
recommended in the management of hypovolemic shock.90–91
Resuscitative Strategy
7 Aggressive fluid resuscitation is clearly a lifesaving modality and a key strategy in the treatment of
shock and prevention of secondary consequences (Algorithm 9-2). However, indiscriminate fluid loading
causes problematic edema in the lungs, gut, brain, and other organs. The amount of fluid used for
resuscitation should be titrated to carefully selected hemodynamic and oxygen transport endpoints.
Solutions currently in development (“artificial blood”) with oxygen transport capabilities may hold the
potential of restoring oxygen transport while minimizing the need for large volumes.
Permissive Hypotension
282
Elevation of systemic arterial pressure in patients with disruption of the arterial system or major solid
organ injury, especially after penetrating trauma, may cause acceleration of hemorrhage, disrupt natural
clotting mechanisms, and cause dilution of clotting factors. Laboratory and clinical evidence support
judicious use of intravenous fluids until hemorrhage is controlled by surgery, angiography, or direct
pressure for penetrating trauma.92 Fluid resuscitation for patients with multisystem blunt trauma,
especially with concomitant traumatic brain injury, represents a more complicated decision process, as
maintaining cerebral perfusion pressure is a competing priority. Avoidance of both excessive fluid
administration and prolonged hypoperfusion is best achieved in all patients not by maintenance of a
marginal blood pressure, but by rapid surgical or angiographic intervention to control bleeding.
Transfusion
Anemia prompts clinical concerns because it may signify blood loss or hematologic disease, but it rarely
causes tissue ischemia. The hemoglobin level that causes concern should depend on the adequacy of
other mechanisms involved in oxygen delivery such as arterial oxygen saturation and cardiac output, the
specific clinical situation, and the organ systems most at risk, balanced against the risk of transfusion.
Clinical evidence suggests that hemoglobin values above 7 mg/dL are adequate in most patients,
including the critically ill, but this has not been explored during shock. In one prospective randomized
trial in critically ill patients, it was clearly demonstrated that a reduction in complications and
improvement in survival were noted when lower hemoglobin values were accepted.93 However, this
study excluded patients with hypovolemia, acute coronary syndrome, and sepsis. Although the role of
transfusion during shock remains problematic, it appears in patients without shock these thresholds of
transfusion are even acceptable for elderly patients with significant cardiac disease.94
Table 9-6 Comparison of Blood Availability
Given this limitation, currently it is held that most patients with class I or II shock can be resuscitated
with balanced salt solutions alone. Patients who lose more than 25% to 30% of total blood volume
require blood for resuscitation, as do patients with persistent evidence of inadequate end-organ
perfusion.20 The decision about the extent of blood cross match prior to being transfused is determined
in part by the urgency of the situation. Blood that has been fully typed and cross matched carries the
least risk of transfusion reactions, but it also takes the most time to obtain. Other transfusion options
include the use of type O or type-specific blood (Table 9-6).
Type O Blood
Type O (universal donor) blood is immediately available without a cross match. Because type O blood
contains no AB cellular antigens, administration of packed red blood cells is relatively safe in patients
with any blood type. Males should be transfused type O Rh-positive blood, while prepubescent females
and females of childbearing age should be given type O Rh-negative blood to avoid sensitization that
would complicate future pregnancies. The administration of more than 4 units of type O blood to a non–
O-blood-type patient, however, theoretically can result in an admixture of blood type. A pretransfusion
blood specimen should be sent to the blood bank when the patient is admitted, and type-specific blood
should be transfused as soon as it is available.
Type-Specific Blood
Type-specific blood is available from most blood banks within 5 to 10 minutes of receipt of the blood
specimen, while the patient is being resuscitated with balanced salt solutions. Although not cross
matched, this blood can be administered safely, as demonstrated in both military and civilian
experiences.95
Autotransfusion
Autotransfusion involves collection of the shed blood and its reinfusion through a filter back into the
patient. Autotransfusion can be as simple as aspiration of the blood into a citrate-containing collection
283
chamber, followed by reinfusion through a 40-mm filter. A more elaborate system, the Haemonetics
autotransfuser (Haemonetics Corp., Braintree, MA), centrifuges the collected blood and delivers
washed, packed red blood cells for reinfusion. The advantages of autotransfusion include transfusion
with warm, compatible blood without delays and with no risk of transmission of hepatitis, human
immunodeficiency virus, or other bloodborne pathogens.
Autotransfused blood can produce disseminated intravascular coagulation and activation of
fibrinolysis. In addition, collection of blood from the peritoneal cavity after hollow viscus injury, even
with cell washing, may lead to bacterial contamination of the autotransfused blood.96 Successful
autotransfusion of contaminated blood has been demonstrated, but blood obtained from enteric-
contaminated cavities probably should not be used, except perhaps in extreme circumstances.97 Despite
the potential benefits, investigators have found that the autotransfuser was used in only 26% of the
trauma patients for whom it was prepared.98 Currently, no evidence exists that autotransfusion
improves outcome compared to exclusive homologous blood transfusions in trauma patients.
Endpoints of Resuscitation
Endpoints of resuscitation can be categorized as either global or regional indicators of perfusion. Blood
pressure and pulse are global measures and are relatively poor determinants of the adequacy of tissue
oxygenation. They must also be interpreted in the context of patient age and pre-existing medical
conditions. Tachycardia is a component of SIRS and does not always resolve with increased preload.
Arterial pressure is maintained by myriad compensatory mechanisms, even in the face of a significant
volume deficit, and interpretation is complicated by highly variable baseline pressures, age, and pre-
existing medical conditions.
Base deficit and serum lactate are also global indicators of perfusion and may help in the detection of
patients who are in otherwise compensated shock. Acidosis arising from regional tissues may not be
apparent in peripheral blood samples, as is frequently the case in patients with intestinal ischemia, in
whom systemic acidosis is a late finding. An elevated base deficit and lactate can be caused by
electrolyte abnormalities, accelerated glycolysis or pyruvate production, and/or decreased clearance by
the liver. They may also reflect dysfunction caused by a period of hypoperfusion that has already
resolved and that does not need further treatment. A positive response toward correction, however, is
indicative of appropriate resuscitation.
A PAC has obvious appeal as a monitor because ensuring adequate oxygen delivery is paramount in
the treatment of shock (Algorithm 9-2). A progressive decline in systemic oxygen delivery (DO2) results
in an increase in the oxygen extraction ratio, evident as a reduction in pulmonary mixed venous oxygen
saturation. When DO2 is reduced below the level needed to maintain normal tissue metabolic activity,
anaerobic metabolism occurs. This is evident as a decrease in total-body oxygen consumption (VO2).
Adequate resuscitation requires eliminating any pathologic decrease in VO2 by restoring oxygen
delivery to an adequate level. In clinical practice, however, there is no precise level of VO2 that can be
used as an endpoint, as tissue oxygen needs vary according to the patient’s condition, level of sedation,
body temperature, and other factors, and are affected by endogenous and exogenously administered
catecholamines.
Oxygen consumption may be especially difficult to interpret in patients with late-stage sepsis because
acquired defects in mitochondrial respiration may prevent utilization of oxygen, resulting in decreased
consumption and progressive acidosis despite normal or high DO2.
The adequacy of resuscitation can also be assessed by measurement of end-organ function and
perfusion, in addition to global measures. Blood flow to the most vital organs (brain and heart) is
preserved during shock at the expense of flow to the skin, muscles, gut, and, ultimately, kidneys.
Detection of ischemia in less vital organs could theoretically identify patients in compensated shock who
have otherwise normal global indicators.
Low urine output (<0.5 to 1.0 mL/kg/hr) is an indicator of inadequate end-organ perfusion, but
inappropriate urine output may initially be maintained by peripheral venoconstriction and maintenance
of cardiac output due to tachycardia. The use of gastric tonometry to measure intramucosal pH has
highlighted the uneven recovery from shock by visceral organs. Persistent visceral hypoperfusion, as
demonstrated by intramucosal acidosis despite correction to normal hemodynamics, is associated with
organ failure and poor outcomes. Unfortunately, direct measurement of visceral hypoperfusion, as well
as hypoperfusion in other regional vascular beds, requires use of technically challenging, labor-intensive
devices that often produce variable unreliable results and has not yet had widespread application.
Presently, the goal of therapy is to restore tissue perfusion, both global and regional as measured by
284
organ function, and to normalize cellular metabolism while avoiding excessive use of fluids and
inotropes.
Recently, several biomarkers, in addition to base deficit and lactate, have demonstrated potential
promise. Among the most promising is procalcitonin for the early recognition of sepsis. However, in
addition to being significantly elevated during sepsis, procalcitonin has recently been demonstrated,
similar to lactate and base deficit, to be prognostic of outcome from hypovolemia based on rate of
clearance.99 Thus, this biomarker along with potential others may lead to early recognition and
treatment of shock.
MONITORS
Central Venous Pressure
CVP has been used as a surrogate for venous return to the right heart and extended to represent
preload. Preload is often diminished in the setting of shock and must be optimized in order to maintain
adequate oxygen delivery. The venous system serves a capacitance function containing roughly two-
thirds of our circulating blood volume. It is a compliant system that, in a healthy state, functions to
maintain adequate venous return to the heart over a variable total blood volume. In states of shock, this
capacitance function may be overcome by too low a circulating volume – as in the setting of
hypovolemic or hemorrhagic shock – or by dysregulation – as in the setting of neurogenic or septic
shock. CVP may be measured directly via an appropriately positioned central venous catheter. The
catheter tip should ideally be positioned at the cavoatral junction – roughly 2 cm caudal to the carina on
chest x-ray.100 Intravenous fluids are administered to achieve adequate preload. Despite challenges for
the ability for CVP to determine preload, CVP still remains used clinically.101 In the surviving sepsis
campaign, CVP is pushed to a goal of 8 to 12 mm Hg, which is thought to optimize preload.20 This
however, has been called into question in recent years with several investigators suggesting that there is
no survival benefit to achieving such high CVPs.20 It has certainly been demonstrated that CVP is not a
perfect measure of venous return to the right heart or cardiac preload as there are several intrinsic
cardiopulmonary factors that influence both CVP and cardiac output. The role of CVP may be most
useful at its extremes and when used within the context of the patients’ clinical situations. A CVP <5
mm Hg in the setting of a young, otherwise healthy trauma patient with ongoing hemorrhage is likely
consistent with hypovolemic shock and warrants volume resuscitation. Alternatively, a CVP of 15 mm
Hg in an elderly patient with known congestive heart failure does not alone provide adequate
information as to a patient’s volume status nor should it guide resuscitation. As such, CVP is one
measure that can help to guide shock resuscitation when evaluated in the proper context.
Pulmonary Artery Catheter

Hemodynamic monitoring utilizing a flow-directed PAC has been a standard in the treatment of shock
for decades and has been considered to be essential for optimal management of certain forms of shock.
However, as a result of a multicenter study that reported that use of a PAC was associated with
increased mortality, the indications for PAC use have recently been questioned.102 PAC patients were
retrospectively compared to matched control patients who were selected using a scoring system. This
scoring system has not been validated, which raises the possibility that physicians inserted a PAC in the
more critically ill patients.
Intensive care unit (ICU) staffing practices may have also been a factor explaining these surprising
results. The study was conducted in “open” ICUs, where any physician on the medical staff could admit
a patient to the unit and insert a PAC. Clinicians may not always interpret PAC data appropriately. In a
multicenter study of physicians’ knowledge and interpretation of PAC data, nearly half (47%) were
unable to appropriately determine the wedge pressure from a clear tracing, and a similar percentage
(44%) could not identify the determinants of oxygen delivery.103 Studies have demonstrated improved
outcome when patients are managed in ICUs staffed by specialists in critical care, despite their more
frequent use of PACs.104
An additional consideration regarding the controversy over the utility of PACs is that currently used
endpoints for PAC-guided resuscitation may be inappropriate. For example, efforts to augment systemic
oxygen delivery have not demonstrated any benefits and, in fact, harm may be caused by this approach,
whereas treatments used to alter the variables ascertained with the catheter may themselves cause harm
(fluid overload, excessive inotropes, blood transfusions). Finally, PACs are associated with specific
285
complications, including the risk of central venous catheter insertion, endocarditis, and pulmonary
artery injury, which may outweigh any potential benefits. As the safety and utility of the PAC have not
yet been evaluated with prospective clinical trials in specific shock states, its usefulness in the
management of shock remains to be determined.
Newer versions of the PAC have been developed that provide additional hemodynamic information,
including continuous determination of cardiac output, ejection fraction, and calculated right ventricular
end-diastolic volume. The pulmonary artery wedge pressure is a proxy for preload. However, the
amount of precontractile stretch achieved with any given wedge or chamber pressure is modulated by
the compliance of the ventricle. Therefore, cardiac chamber pressure may not be an accurate indicator
of ventricular end-diastolic volume, just as end-diastolic volume may not be an accurate indicator of
pulmonary wedge pressure and/or risk of pulmonary edema. The combination of both wedge pressure
and end-diastolic volume may be optimal to maximize preload while avoiding excessive pulmonary
capillary pressure. The use, however, has been mainly supplanted with the use arterial wave contour
analysis and echocardiography.
A comparison of the pH and partial pressure of carbon dioxide (PCO2) of mixed venous blood with a
matched arterial blood sample can provide evidence of shock with tissue hypoxia. Hypoxic cells
generate a hydrogen ion that is buffered by bicarbonate, resulting in increased production of H2O and
CO2. An increase in venous PCO2 results in an abnormal gap between mixed venous and arterial PCO2
and pH and is a sign of anaerobic metabolism. With cessation of hydrogen ion production, this abnormal
gap is quickly eliminated, whereas base deficit and hyperlactatemia may persist for several hours.
Arterial Wave Contour Analysis

Analysis of the arterial wave contour in a mechanically ventilated patient has been shown to be a
marker of fluid responsiveness. This is a dynamic measurement, and as such, provides more information
than static measures such as CVP or PCWP. Inspiration during positive pressure ventilation increases
intrathoracic pressure and decreases venous return to the right heart. This, in turn, leads to a decrease
in left ventricular preload, a lower stroke volume, and a decreased cardiac output. This effect is more
pronounced in the hypovolemic patient, and calculation of PPV has been consistently shown to predict
fluid responsiveness in critically ill patients. PPV is a measure of percent-change in the pulse pressure
over the respiratory cycle, with a PPV greater than 12.5% being consistent with fluid responsiveness.101
Arterial wave contour analysis relies on patients having a sinus rhythm, no spontaneous respiratory
function, and a tidal volume of at least 8 mL/kg. Interpretation of PPV and other arterial wave contour
measurements should be cautioned outside of these parameters.
Bedside Ultrasound and Echocardiography

Improved ultrasound technology – better image quality and improved portability – over the past several
years has led to its frequent use in the emergency department and intensive care settings. Ultrasound
offers the benefits of being noninvasive, real-time, accurate, and reproducible. A focused cardiac
ultrasound can provide information on both left and right ventricular function as well as volume status.
Additionally, a pericardial effusion is easily identified and may be leading to tamponade physiology.
Valvular disease is much more difficult to identify and may require a formal transthoracic or
transesophageal echo.105
In addition to assessment of cardiac function, ultrasound has demonstrated use in assessment of
volume status and fluid responsiveness in shock states. Measurement of the superior vena cava (SVC),
IVC, and left ventricular stroke area (LVSA) have proved helpful in guiding resuscitation. Measurement
of the SVC and LVSA are performed via transesophageal echocardiography, which limits their routine
use in patient management. However, SVC and LVSA variation over the respiratory cycle has been
demonstrated to be predictive of fluid responsiveness.106–107 Measurement of the IVC is performed using
bedside ultrasound. The IVC is identified just caudal to the diaphragm, and an anterior–posterior
dimension is recorded at the end of expiration. In the setting of trauma and shock, an IVC diameter of
<1 cm is consistent with a transient responder and correlates with fluid responsiveness.108,109 The use
of ultrasound in critical care settings is growing and will continue to do so as technology and provider
experience improves.
PHARMACEUTICAL SUPPORT
286
Therapeutic adjustments of preload and afterload form the basis of treatment strategies in all forms of
shock. Optimal volume resuscitation should always precede measures to augment the contractile
function of the heart. Inotropic augmentation of cardiac output may, therefore, be required when
restoration of venous preload fails to provide sufficient cardiac output to satisfy tissue oxygen demands.
The effect of inotropic agents depends on the specific adrenergic receptor affinity, chronotropic effects,
and demands placed on myocardial oxygen consumption of the individual agents (Table 9-7).
Vasodilators reduce demands on the myocardium and augment cardiac function via reduction in
systemic vascular resistance (SVR) or afterload or by dilating the venous system and reducing cardiac
preload. Afterload reduction may preserve stroke volume in the face of a failing myocardium, whereas
venodilation reduces pulmonary capillary wedge pressure and pressure-driven pulmonary edema.
Agents that increase afterload may be needed when blood pressure falls below the autoregulatory range
of the coronary, cerebral, and renal vascular beds.
Inotropes and Vasopressors

Dopamine
Dopamine is an endogenous sympathetic amine that is a biosynthetic precursor of epinephrine and
functions as a central and peripheral neurotransmitter. The effects of dopamine vary from individual to
individual, and are altered with increasing doses. The highest-affinity receptors are occupied at low-
serum concentrations (infusions <2 to 3 μg/kg/min) and consist of dopaminergic receptors in the renal
and splanchnic beds that serve to augment regional blood flow, increase urine output, and cause
natriuresis. However, multiple studies, including prospective randomized trials, have failed to
demonstrate that low-dose dopamine prevents acute renal failure or decreases the need for dialysis in
critically ill patients. At modest concentrations (3 to 5 μg/kg/min), dopamine occupies cardiac β1-
adrenergic receptors and increases myocardial contractility and heart rate. Higher doses (>5
μg/kg/min) cause an increase in heart rate and blood pressure. α-Adrenergic receptors are stimulated at
higher-dose ranges (>10 μg/kg/min), resulting in elevation of blood pressure and peripheral vascular
resistance. Dopamine is, therefore, an effective agent for increasing blood pressure in hypotensive
patients after appropriate fluid resuscitation. Because the relationship among a specific dose, receptor
affinity, and clinical effect is unique to each patient, individual titration is required to achieve the
desired effect.
Table 9-7 Pharmacodynamics of Inotropic/Vasoconstrictor Agents
Dobutamine
Dobutamine, a synthetic catecholamine, has a predominant affinity for β-adrenergic receptors. At
clinically relevant doses (5 to 20 μg/kg/min), dobutamine enhances myocardial contractility with mild
287
to moderate changes in heart rate. It also induces peripheral vasodilation, which limits its utility in
patients with hypotension. It is an appropriate agent when cardiac output augmentation, not blood
pressure support, is required and when a drop in peripheral resistance and preload is clinically tolerable
or beneficial. Treatment of cardiogenic shock following myocardial infarction or cardiac dysfunction
following shock and reperfusion typically requires support of myocardial contractility and reduction of
peripheral resistance, which makes dobutamine an excellent choice in this setting.
Epinephrine
Epinephrine, the endogenous adrenal catecholamine, is released physiologically in response to stress. It
has a broad spectrum of systemic actions, including significant cardiovascular effects. When epinephrine
is administered as a pharmacologic agent (0.01 to 0.05 μg/kg/min), β1-adrenergic effects predominate,
causing increased stroke volume, heart rate, and contractility, along with modest β2-receptor
stimulation. At higher infusion rates, α-adrenergic receptors are stimulated, which overcome β2-
mediated peripheral vasodilation, resulting in an increase in blood pressure and SVR. Renal and
splanchnic vasoconstriction, cardiac dysrhythmias, and increased myocardial oxygen demands limit the
prolonged use of high-dose epinephrine. Transient increases in serum lactate have also been noted,
possibly due to impaired regional blood flow. Epinephrine should be considered as a potential short-
term agent for use in patients with impaired cardiac function not responsive to other agents such as
dobutamine.
Norepinephrine
Norepinephrine, the sympathetic neurotransmitter, also has concentration-dependent cardiovascular
effects. It should be considered as a drug with predominantly α-constrictor effects and less pronounced
β-stimulation and is, therefore appropriate for use in patients who remain hypotensive despite
dopamine administration or as a dopamine alternative. Combined α- and β-stimulation typically results
in an increase in afterload and renal glomerular perfusion pressure, with preservation of cardiac output.
Despite the potential for renal vasoconstriction, as a result of its effects on mean arterial pressure,
norepinephrine is associated with an increase in urine output and creatinine clearance in hypotensive,
and particularly septic, patients. A primary concern is to ensure adequate volume resuscitation prior to
utilization due to risk of severe tissue damage from excessive vasoconstriction on the hypovolemic
patient.
Isoproterenol
Isoproterenol is a synthetic catecholamine with potent β-adrenergic effects. From a cardiovascular
standpoint, both cardiac and peripheral effects are significant. Stimulation of cardiac β1-receptors
prompts an increase in contractility, heart rate, and conduction velocity. The chronotropic response,
however, may predominate. These activities, in conjunction with peripheral vasodilation, generate
significant increases in cardiac output and pulse pressure. Isoproterenol greatly increases myocardial
oxygen demand and limits coronary filling due to tachycardia. As a result, indications for isoproterenol
are limited to patients with hemodynamically significant bradyarrhythmias while preparations are made
for electrical pacing.
Phenylephrine
Phenylephrine is a pure α-agonist and is an effective agent for increasing peripheral vascular resistance
and arterial blood pressure. Although it has no direct effect on the myocardium, the increase in
afterload increases left ventricular work and oxygen demand and may cause a decrease in stroke volume
and cardiac output. It is often used as a first-line agent in patients with neurogenic shock, but its use is
otherwise generally restricted to patients who remain hypotensive when the dosage of agents such as
dopamine or norepinephrine cannot be increased due to excessive tachycardia.
Vasopressin
Vasopressin acts directly on V1 receptors in vascular smooth muscle to cause vasoconstriction and
increases the reactivity of vascular smooth muscle to catecholamines. Release of endogenous
vasopressin is a normal physiologic response to shock. After septic or prolonged hemorrhagic shock,
circulating vasopressin levels are decreased, possibly due to depletion of hypophyseal secretory stores.
This relative deficiency may play a role in causing refractory hypotension. Vasopressin has minimal
effects on normotensive patients, but in patients with septic shock, it is effective in increasing SVR and
288
mean arterial pressure. Vasopressin does not have inotropic properties but has potent splanchnic and
coronary vasoconstrictors. It has been associated with decreased cardiac output due to myocardial
ischemia and increased afterload and may worsen metabolic acidosis in patients in shock by causing
splanchnic ischemia. As a result, early use of vasopressin at only physiologic concentrations to minimize
associated other pressor use may be indicated in the event that other pressor agents are unable to
achieve optimal perfusion.110
Amrinone and Milrinone

Amrinone and milrinone are noncatecholamine inotropes with cardiovascular effects similar to
dobutamine, but with minimal chronotropic activity. As steroidlike phosphodiesterase antagonists, they
increase smooth muscle cyclic adenosine monophosphate (cAMP) and alter calcium metabolism. Cardiac
contractility, stroke volume, heart rate, and cardiac output are increased, while a concomitant reduction
in afterload offsets cardiac workload. The increase in cardiac performance with minimal demands on
myocardial oxygen consumption offers some utility in the treatment of cardiogenic shock or as a
potential alternative to dobutamine infusion. Both agents have a relatively long half-life of nearly 3
hours and should therefore be used with caution in patients at risk of developing hypotension, a major
risk in the critically ill patient.
Vasodilators
Vasodilators are used as a means to augment cardiac function through optimization of preload and
afterload, both of which reduce demands on the myocardium. The failing ventricle responds to afterload
reduction with significant increases in stroke volume. The reason for this is that the compromised
myocardium is working past the plateau and on the down slope of the Starling curve. As a result,
afterload reduction with vasodilator agents may allow cardiac output to increase, resulting in improved
oxygen delivery.
Nitroprusside
Nitroprusside is a balanced but potent arterial and venous smooth muscle vasodilator. It causes a
reduction in afterload that increases cardiac output and has a less prominent venodilatory effect that
reduces pulmonary venous pressure and preload. Hypotension may limit its use, particularly in the
presence of contractility deficits or inadequate preload. Infusions (>3 μg/kg/min) continued for greater
than 48 hours require monitoring of serum thiocyanate levels and arterial pH to detect complications of
cyanide toxicity.
Nitroglycerin
Nitroglycerin is primarily a venous smooth muscle vasodilator, with less significant arterial vasodilation
effects than nitroprusside. Thus, although nitroprusside predominantly decreases afterload, nitroglycerin
predominantly increases venous capacitance. It is an effective treatment for acute myocardial ischemia
because it reduces excessive preload and ventricular end-diastolic pressure, thereby diminishing
myocardial oxygen demand.
Miscellaneous Therapeutics
Corticosteroids
In septic shock, ACTH resistance may diminish the normal cortisol response. Also, peripheral tissue
resistance to corticosteroids may develop through proinflammatory-induced downregulation of normal
corticosteroid receptors. Initial clinical trials showed no reduction in mortality when short courses of
high-dose corticosteroids were used as adjuncts in the treatment of septic shock. However, recent
studies utilizing low or physiologic doses (<300 mg/day) of hydrocortisone for a longer duration (>5
days) of treatment have demonstrated a beneficial impact on mortality, particularly in septic patients.38
Currently, routine use of ACTH stimulation tests is not advocated since they provide little more than
prognostic information.40 Given that hypoadrenal shock complicates various shock states, routine use by
some experts is considered appropriate. However, this should only be based on patients who have
achieved adequate intravascular volume but remain in shock despite high vasopressor administration.
Thus use of corticosteroids at only physiologic doses with immediate tapering once hemodynamics have
improved should be used with caution.39
Metabolites and Electrolytes
289
Severe shock is frequently associated with hypocalcemia. Severe hypocalcemia that causes cardiac
dysfunction or electrical instability should be rapidly treated. Calcium chloride rapidly corrects calcium
deficits, whereas calcium gluconate must be degraded in the liver to release calcium ion, resulting in
slower correction of deficits but less risk of tissue reaction. In the absence of evidence of cardiac
dysfunction, attempts to restore plasma calcium to normal during shock are not warranted. Ischemia
results in decreased cell membrane ATP and failure of the membrane calcium pump. Thus, reduced
serum calcium levels during severe shock are probably due to movement of ionized calcium into the
cells. Increased cytosolic calcium causes release of lysosomal enzymes and activation of phospholipases,
protein kinases, and proteases that cause membrane damage and cytoskeletal destruction.
Administration of exogenous calcium may merely worsen this uncontrolled intracellular calcium influx,
whereas effective resuscitation will usually restore circulating calcium levels to normal.
Many shock resuscitation protocols emphasize correction of metabolic acidosis with fluids and
inotropes until the pH begins to normalize. When interpreting an acid–base disorder, the presence of an
anion gap is supportive evidence of lactic acidosis. However, a non–anion gap acidosis with worsening
base deficit frequently occurs when normal saline is administered in large volumes. Efforts to correct a
non–anion gap acidosis with additional fluids that may no longer be needed will only increase the risk
of fluid overload.
Future Therapies
When initiating therapy for shock, the clinician does not know whether therapy has been started early,
when salvage is still possible, or late, after irreversible changes have occurred within the cell and death
is inevitable. Failure to respond to fluids, inotropes, and vasopressors with restoration of normal oxygen
consumption and aerobic metabolism probably represents a defect in cellular and subcellular function in
critical organ systems. There are many active areas of investigation that reflect the progression of our
understanding of shock that have been outlined in this chapter and that have begun to move the field
beyond the basics of fluid resuscitation and hemodynamic monitoring.
Efforts to control ischemia–reperfusion injury include controlled reperfusion with carbon monoxide or
other compounds to reduce oxidative stress. Induced hypothermia may interrupt generation of harmful
byproducts of ischemia and enable restoration of circulation and repair of structural injuries in a cellular
environment where hypoxia is no longer critical. Additional biomarkers, such as procalcitonin, may
allow earlier diagnosis and treatment of sepsis and shock.99 New biosensors using near-infrared light
may enable transcutaneous identification of critical limitations of blood flow and enable clinicians to
more accurately target areas of regional hypoperfusion.111 A search for agents that optimize circulation
in the microvascular system by preventing activation of the endothelium may enable resuscitative
efforts to restore oxygen to cells as needed to maintain normal respiration and provide critical nutrients.
Ultimately, further understanding of functional genomics may enable clinicians to target transcription
and translational events triggered by shock and thus alter outcome.
References
1. Cannon WB. Pharmacological injections and physiological inferences. Science 1929;70(1821):500–
501.
2. Blalock A. Reminiscence: shock after thirty-four years. Rev Surg 1964;21:231–234.
3. Bogolioubov A, Keefe DL, Groeger JS. Circulatory shock. Crit Care Clin 2001;17(3):697–719.
4. Blalock A, Mason MF. Blood and blood substitutes in the treatment and prevention of shock: with
particular reference to their uses in warfare. Ann Surg 1941;113(5):657–676.
5. Wiggers HC, Ingraham RC. Hemorrhagic shock: definition and criteria for its diagnosis. J Clin Invest
1946;25(1):30–36.
6. Weil MH, Shubin H. Proposed reclassification of shock states with special reference to distributive
defects. Adv Exp Med Biol 1971;23(0):13–23.
7. Whittington LK, Roscelli JD, Parry WH. Hemorrhagic shock and encephalopathy: further
description of a new syndrome. J Pediatr 1985;106(4):599–602.
8. Moore FA, McKinley BA, Moore EE, et al. Inflammation and the Host Response to Injury, a large-
scale collaborative project: patient-oriented research core–standard operating procedures for
clinical care. III. Guidelines for shock resuscitation. J Trauma 2006;61(1):82–89.
290
9. Chaterjee K. The Swan-Ganz Catheter: past, present, and future: a viewpoint. Circulation 2009;147–
152.
10. Alhashemi JA, Cecconi M, Hofer CK. Cardia output monitoring: an integrative perspective. Critical
Care 2011;214–220.
11. Vitek V, Cowley RA. Blood lactate in the prognosis of various forms of shock. Ann Surg
1971;173(2):308–313.
12. Abramson D, Scalea TM, Hitchcock R, et al. Lactate clearance and survival following injury. J
Trauma 1993;35(4):584–588; discussion 588–589.
13. Nguyen HB, Rivers EP, Knoblich BP, et al. Early lactate clearance is associated with improved
outcome in severe sepsis and septic shock. Crit Care Med 2004;32(8):1637–1642.
14. Brown JB, Cohen MJ, Minei JP, et al; Inflammation and the Host Response to Injury Investigators.
Goal-directed resuscitation in the prehospital setting: a propensity-adjusted analysis. J Trauma Acute
Care Surg 2013; 74(5):1207–1212.
15. Cuschieri J, Johnson JL, Sperry J, et al; Inflammation and Host Response to Injury, Large Scale
Collaborative Research Program. Benchmarking outcomes in the critically injured trauma patient
and the effect of implementing standard operating procedures. Ann Surg 2012;255(5):993–999.
16. Davis JW, Kaups KL, Parks SN. Base deficit is superior to pH in evaluating clearance of acidosis
after traumatic shock. J Trauma 1998;44(1):114–118.
17. Davis JW, Shackford SR, Holbrook TL. Base deficit as a sensitive indicator of compensated shock
and tissue oxygen utilization. Surg Gynecol Obstet 1991;173(6):473–476.
18. Davis JW, Shackford SR, Mackersie RC, et al. Base deficit as a guide to volume resuscitation. J
Trauma 1988;28(10):1464–1467.
19. Davis JW, Parks SN, Kaups KL, et al. Admission base deficit predicts transfusion requirements and
risk of complications. J Trauma 1996;41(5):769–774.
20. Rivers E, Nguyen B, Havstad S, et al. Early goal-directed therapy in the treatment of severe sepsis
and septic shock. N Engl J Med 2001;345(19):1368–1377.
21. Rivers EP, Kruse JA, Jacobsen G, et al. The influence of early hemodynamic optimization on
biomarker patterns of severe sepsis and septic shock. Crit Care Med 2007;35(9):2016–2024.
22. Bouman CS, Oudemans-van Straaten HM, Schultz MJ, et al. Hemofiltration in sepsis and systemic
inflammatory response syndrome: the role of dosing and timing. J Crit Care 2007;22(1):1–12.
23. Cui ZG, Kondo T, Matsumoto H. Enhancement of apoptosis by nitric oxide released from alpha-
phenyl-tert-butyl nitrone under hyperthermic conditions. J Cell Physiol 2006;206(2):468–476.
24. Englehart MS, Schreiber MA. Measurement of acid-base resuscitation endpoints: lactate, base
deficit, bicarbonate or what? Curr Opin Crit Care 2006;12(6):569–574.
25. Goodrich C. Endpoints of resuscitation: what should we be monitoring? AACN Adv Crit Care
2006;17(3):306–316.
26. Jones AE, Shapiro NI, Kilgannon JH, et al. Goal-directed hemodynamic optimization in the post-
cardiac arrest syndrome: a systematic review. Resuscitation 2008;77(1):26–29.
27. Alawade ZM, LeFebvre E, Fox EE, et al. Alternative end points for trauma studies: A survey of
academic trauma surgeons. Sugery 2015:158(5):1291–1296.
28. Connelly CR, Schreiber MA. Endpoints in resuscitation. Curr Opin Crit Care 2015:21(6):512–519.
29. American College of Surgeons. Advanced Trauma Life Support for Doctors: Student Course Manual. 8th
ed. Chicago, IL: American College of Surgeons; 2008.
30. Goldberg RJ, Gore JM, Alpert JS, et al. Cardiogenic shock after acute myocardial infarction.
Incidence and mortality from a community-wide perspective, 1975–1988. N Engl J Med
1991;325(16):1117–1122.
31. Roberts N, Harrison DG, Reimer KA, et al. Right ventricular infarction with shock but without
significant left ventricular infarction: a new clinical syndrome. Am Heart J 1985;110(5):1047–1053.
32. Russel JA. The current management of septic shock. Minerva Med 2008; 99(5):431–458.
33. Darville T, Giroir B, Jacobs R. The systemic inflammatory response syndrome (SIRS): immunology
and potential immunotherapy. Infection 1993; 21(5):279–290.
34. Kollef MH. Broad-spectrum antimicrobials and the treatment of serious bacterial infections: getting
it right up front. Clin Infect Dis 2008;47(suppl 1):S3–S13.
291
35. Goris RJ. Pathophysiology of shock in trauma. Eur J Surg 2000;166(2):100–111.
36. Nespoli A, Corso V, Mattarel D, et al. The management of shock and local injury in traumatic
rhabdomyolysis. Minerva Anestesiol 1999;65(5):256–262.
37. Mansfield ND, Forni LG. Recently published papers: treating sepsis, measuring troponin and
managing the obese. Crit Care 2005;9(6):535–537.
38. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA 2002;288(7):862–871.
39. Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J
Med 2008;358(2):111–124.
40. Lipiner-Friedman D, Sprung CL, Laterre PF, et al. Adrenal function in sepsis: the retrospective
Corticus cohort study. Crit Care Med 2007;35(4):1012–1018.
41. Groeneveld AB, Molenaar N, Beishuizen B. Should we abandon corticosteroids during septic shock?
No. Curr Opin Crit Care 2008;14(4):384–389.
42. Gann DS, Carlson DE, Byrnes GJ, et al. Impaired restitution of blood volume after large
hemorrhage. J Trauma 1981;21(8):598–603.
43. Parker MM. Pathophysiology of cardiovascular dysfunction in septic shock. New Horiz
1998;6(2):130–138.
44. Peters J, Mack GW, Lister G. The importance of the peripheral circulation in critical illnesses.
45. Cuschieri J, Gourlay D, Garcia I, et al. Modulation of endotoxin-induced endothelial function by
calcium/calmodulin-dependent protein kinase. Shock 2003;20(2):176–182.
46. Cuschieri J, Gourlay D, Garcia I, et al. Modulation of endotoxin-induced endothelial activity by
microtubule depolymerization. J Trauma 2003;54(1):104–112; discussion 112–113.
47. Barie PS, Hydo LJ. Epidemiology of multiple organ dysfunction syndrome in critical surgical illness.
Surg Infect (Larchmt) 2000;1(3):173–185; discussion 185–186.
48. Baue AE. MOF, MODS, and SIRS: what is in a name or an acronym? Shock 2006;26(5):438–449.
49. Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute
respiratory distress syndrome. J Pathol 2004;202(2):145–156.
50. Matsuda N, Hattori Y. Systemic inflammatory response syndrome (SIRS): molecular
pathophysiology and gene therapy. J Pharmacol Sci 2006;101(3):189–198.
51. Winn RK, Ramamoorthy C, Vedder NB, et al. Leukocyte-endothelial cell interactions in ischemia-
reperfusion injury. Ann N Y Acad Sci 1997; 832:311–321.
52. Winn RK, Sharar SR, Vedder NB, et al. Leukocyte and endothelial adhesion molecules in
ischaemia/reperfusion injuries. Ciba Found Symp 1995;189:63–71; discussion 72–76, 77–78.
53. Winn RK, Vedder NB, Mihelcic D, et al. The role of adhesion molecules in reperfusion injury. Agents
Actions Suppl 1993;41:113–126.
54. Costa EL, Schettino IA, Schettino GP. The lung in sepsis: guilty or innocent? Endocr Metab Immune
Disord Drug Targets 2006;6(2):213–216.
55. Goodman ER, Kleinstein E, Fusco AM, et al. Role of interleukin 8 in the genesis of acute respiratory
distress syndrome through an effect on neutrophil apoptosis. Arch Surg 1998;133(11):1234–1239.
56. Papadakos PJ. Cytokines, genes, and ARDS. Chest 2002;121(5):1391–1392.
57. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung
injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome
Network. N Engl J Med 2000;342(18):1301–1308.
58. Imahara SD, O’Keefe GE. Genetic determinants of the inflammatory response. Curr Opin Crit Care
2004;10(5):318–324.
59. O’Keefe GE, Hybki DL, Munford RS. The G–>A single nucleotide polymorphism at the -308
position in the tumor necrosis factor-alpha promoter increases the risk for severe sepsis after
trauma. J Trauma 2002;52(5):817–825; discussion 825–826.
60. Rotstein OD. Modeling the two-hit hypothesis for evaluating strategies to prevent organ injury
after shock/resuscitation. J Trauma 2003;54(suppl 5):S203–S206.
61. Cuschieri J, Maier RV. Oxidative stress, lipid rafts, and macrophage reprogramming. Antioxid
Redox Signal 2007;9(9):1485–1497.
292
62. Sharma S, Kumar A. Septic shock, multiple organ failure, and acute respiratory distress syndrome.
Curr Opin Pulm Med 2003;9(3):199–209.
63. Xio W, Mindrinos M, Seok J, et al. A genomic storm in critical injured humans. J Exp Med
2011;208(13):2581–2590.
64. Gentilello LM. Advances in the management of hypothermia. Surg Clin North Am 1995;75(2):243–
256.
65. Gentilello LM, Jurkovich GJ, Stark MS, et al. Is hypothermia in the victim of major trauma
protective or harmful? A randomized, prospective study. Ann Surg 1997;226(4):439–447; discussion
447–449.
66. Stoner HB. Studies on the mechanism of shock. The impairment of thermoregulation by trauma. Br
J Exp Pathol 1969;50(2):125–138.
67. Gubler KD, Gentilello LM, Hassantash SA, et al. The impact of hypothermia on dilutional
coagulopathy. J Trauma 1994;36(6):847–851.
68. Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correction of traumatic coagulopathy. J
Trauma 2004;57(4):709–719.
69. Dutton RP, Parr M, Tortella BJ, et al; CONTROL Study Group. Recombinant activated factor VII
safety in trauma patients: results from the CONTROL trial. J Trauma 2011:71(1):12–19.
70. Roberts I, Shakur H, Ker K, et al; CRASH-2 Trial collaborators. Anitfibrinolytic drugs for acute
traumatic injury. Cochrane Database Syst Rev 2011;19(1):CD004896.
71. Hassanein O, Smith A, Coimbra R, et al. Activated prothrombin complex and the treatment of
hypocoagulable trauma patients. Am Surg 2015:81(6);651–652.
72. Gunter OL Jr, Au BK, Isbell JM, et al. Optimizing outcomes in damage control resuscitation:
identifying blood product ratios associated with improved survival. J Trauma 2008;65(3):527–534.
73. Kashuk JL, Moore EE, Johnson JL, et al. Postinjury life threatening coagulopathy: is 1:1 fresh
frozen plasma: packed red blood cells the answer? J Trauma 2008;65(2):261–270; discussion 270–
271.
74. Spinella PC, Perkins JG, Grathwohl KW, et al. Effect of plasma and red blood cell transfusions on
survival in patients with combat related traumatic injuries. J Trauma 2008;64(suppl 2):S69–S77;
discussion S77–S78.
75. Sperry JL, Ochoa JB, Gunn SR, et al. An FFP:PRBC transfusion ratio >/= 1:1 5 is associated with a
lower risk of mortality after massive transfusion. J Trauma 2008;65(5):986–993.
76. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR Study Group. Transfusion of plasma, platelets,
and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the
PROPPR randomized clinical trial. JAMA 2015 313(5):471–482.
77. Ball CG, Kirkpatrick AW, McBeth P. The secondary abdominal compartment syndrome: not just
another post-traumatic complication. Can J Surg 2008;51(5):399–405.
78. Bream-Rouwenhorst HR, Beltz EA, Ross MB, et al. Recent developments in the management of
acute respiratory distress syndrome in adults. Am J Health Syst Pharm 2008;65(1):29–36.
79. Vidal MG, Ruiz Weisser J, Gonzalez F, et al. Incidence and clinical effects of intra-abdominal
hypertension in critically ill patients. Crit Care Med 2008;36(6):1823–1831.
80. Canizaro PC, Prager MD, Shires GT. The infusion of Ringer’s lactate solution during shock. changes
in lactate, excess lactate, and pH. Am J Surg 1971; 122(4):494–501.
81. Alam HB, Stanton K, Koustova E, et al. Effect of different resuscitation strategies on neutrophil
activation in a swine model of hemorrhagic shock. Resuscitation 2004;60(1):91–99.
82. Koustova E, Stanton K, Gushchin V, et al. Effects of lactated Ringer’s solutions on human
leukocytes. J Trauma 2002;52(5):872–878.
83. Deb S, Martin B, Sun L, et al. Resuscitation with lactated Ringer’s solution in rats with hemorrhagic
shock induces immediate apoptosis. J Trauma 1999;46(4):582–588; discussion 588–589.
84. Corso CO, Okamoto S, Ruttinger D, et al. Hypertonic saline dextran attenuates leukocyte
accumulation in the liver after hemorrhagic shock and resuscitation. J Trauma 1999;46(3):417–423.
85. Ross AD, Angaran DM. Colloids vs. crystalloids – a continuing controversy. Drug Intell Clin Pharm
1984;18(3):202–212.
86. Perner A, Haase N, Guttomsen AB, et al; 6S Trial Group:Scandinavian Critical Care Trials Group.
293
Hydroxethyl startch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med
2012;367(2)124–134.
87. Waxman K, Holness R, Tominaga G, et al. Hemodynamic and oxygen transport effects of
pentastarch in burn resuscitation. Ann Surg 1989;209(3):341–345.
88. London MJ, Ho JS, Triedman JK, et al. A randomized clinical trial of 10% pentastarch (low
molecular weight hydroxyethyl starch) versus 5% albumin for plasma volume expansion after
cardiac operations. J Thorac Cardiovasc Surg 1989;97(5):785–797.
89. Velanovich V. Crystalloid versus colloid fluid resuscitation: a meta-analysis of mortality. Surgery
1989;105(1):65–71.
90. Finfer S, Bellomo R, Boyce N, et al; The SAFE Study Investigators. A comparison of albumin and
saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350(22):2247–2254.
91. Caironi P, Tognoni G, Masson S, et al; ALBIOS Study investigators. Albumin replacement in patients
with severe sepsis or septic shock. N Engl J Med 2014;370;1412–1421.
92. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for
hypotensive patients with penetrating torso injuries. N Engl J Med 1994;331(17):1105–1109.
93. Hebert PC. Transfusion requirements in critical care (TRICC): a multicentre, randomized, controlled
clinical study. Transfusion requirements in critical care investigators and the Canadian Critical Care
Trials Group. Br J Anaesth 1998;81(suppl 1):25–33.
94. Hajjar LA, Vincent JL, Filomena RB, et al. Transfusion requirements after cardiac surgery: The
TRACS randomized controlled trial. JAMA 2010; 304(14):1159–1168.
95. Gervin AS, Fischer RP. Resuscitation of trauma patients with type-specific uncrossmatched blood. J
Trauma 1984;24(4):327–331.
96. Boudreaux JP, Bornside GH, Cohn I Jr. Emergency autotransfusion: partial cleansing of bacteria-
laden blood by cell washing. J Trauma 1983;23(1):31–35.
97. Glover JL, Smith R, Yaw PB, et al. Autotransfusion of blood contaminated by intestinal contents.
JACEP 1978;7(4):142–144.
98. Jurkovich GJ, Moore EE, Medina G. Autotransfusion in trauma. A pragmatic analysis. Am J Surg
1984;148(6):782–785.
99. Seligman R, Meisner M, Lisboa TC, et al. Decreases in procalcitonin and C-reactive protein are
strong predictors of survival in ventilator-associated pneumonia. Crit Care 2006;10(5):R125.
100. Stonelake PA, Bodenham AR. The carina as a radiologic landmark for central venous catheter tip
position. Br J Anesth 2006;96(3):335–340.
101. Marik PE, Baram M, Vahid B. Does central venous pressure predict fluid responsiveness? A
systematic review of the literature and the tale of seven mares. Chest 2008;134:172–178.
102. Boyd JH, Forbes J, Russell JA, et al. Fluid resuscitation in septic shock: A positive fluid balance and
elevated central venous pressure are associated with increased mortality. Crit Care Med
2011;39:259–265.
103. Connors AF Jr, Speroff T, Dawson NV, et al. The effectiveness of right heart catheterization in the
initial care of critically ill patients. SUPPORT Investigators. JAMA 1996;276(11):889–897.
104. Iberti TJ, Fischer EP, Leibowitz AB, et al. A multicenter study of physicians’ knowledge of the
pulmonary artery catheter. Pulmonary Artery Catheter Study Group. JAMA 1990;264(22):2928–
2932.
105. Reynolds HN, Haupt MT, Thill-Baharozian MC, et al. Impact of critical care physician staffing on
patients with septic shock in a university hospital medical intensive care unit. JAMA
1988;260(23):3446–3450.
106. Via G. International evidence-based recommendations for focused cardiac ultrasound. J Am Soc
Echocardiogra 2014;27(7):683e1–683e33.
107. Vieillard-Baron A, Chergui K, Rabiller A, et al. Superior vena caval collapsibility as a gauge of
volume status in ventilated septic patients. Intensive Care Med 2004;30(9):1734–1739.
108. Cannesson M, Slieker J, Lehot JJ, et al. Prediction of fluid responsiveness using respiratory
variations in left ventricular stroke area by transesophageal echocardiographic automated border
detection in mechanically ventilated patients. Crit Care 2006;10(6):R171.
109. Yanagawa Y, Sakamoto T, Okada Y. Hypovolemic shock evaluated by sonographic measurement of
the inferior vena cava during resuscitation in trauma patients. J Trauma 2007;63(6):1245–1248.
294
110. Russell J, Walley K, Singer J, et al; the VASST investigators. Vasopressin versus norepinephrine
infusion in patients with septic shock. N Engl J Med 2008:358:877–887.
111. Hopf HW. Molecular diagnostics of injury and repair responses in critical illness: what is the future
of “monitoring” in the intensive care unit? Crit Care Med 2003;31(suppl 8):S518–S523.
295
Chapter 10
Critical Care
Damon Clark and Heidi Frankel
Key Points
1 Intensive care unit (ICU) utilization is expected to increase as “baby boomers” come of age.
2 Surgical patients benefit from receiving critical care delivered by multidisciplinary teams led by an
intensivist. Around the clock intensivist presence (24 × 7) may not affect mortality in ICUs with
high-intensity staffing, but is thought to be most useful in those with less-intense staffing models.
3 Delivery of evidence-based medicine in surgical ICU patients results in improved mortality and
morbidity. Streamlining comprehensively written guidelines into “bundles” and use of checklists may
improve compliance and outcome.
4 Scoring systems have been developed and refined to address population outcome (mortality) and to
quantify organ dysfunction in the ICU.
5 Oxygen delivery and extraction can be monitored using pulmonary artery catheters (PAC). There is
no benefit to supranormalization of values in ICU patients and likely of PAC monitoring in most
instances. Fluid resuscitation using functional dynamic monitoring may be more efficacious than that
targeted to static values. Focused echocardiography may provide advantages to interpretation of
cardiac function over more traditional methods to afford therapies that can improve outcome.
Patients in cardiac arrest or impending cardiac arrest should be managed with principles outlined in
current Advanced Cardiac Life Support Guidelines. One of the three rhythms that can produce
pulselessness can be treated electrically, the other two require pharmacologic therapy. Dysrhythmias
are treated by considering their duration and association with hemodynamic instability and heart
failure.
6 Hypoxemia may result from mismatch of ventilation and perfusion (V/Q), anatomic or physiologic
shunting, hypoventilation, or less so due to impaired diffusion. Carbon dioxide, a readily diffusible
gas, is addressed by altering alveolar ventilation. Acute lung injury (ALI) and adult respiratory
distress syndrome (ARDS) fall along a spectrum of pulmonary disease. Conventional ventilatory
strategies incorporate a low-stretch philosophy. Evidence-based rescue strategies include prone
positioning and early chemical paralysis for those with severe ARDS. Most other ventilated patients
should be lightly sedated, screened for delirium, and kept moving with daily assessment for the
ability to extubate. The role for airway pressure release ventilation, extracorporeal support, and
inhaled prostacyclins is evolving.
7 Venous thromboembolism (VTE) is a significant problem in surgical ICU patients and chemical
prophylaxis alone has been demonstrated to beneficially impact outcome. Low–molecular-weight
heparins are more efficacious than unfractionated heparin in those at the highest risk in this
population, if the risk of bleeding can be mitigated. New oral inhibitors of factors Xa and thrombin
(II) have not been trialed specifically for VTE prophylaxis in general surgery ICU patients, but these
agents will, undoubtedly, play a more important role in the future as more effective strategies to
reverse them are developed.
8 A conservative transfusion trigger (7 g/dL hemoglobin) may be appropriate in most surgical ICU
patients, including those with gastrointestinal bleeding, neurotrauma, cardiac disease, and sepsis.
9 ICU patients should undergo routine assessment and adequate support of their nutritional status to
preserve lean body mass, maintain immune function, and avert metabolic complications. Enteral
nutrition, delivered either gastrically or more distally, is invariably possible and preferred in most
states. Earlier evidence supporting administration of immunonutrition (including components such as
glutamine and omega-three fatty acids) has been refuted, although a hypocaloric, high-protein diet
may be beneficial in all. Patients who are not being enterally fed, particularly those who will require
mechanical ventilation for more than 48 hours or have a coagulopathy are candidates for
pharmacologic prophylaxis of stress gastrointestinal bleeding. Proton pump inhibitors may be
296
superior to histamine-2 antagonists.
10 Acute kidney injury is a common complication in the surgical ICU and portends poor outcome. Few
preventative measures have been proven successful short of rapid attention to diagnosis and
treatment of sepsis and adequate volume resuscitation. Both continuous and intermittent dialysis
may be equally effective in treating patients and may be possible even in those with hemodynamic
instability.
11 To balance the risks of hyperglycemia and iatrogenic hypoglycemia, glucose control in ICU patients
should target levels between 140 and 180 mg/dL. Relative adrenal insufficiency is common in septic
ICU patients. Hypotension unresponsive to volume loading and pressors should prompt
consideration of glucocorticoid administration in this setting. Low levels of thyroid hormone may
not be indicative of hypothyroidism in ICU patients and should only be treated if accompanied by
clinical indications.
12 Successful resuscitation of sepsis requires rapid identification of acutely ill affected patients and
administration of broad-spectrum antibiotics. CVP-targeted resuscitation may be no more effective
than the use of clinical endpoints. Procalcitonin assays may be beneficial to appropriately shorten
the course of antibiotic therapy for bacterial infections without negatively impacting outcome.
Catheter-associated infections are often preventable; their prevention requires coordinated care and
various strategies, the most important of which is prompt catheter removal when no longer
required. Decontamination strategies aimed at reducing ventilator associated pneumonia and
methicillin-resistant Staphylococcus aureus infection may be efficacious.
Surgical patients requiring intensive care are unique in that they include those who have undergone
elective procedures as well as those who have been injured or require emergent or urgent operations.
As such, outcome, expectations and processes of care can be vastly different in surgical than in medical
ICU patients, the majority of whom are admitted emergently. It is, thus important, to consider whether
or not certain medical ICU literature is applicable to surgical patients. Most germane, mortality rates in
surgical ICUs are roughly 5% to 10%, as opposed to greater than 20% in most medical ICUs.1
1 Nonetheless, surgical ICUs and their patients share many features with those in medical ICUs.
Patients admitted to the critical care unit make up a large proportion of hospital cost and resources,
estimated to be roughly 1% of gross domestic product. More importantly, both surgical and medical
ICUs continue to find themselves understaffed. Both the supply of critical care practitioners is
inadequate and the demand is extensive, largely from aging patients with complex comorbidities
undergoing complicated procedures and multitrauma. There are approximately 3,000 boarded surgical
intensivists with less than 200 completing training annually, most of whom do not practice critical care
exclusively. In the United States, these surgical intensivists serve largely in surgical and surgical
specialty units of academic medical centers that account for approximately 10% to 15% of the nearly
6,500 ICUs with roughly 100,000 beds and 5 million admissions annually. The largest growing
demographic in hospitals overall and ICUs in particular, is the group over 65 years of age, now
accounting for over half of all admissions, resulting in ICUs practicing at over two-thirds of capacity.
ORGANIZATIONAL STRUCTURE OF CRITICAL CARE

The intensive care unit provides an environment that allows close monitoring and care by experienced
physicians, nurses, and other ancillary staff. Current ICUs have the following common features: (1) a
designated geographical space, (2) specialized monitoring and therapeutic capabilities, (3) resources to
provide continuous care, (4) appropriate nurse to patient ratio, and (5) specialized personnel. There is
controversy, particularly in surgical ICUs, as to how superspecialized they need be (visceral transplant
vs. cardiac surgery vs. noncardiac thoracic surgery). Practically, this is an issue of institutional volume
and expertise as there is little data to support superspecialization in surgical units (neurosurgical
patients, a notable exception). Diagnostic and therapeutic capabilities include invasive and minimally
invasive cardiac monitoring, basic and rescue modes of ventilation and adjuncts, extracorporeal support,
dialysis and hepatic support, and neurologic monitoring, as described below. ICU nurse to patient ratios
vary from 1:3 to 2:1 depending on patient acuity and therapeutic needs that may be addressed with a
scoring system such as the therapeutic intervention severity score (TISS).3 Finally, dedicated
pharmacists, dieticians, physical therapists, and advanced level practitioners such as acute care nurse
297
practitioners have all been demonstrated to improve process compliance and patient outcomes.4–7
Traditionally there are two types of ICU organizational structures: open and closed formats. In an
open ICU, the patients are admitted under the supervision and care of the primary physician/surgeon.
The primary physician or surgeon is responsible for providing patient care including order entry and
communication with the family, with ultimate decision making power over clinical decisions. The
primary physician/surgeon also continues to care for patients in other areas of the hospital, providing
both continuity, but also deflecting focus from the moment to moment care of the most acutely ill and
injured in the ICU. In the open format, the primary physician has the opportunity for consultation of an
intensivist. Within a closed format ICU, the patient’s care is transferred to an intensivist whose only
responsibility is to take care of patients within the ICU. Of course, hybrid models exist regarding
division of labor with respect to order entry and family communication. A multidisciplinary team led by
an intensivist can function in either closed or open structures (utilizing the intensivist in the consultant
role in the open format); however, the ability to provide immediate and continuous care may be
compromised in fully open surgical ICUs. In fact, the benefit of a high-intensity staffing model (with an
intensivist-led team or mandatory intensivist consultation) is more apparent in surgical than in medical
ICUs (perhaps due to the difficulty of an operative surgeon to simultaneously manage an ICU patient),
with a 15% decrease in ICU mortality.8,9 There is other work that specifically points to the benefit of a
closed ICU structure in decreasing morbidity and mortality.10,11,12 Nonetheless, despite the care model
employed, exquisite communication between members of the primary surgical team, ICU team, patient
(if possible), and family is mandatory to ensure best outcome and satisfaction by all. In recognition of
this, in the United States, The Joint Commission for Accreditation of Hospital Organizations (TJC)
requires a handoff between members of the surgical and ICU teams when a patient is admitted to the
ICU from the operating suites.13
2 The natural progression of work on the success of a high-intensity ICU staffing model on outcome
would be to promote around the clock availability of such services.14 However, these 24/7 intensivist
models did not improve SICU mortality in several studies and reviews, although they reduced morbidity
and resource utilization in others.15–17 This may be a consequence of the fact that studies examining the
effect of around the clock care have largely been carried out at academic medical centers with robust
nighttime fellow coverage.18 A noctensivist can improve morbidity and mortality in ICUs with low-
intensity staffing.
Finally, a taskforce rendered recommendations on the appropriate intensivist/patient ratio in teaching
institutions. A ratio of one intensivist to 14 patients should be maintained to ensure timely completion
of rounds, staff satisfaction, and provision of high quality patient care and education of trainees.19
Evidence-Based Care
Numerous extensively researched evidence-based guidelines have been developed covering many
aspects of critical care, including the management of sepsis, ventilator management, and administration
of nutrition among others, the most important of which will be discussed below.20
3 The most robust evidence lends itself to the multidisciplinary, multiprofessional development of
institutional protocols and clinical practice guidelines. Unfortunately, without electronic prompts or
other mechanisms in place, compliance by even well-intentioned practitioners may be less than ideal.
Thus, ICU care providers have developed memory aids in the form of checklists and bundles. Further,
this simplification of ICU processes, which, in turn, may improve outcome, lends itself to regulatory
scrutiny.
Checklists do not necessarily reinforce evidence-based care (although they certainly can). They are
meant to embody crew resource management strategies. The use of a daily goals checklist in the ICU
enables practitioners to ensure that important components of care are addressed. Vincent described the
acronym “FAST HUG” as a simple checklist mnemonic for ICU use (Table 10-1).21
In our ICU, we have added a component to each of the letters. Use of these checklists improves the
knowledge of the game plan by the entire care team. Pronovost and colleagues demonstrated that use of
a daily goals sheet improved understanding of the daily plan from 10% to 95% and effected a decreased
ICU length of stay.22
Table 10-1A FAST HUG
298
Bundles
The process of bundling evidence-based care practices allows ICUs to keep up with regulatory changes
and practice the most up to date critical care practices. Unlike checklists, ICU care bundles are always
evidence based. Bundles are comprised of interrelated processes and have a limited number of elements
(typically three to seven) whose key processes must be carried out in the same space and time. Bundles
exist addressing ventilator-associated pneumonia, central line infection, catheter-associated urinary tract
infection and pressure ulcer prevention, diagnosis and treatment of sepsis, and promotion of palliative
care. Large collaborative groups in the United States, including the Voluntary Hospital Association, The
Institute for Healthcare Improvement and the Michigan Health and Hospital Association-Keystone
Project, have shown improved patient outcomes after implementation of various bundles.23 Continuing
education is required to maintain appropriate use and compliance with these management bundles. The
implementation and use of sepsis resuscitation bundle and management bundle were significantly
improved after 2 month nationwide education effort to improve compliance with the care for patients
with severe sepsis.24 These evidence-based guidelines and bundles have been shown to improve
mortality and decrease morbidity and ICU related complications. Severe sepsis and septic shock bundles
are associated with reduced in-hospital mortality (Table 10-2). Mortality rates in these centers using
severe sepsis and septic shock bundles decreased by 16.7%.25 It has also been shown that the
implementation of central venous catheter care bundles led to decreased central line associated blood
stream infections (Table 10-3).26 Awakening, breathing, coordination, delirium, and early mobility
(ABCDE) bundles show some improvement in ICU average length of stay and average days on
mechanical ventilation.27 Finally, some have “bundled” a variety of these disparate bundles together to
drive global evidence-based care. The Surgical Care Improvement Project (SCIP) guidelines are perhaps
the most relevant and robust example.
Table 10-1B Extended FAST HUG – as Modified by the Authors from above
Table 10-2 Surviving Sepsis Care Bundle
299
The application of evidence-based guidelines into clinical practice, even facilitated by use of bundles,
is often difficult. Educational and quality improvement programs, described above, can improve the
implementation of and compliance with these evidence-based guidelines. Further, it is important to
realize that bundles and any evidence-based guidelines must be continuously updated as new
information comes to the fore, particularly if the level of evidence or strength of recommendation was
weak. Examples in the care of the septic patient will be discussed below. Finally, although use of
bundles can promote team-building by providing objective feedback of performance, competent and
individualized clinical decision-making should not be sacrificed.
Table 10-3 Central Line Associated Bloodstream Infection (CLABSI) Bundle
Table 10-4 Comparison of ICU Scoring Systems
CRITICAL CARE PROGNOSTICATION AND SCORING

4 ICU scoring systems have been used to provide a framework to describe patients’ severity of illness
for the routine evaluation of ICU performance, quality improvement initiatives and to prognosticate
outcome.28 The most robust prognostication systems compare observed and risk-adjusted hospital
mortality for critically ill patient groups derived from analysis of large data sets. They operate on the
premise that early physiologic derangements prior to resuscitation and therapy present early in the ICU
admission will influence hospital mortality. Other systems have been developed to quantify organ
dysfunction and therapeutic interventions predicted.
The ideal scoring system should be valid, reliable, calibrated, discriminating, and simple. The
Glasgow coma scale score is an apt example. However, since ICU patients are heterogeneous,
documentation is often incomplete and practices are not standardized, such a system is not available in
300
the ICU. The most frequently used severity of illness scores in an adult ICU used to prognosticate
hospital mortality are Acute Physiology and Chronic Health Evaluation (APACHE), the Mortality
Probability Model (MPM), and the Simplified Acute Physiology Score (SAPS) with higher scores
portending increased hospital mortality. APACHE and MPM were developed using data predominantly
from the United States; SAPS was more global (Table 10-4). To stay relevant and useful, these scoring
systems require and have undergone regular updates and regional customizations. These scoring systems
are currently in their third and fourth generations. It is vital to remember that these scoring systems
provide prognostication for the outcome of an ICU population more accurately than for an isolated
patient.
APACHE was developed several decades ago by William Knaus and colleagues at George Washington
University. The inaugural version ranked 34 acute variables from one to four and weighted chronic
health conditions A to D to render a score with higher numbers suggesting more acutely ill patients.
Versions two and three decreased the acute variable to 12 and 17, respectively, and created a simpler
way to weight the chronic health evaluation. The proprietary (and expensive) version, APACHE III,
never had large market penetration and was much more complex than earlier versions. APACHE IV29
which included more variables has many components in the public domain; however, without a
regulatory requirement to provide risk-adjusted ICU metrics and the need to employ personnel to verify
and interpret data, it is also not widely used. Further, since the data is collected at the time of ICU
admission, the possibility of lead-time bias exists. APACHE provides an algorithm for prediction of ICU
length of stay. Several studies have indicated that the current version of APACHE, although labor
intensive, is more accurate in prognosticating outcome due to better calibration and discrimination with
fewer excluded patients. This is particularly true for surgical patients.
SAPS shared many variables and weightings common with APACHE but provided separate
prognostication for medical, scheduled and unscheduled surgical patients; cardiac and burn patients are
excluded.30 Further, it provides customizable equations to predict outcome according to seven distinct
geographic locations.
The MPM uses dichotomous physiologic (not laboratory) variables for the most part (simplifying data
collection), collecting data both upon admission and at 24 hours to measure mortality risk at 24 and 48
hours. However, it excludes more patients than does APACHE. MPM-III has been further modified with
additional variables and different patient exclusions and is known as the ICU Outcomes Model (ICOM)
that has been endorsed by the National Quality Forum of the United States for public reporting of risk-
adjusted hospital mortality of ICU patients.31
The future of ICU prognostication may well involve interpretation of “big data” that relies less on
traditional data acquisition and storage and more on linear or logistic regression modeling. Much work
must be done in this realm before practical applications are available.32
Several organ failure scores exist as well, designed to link homogeneous patients for the purpose of
clinical trials and quality assessment. They can be used to provide initial as well as serial assessments.
The SOFA and Marshall scores consider variables in six categories (respiratory, cardiovascular,
hematologic, central nervous system, renal, and hepatic). The Denver score excludes the hematologic
and neurologic components. A Marshall or Denver score greater than or equal to 4 implies multiorgan
dysfunction (Table 10-5).33,34
TISS provides a sum of all interventions in physiologic categories to assist with resource utilization.
HEMODYNAMIC MONITORING AND TREATMENT

Oxygen Delivery and Consumption
Oxygen delivery (DO2), the rate at which oxygen is transported to the microcirculation from the lungs,
is the product of cardiac output and arterial oxygen content (CaO2) and is normally about 1,000
mL/min. CaO2, in turn, is the product of hemoglobin and oxygen saturation (SaO2) multiplied by 1.34
(g oxygen per 100 mL hemoglobin) added to the partial pressure of oxygen (PaO2) multiplied by 0.003.
Thus, delivery falls in instances of cardiac failure, hypovolemia, anemia, or less so due to poor
oxygenation. Oxygen consumption (VO2), the rate at which oxygen is removed from the blood by the
microcirculation, is the product of cardiac output and the arteriovenous O2 difference (CaO2 − CvO2)
and is normally 250 mL/min in an average adult. Thus, oxygen extraction (OE) ratio or the ratio of VO2
to DO2 is normally about 25%. (The myocardium has the body’s highest extraction ratio at
301
approximately 75%.) Consumption remains constant over a wide range of DO2 by changes in OE. For
example, in situations of decreased delivery such as hemorrhagic or cardiogenic shock, consumption can
be maintained by increasing the extraction ratio. This mechanism may be altered in critically ill patients
who show marked increases in consumption under the influence of stress hormones and catecholamines.
However, there is little evidence that artificially augmenting DO2 to so-called supranormal levels by
means of inotropes or red cell transfusion results in improvement in morbidity or mortality.
Table 10-5 Marshall Multiple Organ Dysfunction Syndrome (MODS) Versus

Denver Multiple Organ Failure (MOF) Organ Failure Scores
Mixed venous oxygen saturation (SvO2) is expressed as 1-VO2/DO2, with normal values of 60% to
80% that can be continuously displayed with an oximetric pulmonary artery catheter or measured from
the distal port. Reductions in SvO2 reflect a mismatch between DO2 and VO2 (Table 10-6).
Hemodynamic Monitoring
Assessment of volume status and cardiac function of the critically ill patient is evolving. Traditional
static measures of volume assessment using central and pulmonary artery catheters (PACs) are being
replaced in many settings by dynamic or functional measures afforded by technologies such as pulse
waveform analysis and focused cardiac ultrasound (ECHO). Similarly, indirect measurement of cardiac
function by PACs is being subsumed by pulse waveform analysis and systolic and diastolic evaluation of
left and right global and regional function using ECHO.
Assessment of Fluid Responsiveness

The concept of volume status using static measures has evolved to “volume responsiveness” using
dynamic or functional measures to assess whether a fluid bolus will improve the stroke volume (SV) and
cardiac performance of a critically ill patient, the principal goal of resuscitation. Static measures such as
central venous pressure (CVP) and pulmonary artery occlusion pressure (PAOP) can give inferential
data of cardiac filling pressures at a single time-point, which then extrapolates to cardiac preload (end
diastolic volume) and volume status of the patient. However, these pressures can be altered depending
on cardiopulmonary physiology, do not always correlate with Frank–Starling principles, and give no
indication of whether the patient will respond to a bolus of infused fluid, which is ultimately what those
tasked with resuscitation want to know.
Static measures of volume status include assay of CVP and PAOP. These measures are made at end
expiration when the pleural pressure is closest to atmospheric pressure. Normal venous waveform
components include the “a” wave (corresponding to atrial contraction), the “c” wave (tricuspid valve
closure and isovolumic right ventricular contraction), and the “v” wave (ventricular ejection driving
venous filling of the atrium) (Fig. 10-1). Clinically, the high point of the “a” wave is the atrial pressure
at maximum contraction, where atrial pressure is greater than ventricular diastolic pressure. Here, the
atrium is contracted and the tricuspid valve is open, which is synonymous with right ventricular end
diastolic pressure, making the ventricle, atrium, and vena cava interconnected. Optimally, this is the
point at which the CVP is measured. Unfortunately, many intracardiac and extracardiac interactions can
302
alter these pressure relationships in the vena cava and diseased heart, and, thus, affect the CVP
waveform. For example, atrial fibrillation fails to produce an “a” wave, and AV-dissociation produces
irregular augmented (cannon) “a” waves with absent “c” and “v” waves, making calculation of mean
CVP difficult. Tricuspid regurgitation and tamponade may produce augmentation of the v wave and
falsely imply adequate or increased intravascular volume in a patient who may be hypovolemic. Thus,
the CVP waveform may fail to provide an adequate reflection of volume responsiveness in diseased
states.
Table 10-6 Oxygen Delivery and Consumption Equations
Figure 10-1. Normal venous waveform with ECG.
5 Further, the use of CVP to guide resuscitation has not been demonstrated to be beneficial in many
large clinical series. A large meta-analysis revealed a very poor relationship between CVP and blood
volume.35 Additionally, several large recent trials of sepsis resuscitation demonstrated that resuscitation
targeted to CVP endpoints did not improve outcome.36,37
Pulmonary artery catheter-based volume assessment employs the principle that a single column of
fluid forms from the pulmonary artery to the left ventricle during diastole. For a given left ventricular
end-diastolic pressure (LVEDP) and compliance, left ventricular end-diastolic volume (LVEDV) can be
estimated. Based on the Frank–Starling principle, the force of ventricular contraction is proportional to
muscle stretch and LVEDV, thus as PAOP estimates LVEDV for a given cardiac output, preload may be
determined. Numerous physiologic changes may alter the relationship between PAOP and LVEDV,
including veno-occlusive disease, pulmonary hypertension, ARDS, increased intrathoracic pressure,
valvular disease, and altered cardiac compliance. Finally, large clinical trials have failed to demonstrate
a benefit to outcome for those resuscitated to a PAOP endpoint.38
Dynamic or functional measures of volume responsiveness include those on both the arterial side and
venous side of the heart. Normally, the inspiratory increase in pleural pressure during positive pressure
breathing reduces right ventricular preload and stroke volume, manifested on the arterial side within
two to three beats in most. Left ventricular stroke volume diminution is maximal during expiration.
These normal physiologic changes during the mechanically supported respiratory cycle are augmented
with hypovolemia that is volume responsive. Pulse waveform analysis uses analysis of the arterial
303
pressure waveform. The area under the curve corresponding to systole (i.e., before the dicrotic notch) is
used to calculate stroke volume (Fig. 10-2). Computer calculation is made of the maximal and minimal
amplitude of the curve. In general, a variation in stroke volume (SVV) of greater than 13% to 15%
reflects volume responsiveness, whereas values below this threshold imply that the patient is beyond
the upper inflection point of the Frank–Starling curve, and will not benefit from further volume loading.
There are instances where it is possible to misinterpret these values. For example, high vasopressor
burden or lack of arterial compliance (such as in diffuse atherosclerosis) may alter blood flow and
arterial wave morphology, respectively. However, clinical applications of SVV as a volume assessment
tool have been promising.39
Venous assessment of volume responsiveness is performed by ECHO, which can also perform arterial
side estimation. ECHO can provide volume assessment with both static and dynamic values. Further,
many static measures can be rendered functional by performing measurements both before and after a
passive leg raise, a maneuver that replicates volume loading. Passive leg raising measurements may be
the only accurate methodology to approximate fluid responsiveness in spontaneously breathing patients.
In these patients, a breath results in an increase in SV and systolic pressure. Static values include
measurement of the inferior vena cava (IVC) on the long axis view, or in some series by the superior
vena cava (SVC) or internal jugular vein (IJV) on the venous side or calculation of the velocity time
integral (VTI) on the arterial side. Collapsibility of the IVC (or SVC/IJV) of at least 15% and as much as
50% during respiration predicts fluid responsiveness.40 Right-sided heart failure may alter the size
relationships of the central veins, thus providing an underestimate of fluid responsiveness using venous
measurements (lack of respiratory variation due to pressure overload and diminished venous return to
the heart). Arterial assessments are typically done of aortic blood velocity approximated from the VTI.
Assessment of Cardiac Function is best understood by recollection of the cardiac pressure–volume
curve depicting the cardiac cycle (Fig. 10-3). Starting at the top right at “A,” the aortic valve opens and
blood is ejected into the outflow tract. At “B” systole ends as the aortic valve closes. A period of
isovolumic relaxation occurs and ventricular pressure falls until the mitral valve opens at “C,” the start
of diastole. Diastole ends as the mitral valve closes at “D” and then there is a period of isovolumic
contraction with both valves closed until the cycle repeats. Note that the distance across the box
represents SV. SV is the amount of blood ejected per beat and is expressed in mL and determined by
preload, afterload, and contractility. The product of SV and heart rate is CO. Ejection fraction (EF), a
more valid estimate of cardiac function, is the proportion of preload or EDV ejected per beat or
SV/EDV.
Figure 10-2. Arterial pressure waveform. Area under systole curve is used to calculate stroke volume. pSBP, peripheral systolic
blood pressure; pPP, peripheral pulse pressure; pDBP, peripheral diastolic blood pressure.
304
Figure 10-3. Left ventricular pressure–volume curve. Ees, LV elastance; Ea, arterial elastance; ESV, end-systolic volume; EDV, end-
diastolic volume; ESP, end-systolic pressure; EDP, end-diastolic pressure; LV, left ventricle. A: aortic valve opens; B: aortic valve
closes; C: mitral valve opens; D: mitral valve closes.
PA catheters determine cardiac output by thermodilution. The thermodilution technique measures

temperature changes sensed by a balloon at the distal end of the catheter after a cold saline injection is
performed through the proximal port. Based on the modified Stewart–Hamilton equation, which
constructs a plot of temperature change against time, measurements of cardiac output can be obtained.
Thermodilution technique assumes that complete mixing of the blood occurs, that there is constant
blood flow in the heart, and that there is no loss in concentration of the indicator between the point of
injection and the distal balloon tip. Slow injections, incorrect volumes of injectate, incorrect
temperature of injectate, either isolated or in combination with anatomic and physiologic cardiac
derangements can alter the accuracy of cardiac output determination.
Pulse contour analysis can also be used to measure stroke volume (and hence cardiac output). Using
PAC thermodilution as the gold standard, accuracy is acceptable.
ECHO does not suffer from many of the shortcomings of CVP, PAC, or arterial line assessment with
regard to the assessment of cardiac function. ECHO can determine left ventricular function (systolic and
diastolic), right ventricular function, and assess wall motion abnormalities, valve defects, pericardial
fluid, and provide real-time information on effectiveness of inotropic and vasopressor therapy. ECHO
can provide information about heart function in a qualitative or quantitative fashion – it can be used to
assess left and right heart morphology, dynamics, and size, and can determine the difference in EF and
stroke volume, and perform quantitative estimates of pulmonary artery and right ventricular pressure.
ECHO is unique in that it is the only tool available that can provide EF data in addition to SV (CO).
Shock states may be due to impaired EF or contractility (requiring inotropy) or due to diminished
volume status and stroke volume (requiring fluid), which is not discernable with a PAC. Various ECHO
methodologies are available to determine and measure EF, including a purely qualitative one that is
reasonably accurate compared to quantitative means.
ECHO can also discern right heart dysfunction, very common in surgical ICU patients by examining
size, morphology and function of the right ventricle. Underfilling of the left heart, typically treated by
volume loading, requires attention to inotropic support in the case of right heart failure. Finally, unique
to ECHO is the ability to assess for diastolic dysfunction as occurs with sepsis, tamponade, and increased
pleural pressure (as with pneumothorax, abdominal compartment syndrome, and massive pleural
effusions).
TREATMENT OF CARDIAC ARREST AND DYSRHYTHMIAS

Dysrhythmias are extraordinarily common in both cardiac and noncardiac surgical ICU patients. Those
most life-threatening can be treated by following current American Heart Association Advanced Cardiac
Life Support (ACLS) guidelines.41 For patients who become pulseless in the ICU, rapid restoration of the
circulation employing basic life support strategies (BLS) is vital. The most important features of the
current BLS guidelines include the recognition that cardiopulmonary resuscitation (CPR), when
indicated, be delivered by pushing hard and fast with complete recoil at a rate of at least 100
compressions/min to a depth of 2 in in adults. CPR providers should deliver no more than 2 minutes of
305
therapy each (or five cycles of compressions) until a personnel switch is made. In adults, the ratio of 30
compressions to 2 breaths is maintained until ventilation can be controlled by intubation and controlled
ventilation. Cricoid pressure is not recommended in current ACLS guidelines. Further, the rapid use of a
defibrillator is key to improving postarrest survival. Of course, in ICU patients, cardiac arrest is often
witnessed and the underlying rhythm known and may not respond to defibrillation. Sadly, cardiac arrest
from a rhythm other than ventricular fibrillation, such as from bradycardia progressing to asystole or
pulseless electrical activity (PEA), portends a poor prognosis, often as the result of acidosis or profound
hypoxia incidental to sepsis and multiple organ failure. Another important feature of the current BLS
and ACLS guidelines that may impact surgical ICU patients is the recognition of the need for postcardiac
arrest care. This certainly includes fluid resuscitation and administration of pressors and inotropes as
needed. However, there may also be a need to interrogate via coronary angiography and treat for acute
coronary syndrome if anticoagulation can be tolerated and for consideration of postarrest hypothermia
to preserve neurologic function. Although hypothermia protocols were established to address out of
hospital cardiac arrest with coma, there has been increasing use of the modality for hospitalized patients
as well. Current guidelines also address new technology with biphasic electrical sources that deliver
shocks for dysrhythmias with a pulse and defibrillation in those with ventricular fibrillation. Another
important component of the recommendations is the use of end-tidal CO2 monitoring to ensure
adequacy of CPR quality.
Three dysrhythmias produce pulselessness: ventricular fibrillation, asystole, and PEA. Only
ventricular fibrillation is responsive to defibrillation which is with 120 to 200 J using a biphasic device
as per manufacturer’s recommendations. PEA and asystole are treated by administration of epinephrine
(1 mg every 3 to 5 minutes) and/or vasopressin (40 U one-time dose). Pulseless ventricular tachycardia
is treated like ventricular fibrillation with additional shocks given after five cycles of CPR (2 minutes).
In addition, epinephrine and vasopressin are administered as CPR continues. Continued pulseless
ventricular tachycardia and fibrillation can be treated with amiodarone (300 mg with a second dose of
150 mg if refractory) or lidocaine (1.0 to 1.5 mg/kg).
For the remainder of dysrhythmias, several key features should be noted. Is the patient,
hemodynamically stable or unstable? Is the EF normal or altered? Is the dysrhythmia acute or long
standing? Hemodynamic instability in association with a rhythm disturbance often renders electrical
therapy more desirable, if possible. In those with a low EF, antiarrhythmics that are also negative
inotropes should be avoided. Finally, even duration of as little as 48 hours can increase the risk of
thrombotic complications of some dysrhythmias (e.g., atrial fibrillation) and can alter therapeutic
decisions.
PULMONARY GAS EXCHANGE

Consists of the intake of oxygen by pulmonary capillaries from the alveoli and the excretion of carbon
dioxide in expired breaths.
Oxygenation
Normal lung function and gas exchange require patent and dry alveoli with a narrow interface with the
pulmonary capillaries. Once red blood cells become saturated with oxygen, the rest dissolves into the
plasma and the measured partial pressure of oxygen (PO2) is 100 mm Hg with an oxygen saturation
(SaO2) of 100%. Since a small portion of blood is diverted away from the pulmonary circulation (via
bronchial vessels), a normal PaO2 is 90 mm Hg with 98% saturation. Insufficient blood oxygenation is
termed hypoxemia. This is to be differentiated from hypoxia, which is abnormally low oxygen content
in a tissue or organ. The alveolar to arterial (A-a) oxygen gradient is a common measure of oxygenation
(“A” denotes alveolar and “a” denotes arterial oxygenation). PaO2 is measured by arterial blood gas,
while PAO2 is calculated using the alveolar gas equation: PAO2 = (FiO2 × [Patm − PH2O]) − (PaCO2
÷ R) where FiO2 is the fraction of inspired oxygen (0.21 at room air), Patm is the atmospheric pressure
(760 mm Hg at sea level), PH2O is the partial pressure of water (47 mm Hg at 37°C), PaCO2 is the
arterial carbon dioxide tension, and R is the respiratory quotient. The normal gradient is about 10 mm
Hg. Dividing the PaO2 by the FiO2 estimates the A-a gradient, which normally approximates 500.
Perturbations causing hypoxia and hypoxemia may be the result of hypoventilation relative to
perfusion (V/Q mismatch), impaired diffusion, or shunt. Hypoventilation, a result of neuromuscular
dysfunction (or more typically iatrogenic due to medications) and impaired diffusion (occurring with
306
pulmonary edema or interstitial lung disease) can be treated effectively by exogenous administration of
oxygen. The A-a gradient is normal in hypoxemia due to pure hypoventilation and increased in V/Q
mismatch. V/Q mismatch, the cause of most hypoxemia in the ICU, occurs with decreased airflow to the
alveoli in relation to the amount of pulmonary capillary blood flow. In the normal lung, there is V/Q
mismatch because perfusion and ventilation are heterogeneous. Both ventilation and perfusion are
greater in the bases than in the apices. However, the difference between apical and basilar ventilation is
less than the difference between apical and basilar perfusion. Therefore, the V/Q ratio is higher in the
apices than in the bases. In the diseased lung, V/Q mismatch increases because heterogeneity of both
ventilation and perfusion worsen resulting in hypoxemia. Common causes of hypoxemia due to V/Q
mismatch include obstructive lung diseases, pulmonary vascular diseases, and interstitial diseases.
Shunting occurs when there is adequate ventilation of the alveoli but decreased pulmonary capillary
blood flow. Shunting may be anatomic as with intracardiac shunts and hepatopulmonary syndrome or
physiologic as when nonventilated alveoli are perfused as with pneumonia. Hypoxia due to shunting
with venous admixture as with severely depressed cardiac output or anemia cannot be overcome by
administration of oxygen (Fig. 10-4).
Figure 10-4. West lung zones. Zone 1: Not observed in healthy lung. Alveolar pressure exceeds pulmonary blood vessel pressure
leading to alveolar dead space. Zone 2: Located approximately 3 cm above heart. Pulmonary vessel pressure exceeds alveolar
pressure in a pulsatile fashion and allows pulmonary blood flow and alveolar distention. Zone 3: Majority of healthy lungs with
continuous blood flow and oxygenation. PA, Alveolar Pressure; Pa, arterial pressure; PV, venous pressure.
Ventilation and CO2 Removal

Ventilation refers to the exchange of air from the atmosphere to the lungs and alveoli. The rate at which
alveolar ventilation occurs determines the amount of carbon dioxide (CO2) excretion, a readily
diffusible substance. The amount of CO2 produced and requiring elimination is related to the respiratory
quotient (RQ). RQ is the ratio of CO2 produced to O2 consumed and is normally 0.8, depending on the
diet. Chemoreceptors in the medulla are responsive to pH changes and when patients become acidotic
they hyperventilate to decrease PaCO2 to maintain homeostasis at 40 mm Hg. End tidal CO2 may be
lower than PaCO2 if substantial lung is ventilated but not perfused (dead space).
Pulmonary Mechanics
The relationship between ventilatory volumes and pressures is referred to as pulmonary mechanics and
depends on compliance. The functional lung in acute lung injury is smaller with heterogeneous disease,
necessitating a protective lung strategy of ventilation that will be described below.
Figure 10-5. Flow–time scalar showing autoPEEP.
VENTILATOR MODES AND GRAPHICS

One of the initial steps in evaluating a patient with respiratory failure is to establish a patent and
307
protected airway. The ICU team must determine if the patient has an acute issue causing the respiratory
failure that can be treated without mechanical ventilation. Through the use of physical examination,
bedside ultrasound and radiography, the ICU team may diagnose a pneumothorax or acute pulmonary
edema that can be treated without intubation. If the patient has acute respiratory failure without an
easily treatable process, intubation and mechanical ventilation may be safest. When setting up the
mechanical ventilator there are several options and modalities from which to select.
Mechanical ventilation improves oxygenation and ventilation by attempting to improve V/Q
mismatch by decreasing the amount of shunt. Current recommendations are for low tidal volume (Vt)
settings of 6 to 8 mL/kg for the prevention of barotrauma in surgical ICU patients.42 Respiratory Rate
(RR) is typically set at 12 to 16 breaths/min. RR is altered to achieve an optimal PaCO2. Positive end
expiratory pressure (PEEP) is applied to prevent significant alveolar collapse during expiration and is
particularly important in low lung volume ventilation strategies. PEEP is typically started at 5 cm H2O
but can be titrated up to improve oxygenation. The initial setting for patients with respiratory failure is
an FiO2 of 1.0. After initial check of ABG the FiO2 is weaned down to maintain a minimal PaO2 of 60
mm Hg and O2 saturation of >90% with goals of FiO2 <0.4 to prevent O2 toxicity.
Ventilatory mechanics can be displayed graphically and include scalars and loops. Scalars are plots
against time – either flow, pressure, or volume. Several loops are helpful clinically and include the
pressure–volume and flow–volume loops. Each graphic can be important in demonstrating a physiologic
anomaly and displays a certain pattern depending on the ventilator mode. The flow versus time scalar is
helpful for identifying air trapping or auto-PEEP that can accompany certain ventilator modes (Fig. 10-
5). This can result in barotrauma or hemodynamic instability. Measures to decrease auto-PEEP include
decreasing tidal volume, respiratory rate, or inspiratory time (depending on ventilator mode) or
increasing flow rate. The pressure time scalar allows the practitioner to view and calculate compliance
(Fig. 10-6). Further, one can observe elevations in peak airway pressure that may occur as a result of a
large pneumothorax or kinked endotracheal tube or a sharp decrease that may represent an airway leak
or disconnection. The volume versus time scalar allows one to identify an airway leak as well (Fig. 10-
7). Ventilators often display all three scalars simultaneously. A spontaneously breathing patient is
identified by the negative deflection in the pressure–time scalar at breath initiation (Fig. 10-8). Distinct
ventilator modes have unique methods of cycling, triggering, and limitations of breaths. In controlled
mandatory ventilation, breaths are volume-cycled, time-triggered, and flow-limited (Fig. 10-9). In
pressure-controlled ventilation, breaths are time-cycled, time–triggered, and pressure-limited. Note the
distinct difference in the flow and pressure versus time scalars compared to CMV (Fig. 10-10). Pressure
supported breaths are flow-cycled, patient-triggered, and pressure-limited (Fig. 10-11). Pressure and
volume controlled ventilation can be set in an assist control (AC) mode or intermittent mandatory
ventilation (IMV) mode. With the AC mode the patient receives a set number of breaths delivered per
minute whether with pressure or volume. Patients who initiate breaths on IMV will have tidal volumes
determined by their own respiratory effort and not the ventilator. Patients who are critically ill may
require AC for full support but these patients should be weaned to an IMV or PSV mode quickly to
prevent respiratory muscle atrophy.43
Figure 10-6. Pressure–time scalar.
ACUTE RESPIRATORY FAILURE

Diagnosis
6 Past consensus definitions of adult respiratory distress syndrome (ARDS) and acute lung injury (ALI)
308
categorized them by acute onset hypoxemia, bilateral infiltrates on chest radiography, and absence of
left atrial hypertension (i.e., noncardiac in etiology).44 ALI and ARDS were differentiated by the degree
of hypoxia, with ALI typified by a ratio of PaO2/FiO2 of less than 300 and ARDS 200. Newer definitions
make an attempt at describing timing relative to a known insult and acknowledge that cardiac failure is
now often diagnosed without the aid of a pulmonary artery catheter. Most importantly, ALI is now part
of ARDS spectrum that is classified as mild, moderate, or severe if the PaO2/FiO2 ratio is between 200
and 300, between 100 and 200, and less than 100, respectively.45 Further, this gradation of disease is
consistent with therapy, wherein less acute patients might be successfully treated with noninvasive
ventilation, moderately ill patients with higher PEEP and possibly neuromuscular blockade, and
severely ill patients possibly requiring prone positioning therapy and extracorporeal support.
Figure 10-7. Volume–time scalar.
Figure 10-8. Pressure–time scalar with alternating ventilator-assisted breaths and spontaneous breaths.
Ventilator Management
Conventional Modes
The ventilatory standard of care was set forth as a result of an early study from the NIH ARDS Network.
By all metrics, the patients ventilated at 6 mL/kg had better outcome than those who received 12
mL/kg. Thus, as a result, the standard of care for ventilating ARDS patients became the use of low tidal
volumes, or low stretch therapy to diminish the incidence of ventilator-associated barotrauma.46
Rescue Therapies
Involving different ventilator modes share the fact that they achieve their end by raising mean airway
pressure while preventing elevation of peak airway pressure. How the disparate modes of ventilation
achieve this varies.
High PEEP. Ideally, to prevent atelectasis and avoid overdistension, PEEP is titrated to the safe window
between the lower and upper inflection points of the respiratory pressure–volume curve (Fig. 10-12).
The precise PEEP level to optimize outcome from ARDS, particularly in the face of low stretch
ventilation, has been the subject of several trials. The Assessment of Low Tidal Volume and Elevated
End-Expiratory Pressure to Obviate Lung Injury (ALVEOLI) trial did not demonstrate a benefit to adding
high PEEP to those ventilated with lower tidal volumes.47 Two other trials (LOVS and EXPRESS)
reached similar conclusions.48,49 A systematic review and meta-analysis showed no statistically
significant difference in hospital mortality overall but worse in those with severe established ARDS
treated with high PEEP.50
309
Figure 10-9. Controlled mandatory ventilation. Breaths are volume-cycled, time-triggered, and flow-limited.
Perhaps the more valuable variable to consider preventing barotrauma and atelectasis is not the PEEP
level, but rather the transpulmonary pressure. Transpulmonary pressure is the difference between
airway pressure and pleural pressure. As airway pressure is normally slightly positive and pleural
pressure slightly negative, transpulmonary pressure is typically zero. If transpulmonary pressure were
negative, it would favor atelectasis, whereas a positive value would promote barotrauma and
hemodynamic compromise. In ICU patients, there are many forces extrinsic to the lung that can raise
pleural pressure and promote atelectasis. These include obesity, intra-abdominal hypertension, and
anasarca. Thus, in these circumstances, it might be beneficial to utilize higher PEEP levels. Although it
is not possible to measure pleural pressure directly, esophageal pressure is a reasonable surrogate.
Although titrating PEEP to esophageal pressure has not yet been proven clinically efficacious, it may in
the future.
Figure 10-10. Pressure controlled ventilation: Breaths are time-cycled, time–triggered, and pressure-limited.
310
Figure 10-11. Pressure support (PS). Breaths are flow-cycled, patient–triggered, and pressure-limited. Pressure support breaths are
second and fourth breaths.
High-Frequency. Modes include high-frequency jet and oscillatory ventilation. Both utilize ultrafast
subtidal ventilation and can be employed for rescue or treatment of bronchopleural fistulae. In general,
heavy sedation and/or paralysis are required. The ventilator decouples oxygenation ventilation such
that unique settings are used to manipulate either one. The ventilatory circuit is heavy and cumbersome
in this mode and secretion clearance is problematic. Importantly, two large trials failed to show
improvement in ARDS patients, with one demonstrating an increased mortality in the high-frequency
group.51,52
Airway Pressure Release Ventilation (APRV). takes advan-tage of spontaneous breathing (and hence
the ability to keep patients more awake) with CPAP and a brief pressure release, generating a very high
inspiratory to expiratory (I:E ratio). The extremely short phase time of pressure release builds up
intrinsic PEEP to prevent atelectasis. There are increasing studies in the literature that demonstrate that
APRV is at least equivalent to low stretch ventilation in terms of safety and outcome.53,54 As APRV may
be better tolerated than low tidal volume ventilation, some would say this provides an advantage. There
is also some suggestion that routine use of APRV may decrease the incidence of and mortality from
ARDS.55
Figure 10-12. Pressure–volume curve with added PEEP. V, volume; P, pressure; LIP, lower inflection point; UIP, upper inflection
point. Ideal PEEP is set between LIP and UIP.
Volumetric Diffusive Respiration (VDR). Is a hybrid mode that combines convective gas delivery
similar to CPAP, diffusive gas delivery similar to oscillatory modes and a unique percussive mode to
promote secretion removal. As such, it has been used extensively in the burn patient population.
However, the technology is not widely available and large trials of use in rescue therapy of ARDS
patients have not been completed.
Extracorporeal Support. via extracorporeal membrane oxygenation (ECMO) was thought to provide a
beneficial effect to those patients in the European Conventional Ventilation or ECMO for Severe Adult
Respiratory Failure (CESAR) trial.56 However, it was apparent on further analysis that patients with
311
severe ARDS benefit most from transfer to a center that had ECMO capabilities, whether or not the
therapy was actually used. Data from recent viral pneumonia epidemics are similarly confusing.
Regardless of the effect on mortality, it is apparent that ECMO may be thought of as a last ditch effort
to improve oxygenation, but should not be employed after lung fibrosis and irreversible organ failure
have transpired. For sure, current technology involving smaller access catheters, more portable
oxygenators and venovenous deployment has made ECMO far less morbid than initial experience with it
decades ago with prior mortality rates in excess of 50%. The definitive trial without crossover treatment
to validate the use of ECMO for severe ARDS has not been performed.
Ventilator Associated Events

Ventilator-associated pneumonia (VAP) is the most common life-threatening healthcare associated
infection, although there is some evidence that it is less morbid in surgical than in medical patients.57
VAP is associated with increased ICU and hospital length of stay and costs, and may often be
preventable. Nonetheless, it can be extraordinarily difficult to define, particularly in injured patients
who may be febrile and have pulmonary infiltrates for reasons other than pneumonia. Further, if
attempts are made to diagnose the entity predominantly by microbiologic criteria (using
bronchoalveolar lavage to culture >105 organisms), then the incidence of VAP may be overstated.
Thus, the CDC has worked with various critical care societies to define the surveillance definition of
ventilator-associated events (VAE) which are publically reportable and include probable and possible
VAP, which are not reportable. Briefly, VAE require patients to have a baseline period of more than 2
calendar days on the ventilator followed by a sustained decrement in oxygenation. Note there are no
longer radiographic criteria for VAE or VAP. An infection-related VAE requires a change in temperature
or white blood cell count and the initiation of a new antibiotic that is continued for 4 days. The
differentiation between possible and probable VAP involves positive cultures as previously prescribed.58
Liberation from Ventilation

Automated, computerized liberation protocols significantly shorten time on ventilator and success rate
compared to those directed by physicians. As opposed to the concept of “weaning” patients from
support, it is now apparent that the need for ventilation can be approached in a more binomial, on–off
approach. Thus, current practice is to complete daily spontaneous breathing trials (SBTs) of no longer
than 30 minutes to assess patients’ readiness for liberation from ventilation. Of course, these trials
should not be conducted in patients with hypoxia, hemodynamic instability or neurologic disease. SBTs
may be accomplished using a T-piece trial or CPAP with or without low PSV (<10 mm Hg), the latter
to enable ventilatory monitoring of work of breathing and respiratory effort. If patients develop
tachypnea, tachycardia, hypoxia, hypercapnia, and/or use accessory muscles during the SBT they are not
ready to be extubated. Typically, the parameter that predicts extubation success most accurately is the
rapid shallow breathing index or the tidal volume divided by the respiratory rate with a level of less
than 105 most predictive of success.59 Further, the requirement for airway support, as might be
expected in those with burns, head injury, or anasarca must be considered separately from the
requirement for ventilatory support. Checking for a cuff leak, although conceptually of benefit in
identifying patients with airway edema, may not be an accurate metric of those with a stable airway.
Trials in the medical literature suggest that a short course of steroids may benefit some to diminish
airway edema; these have not been replicated in surgical patients.60 Finally, some patients, such as
those with COPD, may benefit from extubation to noninvasive modes of ventilation such as bilevel
positive airway pressure (BiPaP) or CPAP. Additionally, the use of high-flow nasal cannula oxygen,
typically delivered at 40 L/min or greater may prevent reintubation.
Adjunctive Therapies
Inhaled Nitric Oxide and Prostaglandins. Inhaled Nitric Oxide (iNO) affords selective vasodilation of
the pulmonary vasculature without systemic effect. It improves oxygenation and lowers pulmonary
artery pressures. If used, methemoglobinemia can result, thus, monitoring should be conducted. Five
early meta-analyses showed improved oxygenation without a mortality benefit, with three
demonstrating increased renal failure.61 A more recent meta-analysis failed to show a mortality
advantage for iNO use for mild, moderate, or severe ARDS.62 Inhaled and/or intravenous prostacyclins
such as epoprostenol can also lower pulmonary artery pressures and improve oxygenation. A 2010
Cochrane review demonstrated no safety or outcome differences between iNO and epoprostenol;
however, at present, the latter is substantially cheaper. Although neither agent improves mortality, it
312
seems reasonable to employ prostaglandins in ARDS patients with concomitant pulmonary
hypertension.63
Positional Therapy. Prone positioning therapy can be done in conjunction with many other therapies
previously described. It can be accomplished on a conventional ICU bed or one specially equipped to
provide this therapy. Either way, extreme caution must be taken to avoid tube and line dislodgement
and development of pressure-related skin complications. The ideal amount of time to keep a patient in
the prone position is of debate. Often, a patient is turned every shift or if a procedure is required. A
recent large study in French ICU patients demonstrated a significant improvement in mortality in ARDS
patients treating with prone positioning therapy.64 Similarly, a systematic review and meta-analysis
reinforced the mortality benefit of nearly 25% by prone positioning therapy for ARDS.65
Fluid Management. Another large trial conducted by the ARDSnet group Fluid and Catheter Treatment
Trial (FACTT) demonstrated that ARDS patients have better outcome if managed with conservative fluid
strategy that need not be guided by a PAC.38 Of course, these findings must be reconciled with
extensive data supporting improved outcome in septic patients who received more robust fluid
resuscitation.66,67
Steroids. Trials regarding the use of steroids in ARDS are old and heterogeneous. At present, the use of
steroids cannot be recommended, but future trials controlling for other factors may indicate otherwise.
Sedation and Paralysis. Recently released pain, agitation, and delirium guidelines underscore several
features regarding the sedation of ICU patients. First, most ventilated ICU patients benefit from light
sedation and continued emphasis on mobility (even if ventilated) and screening for delirium. If sedative
agents are required, a strategy that employs narcotic analgesics first is preferred. If additional agents
are necessary, there is substantial evidence that a strategy that relies heavily on use of benzodiazepines
will result in a higher incidence of delirium, time on ventilator, and greater costs.68 Ideal sedatives
should be easy to titrate, short acting with rapid onset, and without accumulation with prolonged use.
These sedatives should also have minimal adverse effects, minimal metabolism, and no active
metabolites. Traditionally used sedatives and analgesics morphine, propofol, and benzodiazepines have
well-known adverse effects, active metabolites and tend to accumulate with prolonged use. Fentanyl is
widely used in ventilated surgical ICU patients due to its excellent pain control, rapid onset, short
duration of action, and lack of active metabolites. Dexmedetomidine is a sedative with alpha 2-
adrenoreceptor agonist properties that is used as an alternative for analgesia and sedation in the surgical
ICU. Dexmedetomidine has been shown to decrease the incidence of delirium and decreased duration of
mechanical ventilation versus benzodiazepines while not being inferior to benzodiazepines and propofol
in maintaining comfort and sedation.69 Using sedation scales in the ICU such as the Richmond Agitation-
Sedation Scale (RASS) provide a universal numerical scale to communicate between ICU team members
the target and actual sedation. Although we should not use long-term neuromuscular blockade (NMB) in
those with mild ARDS, a recent French study demonstrated a significant benefit to short-term use in
terms of mortality.70 A much larger propensity-matched retrospective study documented a 4.3%
absolute reduction in mortality with short-term use of NMB in severe ARDS.71
VENOUS THROMBOEMBOLISM PROPHYLAXIS IN THE ICU

Much attention has been focused on the prevention of venous thromboembolism (VTE) in hospitalized
patients, particularly in the United States, Canada, and the United Kingdom where national initiatives
are present. VTE prophylaxis is a quality metric promoted by such endeavors as the SCIP discussed
elsewhere in this text. The surgical ICU patient is a particular target for VTE and has unique features
rendering prophylaxis more challenging than it may be in a ward patient. VTE is a common cause of
preventable morbidity and mortality in critical care patients. A large amount of VTE complications
occur following surgery and injury.12,72 Further, the risk of bleeding in the multitraumatized, immobile,
and/or freshly postoperative patient may be heightened in the ICU patient. Finally, safe administration
of a chemoprophylactic agent as described below must take into account drug metabolism that may be
altered with renal or hepatic failure seen in ICU patients and desire to rapidly reverse the medication if
frequent procedures are needed.
313
Table 10-7A Caprini Risk Assessment for Venous Thromboembolism (VTE) in
Surgical Patients
Incidence
The risk for developing asymptomatic lower extremity deep venous thrombosis (DVT) depends on the
assessment of general risk factors described below and the type of surgical patient. The incidence can
vary from less than 10% (in mobile, thin patients undergoing brief, minor surgery) to over 80% (in
those with spinal cord injury or elderly, obese hip fracture patients) in the absence of prophylaxis.
However, the true incidence may be unknown. It has become clear that upper extremity DVT (which is
not routinely screened) is more common than previously appreciated and may result in pulmonary
embolism at a higher rate than thought in the past,73 thus dramatically affecting VTE rates. The
incidence of fatal pulmonary embolism in surgical patients ranges from less than 1% in most undergoing
elective general surgery to as high as 5% to 8% in those receiving operations for hip fractures.74 The
projected VTE incidence of the surgical ICU would, thus, depend on the composition and the use of
screening for asymptomatic patients.
Risk Factor Scoring

Surgical critical care patients are at increased risk of VTE via Virchow triad of stasis, vessel wall injury,
and hypercoagulability. Acquired risk factors in the surgical critical care patients are a consequence of
surgery, trauma, immobilization, obesity, malignancy, advanced age, and invasive monitoring devices.
The American College of Chest Physicians (ACCP) 2012 guidelines75 stratify surgical patients into four
risk categories: very low, low, moderate, and high. The most widely used tool to assist in classification
is the Caprini score (Table 10-7).76 A quick glance at the assessment would reveal that the vast majority
of surgical ICU patients over the age of 40 would fall into at least the moderate risk category; if a
central venous catheter were present, then they would be considered high risk.
Approaches to Prevention of VTE

Screening – Secondary Prevention
This strategy involves the early detection of subclinical venous thrombosis by regular screening tests.
These tests include Duplex ultrasonography and laboratory assays such as evaluation of d-dimer,
discussed in further detail elsewhere in this textbook. As most ICU patients will fall into moderate and
high risk categories for VTE (in whom d-dimer assays are universally elevated), there is virtually no
role for utilizing d-dimer acquisition for diagnostic purposes. Further, although many groups feel
differently and perform routine screening lower extremity Duplex ultrasonography, the authors believe
that there is little role for this strategy if screening upper extremity studies are not performed
concomitantly. Further, as will be discussed below, the safety of early administration of
chemoprophylactics is now being proven in even the highest-risk patients (e.g., neurotrauma).77
Table 10-7B Caprini VTE Percentage Risk Based on Score
314
Treatment – Primary Prophylaxis
Interventions for the prevention of VTE include elastic stockings, intermittent pneumatic compression
devices, low-dose unfractionated heparin (UFH), low–molecular-weight heparin (LMWH), indirect
factor Xa inhibitors such as fondaparinux, direct thrombin and Xa inhibitors, aspirin, and inferior vena
cava (IVC) filters.
Mechanical Devices
Alone are utilized for surgical ICU patients at the lowest risk for VTE. Intermittent compression devices
may afford additional protection from VTE in those in high-risk groups if used in concert with chemical
agents.78
Chemical
7 UFH and LMWH. Few studies have performed a head-to-head analysis of these agents for VTE
prophylaxis in surgical ICU patients. A study of injured patients completed by Geerts and published in
199679 demonstrated that use of LMWH resulted in a significantly lower incidence of VTE (31% vs.
44%). This likely drove the 2009 ACCP recommendation that moderate and high risk ICU patients
should preferentially receive LMWH for prophylaxis (with a IA strength and level of recommendation),
However, in the interim, Dr. Geerts and colleagues performed a multicenter, RCT (PROTECT) that did
not demonstrate a difference in the development of DVT or proximal DVT in those who received LMWH
in the form of dalteparin compared to those administered twice-daily UFH.80 There was no difference in
bleeding rate, but a higher incidence of PE was noted in the UFH patients (and a nonsignificant increase
in heparin induced thrombocytopenia). This study, undoubtedly, drove the 2012 ACCP recommendation
that UFH or LMWH can be used interchangeably (2C recommendation).75 However, it is vital to
mention that the authors excluded injured, orthopedic and neurosurgical patients from this study. eerts
himself provides guidelines suggesting that ICU patients at high risk for VTE including injured and
major surgery patients should receive LMWH preferentially. UFH should be reserved for moderate-risk
ICU patients. High-risk patients at risk for bleeding should receive mechanical prophylaxis until the risk
for bleeding is abrogated, and then LMWH should be initiated.81 Literature suggests that this may be
substantially earlier than we might have thought in the past.82 Finally, in those with renal dysfunction,
consideration must be given to avoiding LMWH, or at least monitoring Xa levels, although there is little
literature to offer guidance in this regard.
Indirect Xa inhibitors include fondaparinux and have been studied extensively in the orthopedic (non-
ICU) and general surgery population. In both these populations, it may be more efficacious than LMWH
without an increase in bleeding risk.75 How this extrapolates to the ICU population is unknown;
however, it may be helpful in those with HIT.
There is even less experience using oral Xa (rivaroxaban and apixaban) and thrombin II (dabigatran)
inhibitors in the ICU. These agents may be less than helpful because of a long half-life and inability to
reverse (particularly dabigatran that may be best removed by hemodialysis). Nonetheless, we should
appreciate that all three agents had a lower rate of significant bleeding such as intracranial hemorrhage
in outpatients who were being treated for atrial fibrillation. Rivaroxaban is metabolized renally and
apixaban both hepatically and renally. Due to similar concerns of time and ability to reverse, the use of
aspirin and warfarin may be limited in the ICU.
IVC Filter. At present, the current ACCP guidelines do not recommend insertion of prophylactic IVCF in
those who cannot be anticoagulated. They recommend initiating chemoprophylaxis as soon as is
practical.75
TRANSFUSION OF THE ICU PATIENT

8 Transfusion of packed red blood cells, ostensibly to promote oxygen delivery, is extraordinarily
315
common in surgical ICU patients. Nearly 85% of those who remain in the SICU after a week and over
40% overall will be transfused, many of whom are not actively bleeding.83 It was reflexive practice a
decade or so ago to prescribe a transfusion for ICU patients whose hemoglobin levels fell below 10 g/dL
with at least two units being administered. However, packed cell transfusion may not dramatically
improve oxygen delivery, particularly in situations where the oxygen dissociation curve has been shifted
to the left, as with decreased 2,3-diphosphoglycerate concentrations (Table 10-8). In addition, in many
patient populations, transfusion of packed cells has been associated with increased infections and organ
failure. The Transfusion requirements in Critical Care (TRICC) trial published in 199984 provided data
to question the universal practice of red cell transfusion. This multi-institutional trial of patients in
Canadian ICUs was designed as a noninferiority trial comparing a restrictive transfusion strategy, aimed
at maintaining a hemoglobin level greater than 7 to 9 g/dL, to a liberal one, targeting a level of 10 to
12. Hebert and colleagues demonstrated no difference in mortality between the groups, the primary
outcome measured. Although patients with significant cardiac history were excluded a priori, nearly 300
were studied, and there was no outcome difference in this group either.85
Nonetheless, despite widespread dissemination of this landmark article, transfusion practice did not
widely change in many surgical ICU patients since and there is still a sense that older, cardiac, actively
bleeding, neurosurgical, and septic patients should be excluded from restrictive transfusion practices.
However, subsequent studies have further questioned this dogma. A large propensity matched study
analyzed the effect of transfusion on ICU patients who were not actively bleeding. It revealed that
nontransfused patients (including those with a significant cardiac history) had a lower hospital mortality
and incidence of infection and acute kidney injury.86 The RELIEVE trial was a multicenter randomized
controlled trial of ventilated ICU patients over the age of 55, including one-third with ischemic cardiac
disease. Those in the restrictive group received almost a quarter fewer transfusions and had over a 30%
lower mortality rate.87 A meta-analysis of the effect of blood transfusion during myocardial infarction
noted that the therapy was associated with a relative risk of 2.91 for mortality and 2.04 for a
subsequent MI with a number to treat of 8.88 Further, a British propensity-matched study of cardiac
surgery patients revealed odds ratios of 3.8 and 3.5, respectively, for infection and ischemia after
transfusion and ratios of 6.69 and 1.32, respectively, for 30-day and 1-year mortality in transfused
patients.89 This risk of transfusion in cardiac surgery patients is apparent even with administration of
small-volume (i.e., one or two units of packed cells) transfusions.90 A large, randomized controlled trial
of cardiac surgery patients over the age of 18 undergoing a bypass or valve replacement revealed no
change in 30-day all-cause mortality or morbidity utilizing a transfusion trigger of 8 versus 10 g/dL of
hemoglobin.91 Further, a large single center study randomized those with severe acute upper
gastrointestinal bleeding – almost 75% variceal – to a transfusion target of 7 versus 9 g/dL of
hemoglobin. Nearly half of those in the restrictive group did not receive a transfusion and the mean
time to endoscopy was 6 hours. The restrictive group had a 45% relative reduction in mortality and all
adverse events, mostly confined to those in Child’s groups A and B (there was no difference in those in
Child’s C classification group). This study reinforced the findings of a previous observation study that a
liberal transfusion target in active upper gastrointestinal bleeding doubled the risk of rebleeding and
increased mortality by 28%,92 presumably by promoting “popping the clot.” In a randomized clinical
trial of patients with traumatic brain injury, a hemoglobin target of 10 compared to 7 g/dL was
associated with no improvement in neurologic outcome at 6 months but a higher incidence of adverse
events including thromboembolism.93 Finally, in a multicenter, RCT of septic patients, a hemoglobin
target of 7 g/dL with transfusion of leukoreduced cells was not associated with difference in 90-day
hospital mortality of adverse events compared to 1 of 9 g/dL.94
Table 10-8 Factors Altering the Oxygen Dissociation Curve
Although administration of both erythropoietin95 and intravenous iron96 would seem sound practice
316
to mitigate against transfusion and the harmful effects thereof, in clinical practice in the SICU, neither
has been effective in dramatically impacting transfusions or outcomes. It may be most prudent to “ride
out” the anemia seen in ICU patients, minimize unnecessary blood draws, and improve oxygen delivery
by other means (although they, too, have not afforded improved outcomes).
METABOLISM AND NUTRITION

Classic texts on surgical nutrition emphasize the metabolic and hormonal differences between the states
of starvation, one of decreased metabolic rate, and that of stress, one of increased metabolism driven by
so-called stress hormones. In reality, many surgical and trauma patients experience stress after a fast,
although the use of early nutrition in almost all has largely prevented this.
In starvation, fat oxidation is the principle energy source after glycogen stores are exhausted within
24 hours. Patients turn to gluconeogenesis (particularly in cells that are obligate glucose users such as
neurons and red blood cells) for fuel, resulting in increased free fatty acids, ketones, and glycerol. This
amplified gluconeogenesis results in exhaustion of amino acid levels and protein wasting. Eventually,
glucose levels drop as does insulin. Stress hormones, including cortisol and catecholamines, promote
protein catabolism. As glucose is used up, a switch is made to fat metabolism with the inability to keep
up via gluconeogenesis.
Critically ill patients are in a catabolic stress state with a systemic inflammatory response.
Malnutrition in critically ill patients leads to worse outcomes; inability to wean from the ventilator,
pressure ulcers, and increased risk of infectious complications. For these reasons, it is critical that ICU
patients undergo assessment and adequate support of their nutritional status. Goals of nutrition support
are to preserve lean body mass, maintain immune function, and avert metabolic complications.1,97
Metabolic Requirements and Assessment

Metabolic requirements for ICU patients for both calories and protein needs are based on ideal body
weight. Equations, such as the Harris–Benedict calculation, can assist in determination of caloric
administration and are based on the patient’s baseline energy expenditure, referred to as the basal
metabolic rate (BMR) and/or basal energy expenditure (BEE). BMR is the estimated rate of energy used
by the body at rest and is only sufficient for the functioning of vital organs. The BEE varies with age,
lean body mass, and sex. In most circumstances, ICU patients should receive 25 to 30 kcal/kg/day and
1.2 to 2.5 g/kg/day of protein (highest in stressed burn patients). In fact, hypocaloric, high-protein
diets may be best for many, if not most, ICU patients. Starting critically ill patients at 8 to 10
kcal/kg/day and attempting to achieve goal nutrition of 25 to 30 kcal/kg/day within a week is
optimal.98
The most important nutritional assessment of our ICU patients is the least high tech – that is, a careful
history and physical examination documenting diet status, weight loss, and the nature of the operation
or trauma. We often supplement this with quantitative assessment of protein and caloric adequacy.
These include simple laboratory tests and more complicated evaluations. A variety of visceral proteins
with relatively short half-lives have been assayed for their relation to protein status. These include
prealbumin, transferrin, and retinol-binding protein (with half-lives of 2, 8, and 10 days, respectively)
as opposed to albumin whose half-life is 21 days. However, even prealbumin levels may respond to
factors other than nutritional status, including ongoing inflammation. The most accurate assessment is
via indirect calorimetry. This allows for the direct measurement of oxygen consumption (VO2). It is best
determined in those on stable ventilator settings with an inspired oxygen fraction of less than 65% and
no airway leaks. However, use of indirect calorimetry to guide nutritional support has not been
demonstrated to result in improved outcomes to justify its expense.
Energy Sources
Carbohydrates, fat, and protein each contain a unique amount of calories per gram and respiratory
quotients (RQ), a ratio of CO2 consumption (VCO2) over oxygen consumption (VO2). Ratios that exceed
one will result in the body’s need to eliminate additional CO2, which can be of consequence in those on
ventilator support with lung disease. The goal of ICU nutrition is to provide energy from carbohydrate
and fat sources, so that exogenous proteins can be used for anabolism and not catabolism. This principle
is the protein sparing effect of carbohydrate and fat administration. Less than 500 kcal/day are protein
sparing, although in most instances, we provide many more calories with traditional ICU nutrition.
317
Carbohydrates provide 3.4 kcal/g and have the highest RQ of 1.0. Thus, excess carbohydrate
calories can result in prolonged ventilator needs. An RQ of greater than one is seen with glycogen
storage. The ICU patient should be provided with 5 to 6 g/kg/day of carbohydrates.
Fat provides 9.0 kcal/g with an RQ of 0.7. ICU patients should receive 1 g/kg/day or less of fat. Fat
deficiency used to be fairly common in ICU patients before early and adequate nutrition. Deficiency can
result in anemia, thrombocytopenia, respiratory distress, and rash. Excess fat can promote cholestasis
and fatty liver resulting in coagulopathy. In fact, it is possible to administer nearly all of one’s
nonprotein calories as carbohydrates, providing essential fatty acids are administered. However, this
would result in an increased RQ (with ventilatory consequences) and issues of glycemic control. Fatty
acids exist in two varieties, omega-three and omega-six. Omega-three fatty acids are derived from
linolenic acid, found in fatty fish such as salmon, and are less pathogenic than omega-six fatty acids
derived from linoleic acid. In stress, after the body exhausts its supply of carbohydrates, it relies on
lipolysis which lowers the RQ (until the supply of fatty acids is also consumed and proteolysis occurs).
Protein delivers 4.0 kcal/g with an RQ of 0.8. Essential amino acids cannot be synthesized
endogenously and must be provided in the diet and include: methionine, threonine, tryptophan, valine,
phenylalanine, isoleucine, leucine, lysine, and histidine. Diets specialized for those with renal failure
deliver their protein in the form of essential amino acids. Semiessential amino acids such as arginine and
glutamine are difficult for the body to manufacture in times of stress and are obligately utilized by
certain cell types. Protein is the important component of nutrition due to the body’s obligate synthetic
needs. We are able to measure the efficacy of protein nutrition by assaying nitrogen balance – a balance
sheet between protein in and nitrogen out measured in the urine. This, of course, requires that we
remember that a gram of protein contains 6.25 g of nitrogen. Severely burned patients can lose 25 g N
(125 g pro) daily. In certain conditions, such as sepsis, we may not be able to provide enough protein to
avoid negative nitrogen balance.
Vitamins and minerals. Contemporary supplemental nutrition contains sufficient trace elements and
vitamins to make deficiency in ICU patients a thing of the past in most instances. A resurgence in this
has occurred with the care of bariatric patients and the deficiencies they experience post bypass, most
notably of thiamine. Interesting to note, virtually all enteral formulae contain vitamin K – some in
rather large amounts – so anticoagulation may be difficult (Table 10-9).
The nutritional support of the malnourished and nourished patient employs different strategies to
optimize outcome. Malnourished patients may benefit from preoperative nutritional support for at least
7 days that can be delivered enterally, if possible. Well-nourished patients should have nutrition
resumed within 48 hours; however, it is safe, if not wise to delay parenteral nutrition for 5 to 7 days if
the enteral route is not possible. There is much controversy and regional variability regarding this issue
with the Europeans preferring earlier initiation of parenteral nutrition, as will be discussed below.
Enteral Nutrition
9 In general, enteral nutrition should be used early and often in ICU patients. Standard enteral formulas
include fatty acids, carbohydrates, protein, vitamins, minerals, and micronutrients. A standard formula
is isotonic to serum and has a calorie density of 1 kcal/mL. A concentrated formula is used in patients
who may benefit from low volume nutrition. Concentrated formula is hyperosmolar with a calorie
density of 1.2 to 2.0 kcal/mL. There are specific formulations that address types of organ dysfunction.
So-called pulmonary formulations are low in carbohydrates; renal formulas are concentrated with
essential amino acids and hepatic formulas contain branched chain amino acids. Further, enteral feeds
are either polymeric or elemental – that is, broken down to the basic building blocks of the energy
substrates – proteins as free amino acids, fats as medium chain triglycerides, and carbohydrates as
oligosaccharides at a calorie concentrations of 1 to 1.5 kcal/mL. Elemental feeds may be useful in the
stressed patient as they require minimal intraluminal digestion. Elemental formulas should be
considered in patients with nutrition absorption disorders and those that fail to tolerate standard enteral
nutrition.
Table 10-9 Vitamin Deficiencies
318
There are several complications related to enteral nutrition in the ICU, the most significant of which
is aspiration. To decrease the aspiration risk, the ICU staff should maintain head-of-bed elevation at 45
degrees or greater and consider promotility agents. Regular assay of gastric residuals may not decrease
aspiration risk.99
Parenteral nutrition requires the insertion of a central catheter or a centrally directed peripheral
one. As such, the complications of parenteral nutrition include the risks of catheter insertion and
infection in addition to the metabolic consequences of feeding (such as hyperglycemia) that can also be
seen with enteral nutrition. Parenteral nutrition can be prepared in standard or concentrated
formulations depending upon the glucose with added amino acids and fat. There may be evidence that
hypocaloric formulas with limitation of fat early on are beneficial.97
Immunonutrition
In addition to use of omega-three fatty acids, there are other ingredients that may be helpful to use in
the stressed patient. In small, early nonrandomized trials, semiessential amino acids arginine and
glutamine have been shown to be beneficial and the use of high-protein/low-calorie strategies may be
most optimal, particularly using branched chain amino acids. There was thought to be a notable
exception to this strategy – arginine, in particular, was not advised in the patient who is already
infected.100 Arginine is metabolized to nitric oxide which may increase permeability, hemodynamic
instability, and translocation in septic patients. However, this may be mitigated by increased production
of arginase in septic patients. Increasing literature actually supports increased perfusion by giving
arginine in sepsis.101,102 Thus, arginine administration is likely safe in sepsis, but the preferred dose is
still of debate. Glutamine is rapidly depleted from muscle stores and thought to be important in
minimizing translocation as it assists in maintaining gut barrier function as an enterocyte fuel. A
hypocaloric, high-protein strategy appears to be most beneficial with a calorie to nitrogen ratio of 100–
150:1 compare to the more traditional 300:1. However, large randomized trials discussed below
question the clinical efficacy of immunonutrition.
Controversial Issues in ICU Nutrition

Delivery of Early Enteral Nutrition
Most critically ill patients are unable to ingest enteral nutrition and have a need for access to the enteric
track. There is no compelling evidence that enteral feeds need be delivered in a specific location – that
is, there is little data to suggest that postpyloric feeding results in lower aspiration rates or in better
food tolerance with higher caloric provision.103 Gastric tube feeding is the most common method to
deliver enteric nutrition. Via an orogastric or nasogastric route, sump tubes or smaller-caliber feeding
tubes are placed into the stomach with confirmation by abdominal x-ray. Surgically placed gastric
feeding tubes, whether placed percutaneous or via an open procedure, can also be used for a more long-
term enteral nutrition access. Postpyloric tube feeding should be considered in patients who cannot
tolerate gastric enteral nutrition or patients who have undergone surgical procedures that have altered
anatomy. Placement of a postpyloric tube can be done with blind placement via the nasal or oral route.
These tubes may also be placed via open surgical procedures with a single tube inserted directly in the
intestine distal to the pylorus or with a tube with a port to drain the stomach and a distal port to deliver
enteral nutrition into the duodenum. Postpyloric placement of enteral nutrition access has no benefit
over gastric feeding access in terms of energy delivered or rate of aspiration pneumonia, and so it is
recommended to proceed with enteral nutrition via the gastric route.103
319
Perioperative delivery of enteral nutrition may be challenging in certain circumstances. However,
lessons learned in burn patients reinforce the notion that continuous feeding for nonabdominal
procedures is safe.104 Similarly, presence of an open abdomen is not a contraindication to provision of
enteral nutrition.105
Compared to intravenous dextrose or no nutrition, early enteral nutrition results in lower morbidity
(largely infectious), mortality, and cost in ICU patients.106–108 Bowel rest is not beneficial in ICU
patients. Just as asystole does not rest the heart, starvation does not inhibit bowel function, rather it
decreases splanchnic flow and results in bacterial overgrowth and translocation. Enteral nutrition
promotes blood flow, arguing against the routine practice of discontinuing it in those on pressors.109,110
There is some sense that if full feeding is not possible for whatever reason, that partial or trophic
nutrition be employed. This strategy aims to prevent the overgrowth of bacteria in a static
gastrointestinal tract that could result in translocation into the portal circulation causing sepsis and
fueling multiple organ failure. However, the EDEN study comparing the use of trophic versus full
feeding in ARDS patients did not demonstrate a benefit to the former in terms of infection rate,
ventilator days, ICU length of stay, or mortality. Of course, this study does not address what one should
do if full feeds are not possible – maintain trophic only enteral feeds, add partial or full parenteral
feeds, or employ another strategy.110 Earlier enteral versus parenteral nutrition studies were fraught
with issues of overfeeding, imprecise glucose control, and the potential for substandard intravenous
catheter care, all of which would raise the risk of infection in those parenterally fed.
Strategies When Unable to Feed Enterally/Role of Supplemental Parenteral Nutrition
Several recent studies have addressed the role of supplemental parenteral nutrition to be used in
instances when enteral nutrition might not be possible. In the large EPaNIC study from Europe of over
4,000 patients randomized to “early” or “late” parenteral nutrition if caloric goals were not met by day
2, early patients did worse. Those randomized to receiving late parenteral nutrition (by day 7) had
shorter ICU and hospital length of stay, fewer infections, less ventilator and dialysis days, and lower
cost. The more parenteral nutrition patients received, the worse the outcome.111 In a large Australian
randomized trial, the only parameter that was improved by supplemental parenteral nutrition was a
clinically insignificant, but statistically significant, difference in ventilator days (less than one half
day).112 The Swiss SPN study of supplemental parenteral nutrition demonstrated no difference in
mortality, infections to day 28, length or stay or ventilator days between groups.113 In injured patients,
the use of parenteral nutrition has largely been abandoned, used in fewer than 5% of patients in one
study. Supplemental parenteral nutrition in a cohort of severely blunt injured patients doubled both the
rate of infections and mortality.112 Finally, a recent randomized controlled multicenter trial – CALORIES
– compares the use of early enteral and parenteral nutrition. Interestingly, the authors found no
difference in the infection rate, adverse events, or mortality.114 While some can interpret this study as
one that supports the safety of early parenteral nutrition, an alternate view would be that less expensive
early enteral nutrition is, in fact, able to be administered in most ICU patients.
Delivery of Immunitrition
Glutamine and omega-three fatty acids (fish oils). Previous retrospective studies of immune modulating
nutrients such as glutamine, selenium, and omega-three fatty acids indicated an outcome benefit in
terms of diminished infections and improved survival using high-protein enteral formulas. However,
newer studies are not as conclusive. In the REDOXS trial examining the effect of supplemental
intravenous or oral glutamine in septic patients with multiple organ failure, glutamine administration
resulted in an increased mortality rate of over 5%.115
There is not convincing evidence that utilizing an omega-three-rich lipid composition in parenteral
nutrition affects mortality or ICU length of stay,116,117 but this may be a function of route delivered and
baseline nutritional status. It’s not clear that there is a benefit for enteral administration either, with
some showing great benefit while others do not. Finally, the recent MetaPlus study described a
multicenter, randomized, double-blind trial of 301 mechanically ventilated adult patients using
comprehensive immunonutrition. There was no difference reported in infection rate, ventilator days,
and ICU and hospital length of stay between groups. Further, although not seen in trauma and surgical
patients, in this study, immunonutrition was associated with substantially higher 6-month mortality (54
vs. 35%) in medical ICU patients.118
Nutrition for Specific Indications

Acute Pancreatitis
320
Enteral nutrition, if possible, is preferable in acute pancreatitis as it decreases length of stay, improves
resolution of SIRS, decreases infection rate, and does not stimulate exocrine pancreatic secretion to a
great extent. A recent Cochrane review of eight trials revealed a relative risk of death of 0.18 and 0.46
for multiple organ failure for those with severe acute pancreatitis who received enteral nutrition.119
Obesity
Goals in management of the obese patient are to reduce fat mass, improve insulin sensitivity, and
preserve lean body mass. A high-protein, hypocaloric strategy is favored with 22 to 25 kcal/kg/day
based on ideal body weight and 2.0 to 2.5 g/kg/day of protein.
Stress Gastrointestinal Bleeding Prophylaxis
Endoscopic evidence of upper gastrointestinal bleeding is extraordinarily common in ICU patients. It is
present shortly after admission in high-acuity ICU patients and thought due to impaired mucosal
protection and less so due to acid hypersecretion and Helicobacter pylori infection. The latter two are
features typical of more distal ulcers that can also result in upper gastrointestinal bleeding. Overt
bleeding, manifested by coffee ground upper intestinal aspirates or hemoccult positive stool, is
appreciated in up to 25% of patients in the ICU. Clinically significant bleeding resulting in the need for
a blood transfusion and/or hemodynamic instability is much less common, noted in less than 5% of ICU
patients, with or without pharmacologic prophylaxis. The strongest risk factor for stress gastrointestinal
bleeding in the ICU is the need for more than 48 hours of mechanical ventilation, although
epidemiologic studies pointing to this observation are dated.120 The next most common risk factor is the
presence of coagulopathy. It seems prudent that pharmacologic prophylaxis of stress gastrointestinal
bleeding in ICU patients be limited to those with these two risk factors. There may, however, be a role
to avoid pharmacologic agents even in the highest-risk patients, particularly if they are being enterally
fed.121 If pharmacologic prophylaxis is prescribed, proton pump inhibitors (PPI’s) appear to be superior
to histamine-2 receptor antagonists in diminishing gastrointestinal bleeding; however, there is no
change in mortality, length of stay, or pneumonia incidence in ICU patients.122 However, PPI’s increase
the risk for infection with Clostridium difficile, although this association has not been appreciated in ICU
patients to date.
ACUTE KIDNEY INSUFFICIENCY (AKI)

Acute renal failure complicates at least 5% and as many as 30% of all surgical ICU admissions with a
mortality of over 50%, as the most prognostic component of multiple organ failure. In analysis of a
cohort of hypotensive, severely blunt injured patients enrolled in the “Inflammation and the Host
Response to Injury” (Glue Grant) database, AKI occurred in one-quarter of patients with a threefold
adjusted risk for hospital death.123 AKI can be graded along a spectrum as described by the RIFLE
classification (from risk to injury to failure to loss to end-stage kidney disease) as defined by the Acute
Dialysis Quality Initiative (ADQI), and may be oliguric or nonoliguric (urine output < or >400 mL/day
in adults). Oliguric renal failure and higher grades of injury portend a higher mortality. An additional
classification system has been developed by the Acute Kidney Injury Network (AKIN) and is also
composed of urine output and serum creatinine criteria as described in Table 10-10. AKIN has the
advantage of considering minor variations in serum creatinine better than does RIFLE and it avoids
interpretation errors in the absence of a baseline creatinine value. Neither classification system,
however, is favored in terms of predicating incidence of and outcome from AKI. However, to simplify
matters, the Kidney Disease Improving Global Outcomes (KDIGO) work group recently proposed a
hybrid definition.124–126
Etiology
Acute kidney injury and ultimately failure is the result of forces extrinsic to the kidney or inherently
parenchymal (about 90%). Prerenal versus postrenal causes can be distinguished with serum and urine
osmolality and basic metabolic panel measurements (Table 10-11). Radiographic diagnostic studies (i.e.,
ultrasound and CT scan) can diagnose hydronephrosis or a distended bladder as causes of postrenal AKI.
Prerenal azotemia, in which the kidney perceives a lack of perfusion, may occur with both hypovolemia
and hypervolemia, the latter with congestive heart failure and impaired cardiac function. Initially, the
kidney is able to maintain perfusion by selectively dilating the afferent arteriole and vasoconstricting
the efferent arteriole of the juxtaglomerular apparatus. As hypotension persists and the renin–
321
angiotensin system is activated, systemic vasoconstriction occurs and cortical hypoperfusion occurs. It is
important to note that laboratory markers are able to distinguish between prerenal and renal causes of
AKI, but not between hypovolemic and hypervolemic/cardiogenic states that may be the proximal
cause.
Table 10-10 RIFLE AKIN and KDIGO Classification of Renal Failure
Table 10-11 Prerenal Versus Acute Tubular Necrosis as the Cause for Acute
Kidney Injury
Acute tubular necrosis (ATN) results as a consequence of ischemia (most) or nephrotoxic agents. The
former may occur in the face of sepsis, hypovolemia, or cardiogenic shock. The latter includes common
ICU medications, radiocontrast media, or pigments (myoglobin and hemoglobin). Medications that may
cause ATN include aminoglycosides, cephalosporins, amphotericin, and cisplatin. Contrast nephropathy
occurs in about 5% of those exposed; particularly at high risk are elderly diabetics with pre-existing
kidney disease. Rarely will patients with contrast nephropathy progress to requiring dialysis. Only
administration of intravenous saline precontrast administration has been demonstrated to lessen the
incidence of contrast nephropathy.127 The use of n-acetyl cysteine or bicarbonate has not been
beneficial. In those with pre-existing renal insufficiency who nonetheless require administration of
contrast media, there may be a role for prophylactic continuous dialysis. Hemoglobin pigment rarely
causes ATN in surgical ICU patients. A rare but morbid cause would be the administration of incorrectly
crossmatched blood products. Myoglobinuria as a consequence of rhabdomyolysis is far more common
in the ICU and occurs after severe trauma, compartment syndrome, electrical burns, seizures, or coma
322
with prolonged immobilization. Myoglobinuria should be suspected in patients with dark urine and a
positive urine dipstick without red cells on microscopy. Patients with a serum myoglobin level
exceeding 10,000 ng/mL or a creatinine phosophokinase (CPK) greater than 20,000 IU/L are a risk for
pigment nephropathy. Myoglobin is both a potent vasoconstrictor (FeNa is <1%) and a direct tubular
toxin when converted to ferrihemate in an acid environment. However, alkalinization of the urine (with
administration of sodium bicarbonate) has not been proven to be more effective than volume
administration and forced dieresis to achieve a urine output of 2 mL/kg/hr.128
Postobstructive uropathy is rare in the ICU and leads to AKI as the result of a mechanical obstruction
to urinary flow. An obstructed urinary catheter is the most common cause and should prompt ICU
personnel caring for a patient with an abrupt cessation of urinary output to interrogate the patency of
the catheter.
10 Prevention of acute renal failure is most effectively achieved by controlled fluid resuscitation of
volume repletion. There is little evidence to benefit of colloid over crystalloids. Higher–molecular-
weight hydroethyl starch preparations should be avoided, however, as they are nephrotoxic through
tubular obstruction. If a mean arterial pressure (MAP) of greater than 65 mm Hg cannot be maintained
solely with fluid administration, it is reasonable to initiate norepinephrine therapy. There is no role for
the use of low-dose dopamine for protection against AKI or improvement of diuresis, as noted by
several meta-analyses.129,130
Treatment of Acute Renal Failure

General Care
Attention must be directed toward management of electrolyte disturbances and hypervolemia in those
with renal failure or impending failure. Hyperkalemia, hyperphosphatemia, metabolic acidosis, uremia,
and congestive heart failure may all be of consequence. It is important to remember that treatment for
hyperkalemia can either be temporizing or definitive. Temporizing treatment such as the administration
of calcium or insulin will stabilize cell membranes and lessen cardiac irritability by forcing potassium
intracellularly. However, only removal of potassium through the gastrointestinal tract, the urine or
dialysis offers definitive therapy. Thus, if a surgical ICU patient is oliguric and not a candidate for
enteral or rectal administration of a potassium binder, then dialysis must be promptly administered to
those with markedly elevated potassium levels or ECG changes. Similarly, uremia causing a significant
pericardial effusion or encephalopathy may be temporized or treated definitively with dialysis. Platelet
dysfunction is also associated with AKI, particularly in face of a BUN in excess of 100 mg/dL. The
administration of desmopressin (DDAVP) or analogues may be of benefit. Finally, as the strategy for
renal replacement therapy is developed, attention must be directed toward optimizing nutritional status
without worsening electrolyte disturbances or hypervolemia. Prior to initiation of dialysis, it may be
necessary to limit protein administration so as to avoid exacerbating uremia. However, as renal failure
typically occurs in the catabolic milieu of multiple organ failure, it is vital to administer an adequate
protein substrate as well as calories to prevent excessive gluconeogenesis and protein breakdown. This,
in turn, leads to worsening uremia.
Diuretics
There may be a theoretical attraction to using diuretics to ameliorate AKI. However, in practice
diuretics have not been successful in either preventing or ameliorating AKI. Rather, prophylactic
diuretics often raise serum creatinine levels. Systematic reviews and meta-analyses131,132 have
demonstrated that diuretic use does not alter outcome from AKI, but has a significant risk of morbidity
(such as hearing loss) and even mortality in some. Finally, if diuretics are used, there is no evidence in
systematic review and meta-analysis that continuous dosing is superior to bolus administration.133,134
Renal replacement therapy (RRT) is indicated for intractable fluid overload, hyperkalemia
(potassium concentration greater than 6.5 mmol/L or 5.5 with ECG changes), severe metabolic acidosis
(pH <7.1), uremic encephalopathy or pericarditis and overdose with a dialyzable agent. Hemodialysis
is typically performed in ICU patients and may be continuous or intermittent. Both the Randomized
Evaluation of Normal versus Augmented Level Renal Replacement (RENAL) study and the Veterans
Administration/National Institutes of Health Acute Renal Failure Trial Network (ATN) failed to
demonstrate a benefit from increasing the intensity of RRT beyond 20 to 25 mL/kg/hr of effluent flow,
the former trial utilizing continuous modes, the latter intermittent.135,136
Continuous renal replacement therapy (CRRT) includes slow continuous ultrafiltration (SCUF)
and continuous venovenous and arteriovenous modes. Patients who are placed on CRRT must have a
323
temporary double lumen dialysis catheter placed in the internal jugular, femoral, or subclavian vein (in
order of preference). Once the dialysis catheter is inserted, the blood flow through the filter is moved
by a peristaltic pump. SCUF is utilized exclusively for volume removal which can be achieved at up to 2
L/hr. No replacement fluid is used, thus, there is minimal clearance of toxins. Arteriovenous circuits,
employing the patient’s own perfusion pressure to drive the system, are rarely used currently. Rather a
pump is used to drive a continuous venovenous circuit that can provide hemofiltration, hemodialysis,
or, most often, both. Continuous venovenous hemofiltration (CVVH) uses replacement fluid in the same
direction as the blood flow to dilute toxins in plasma as the toxins are removed with the ultrafiltrate.
Clearance of toxins is through the process of convection based on particle size where small, medium,
and large molecules are sieved out across a pressure gradient. Thus, electrolytes are leeched out and
replacement fluid is warranted. Continuous venovenous hemodialysis (CVVHD) uses a dialysate that
flows through the filter in the opposite direction of blood flow (and no replacement fluid) to remove
toxic waste and fluid of small molecules (such as urea) through the process of diffusion across a
concentration gradient. Finally, continuous venovenous hemodiafiltration (CVVHDF) combines both
convection and diffusion through a high-permeability membrane, using both dialysate and replacement
fluids. In those at a high risk of bleeding, it is reasonable to consider citrate anticoagulation (in the
absence of liver failure) or no anticoagulation with predilution administration of replacement fluids. In
those with moderate bleeding risk and/or frequent filter clotting, low-dose unfractionated heparin or
LMWH should be administered or argatroban in those with heparin-induced thrombocytopenia. The use
of CRRT may be preferred in those with brain edema, persistent metabolic acidosis, large fluid removal
requirements, and severe hemodynamic instability although hybrid modes, described below, may play a
role. Most patients have optimal clearance and treatment with running CRRT at 30 mL/kg/hr.137 There
has been some discussion about using high flow CRRT (70 mL/kg/hr) for the treatment of sepsis. In
patients with severe sepsis or septic shock without renal failure, there is no role for high volume
hemofiltration as reinforced in a recent multicenter study, the high volume in intensive care (IVOIRE)
trial.138
Intermittent hemodialysis (IHD) is performed at high flow rates (>300 mL/min) in a short session
relying on diffusion to clear toxins. Although it is thought that IHD is contraindicated in the face of
hemodynamic instability, it is possible to utilize this mode. Sufficient data do not exist to determine
which dialysis mode is optimal in promoting eventual renal recovery. Analysis suggesting a lower rate
of recovery with IHD relies heavily on data from older observational trials.139,140
Hybrid modes include sustained low efficiency dialysis (SLED). This can be thought of as stretching
out an intermittent dialysis session to promote improved hemodynamic stability and take advantage of
the cost benefits of IHD. SLED uses a conventional hemodialysis machine over 8 to 12 hours with lower
blood and dialysate flow rates. Various strategies exist to improve hemodynamic tolerance.
ENDOCRINE ISSUES IN THE ICU

Glucose Control
11 Hyperglycemia is common in critically ill patients and associated with poor clinical outcomes.
Critically ill patients are hypermetabolic due to elevated cortisol, growth hormone and catecholamine
levels, leading to increased hepatic gluconeogenesis, insulin resistance and hyperglycemia. Since
critically ill patients with hyperglycemia have increased mortality and complications including infection
and worse neurologic outcomes, assiduous glucose control has been practiced in critically ill
hyperglycemic patients.141,142 However, the optimal blood glucose range is controversial. Intensive
insulin therapy (IIT) typically employs continuous insulin infusions to maintain glucose levels of 80 to
110 mg/dL. Conventional blood glucose therapy could utilize either bolus or continuous insulin to
maintain glucose levels at a higher range. The Leuven surgical trial of mostly cardiac surgery patients
provided the groundwork for the use of IIT. One thousand five hundred and forty-eight patients were
randomized to IIT with infusion insulin versus conventional glucose management of 180 to 200 mg/dL.
IIT resulted in lower ICU and hospital mortality (4.6% and 7.2% vs. 8% and 10.9%, respectively), renal
failure, transfusion requirement, blood stream infections, and critical illness neuropathy, with more
frequent hypoglycemia.143 Other trials that included surgical patients reached opposite conclusions. The
Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) trial was a multicenter trial that was
stopped early because of the increased rate of hypoglycemia and serious adverse events in the IIT group
without a difference in mortality.144 Similarly, the multicenter Glucontrol trial was terminated early
324
because of the high rate of hypoglycemia in the IIT group.145 The largest trial, Normoglycemic in
Intensive Care Evaluation Survival Using Glucose Algorithm Regulation (NICE – SUGAR) included over
6,000 medical and surgical ICU patients randomized to IIT with blood glucose targets of 81 to 108
mg/dL and conventional blood glucose targets of <180 mg/dL. The IIT group had decreased mean
blood glucose levels, significantly higher mortality and more incidence of severe hypoglycemia.146
Current guidelines recommend moderate blood glucose control of 144 to 180 mg/dL for critically ill
patients to avoid both marked hyperglycemia and iatrogenic hypoglycemia.147 This can be achieved
predominantly by avoiding the use of glucose-containing intravenous fluids to avoid the need for insulin
administration. If insulin is needed, continuous infusions and intermittent short-acting agents may be
safer in ICU patients.
Adrenal Insufficiency
Absolute adrenal insufficiency is rare in critically ill patients, with an incidence estimated at less than
5%.148 Relative adrenal insufficiency, manifested by hypotension and fever (and rarely with electrolyte
abnormalities), is common in ICU patients and associated with worse outcomes. In general, most
(absolute) adrenal insufficiency is secondary to abrupt withdrawal of therapeutic steroids. In the ICU,
however, although total levels of cortisol may be normal, they may not respond appropriately to stress
situations. Further, the typical diurnal variation of cortisol appreciated in normal volunteers is not seen
in ICU patients, as stressors are not eliminated at night, making cortisol assay an easier task. In the past,
relative adrenal insufficiency was defined by a cortisol level of less than 11 to 25 mcg/dL and/or failure
to raise the level by more than 9 mcg/dL after stimulation by high-dose (250 mcg) ACTH.149 However,
there is much debate as to what cortisol level is appropriate in septic shock, what constitutes an
adequate response to ACTH stimulation and what dose of ACTH should be used. After careful study, it
appears that ACTH, or its synthetic analogue, cosyntropin, stimulation is not helpful in distinguishing
those with relative adrenal insufficiency who would derive benefit from steroid administration. Prior
work in the 1980 s and 90 s did not show benefit to high-dose steroid administration in septic shock.
The more recent Annane French trial demonstrated a benefit to administration of low-dose steroid
administration with concomitant mineralocorticoids in septic shock in terms of mortality.150 However,
the Corticosteroid Therapy of Septic Shock (CORTICUS) trial, a large multicenter study, did not
demonstrate a mortality benefit to administration of steroids in septic shock.151 However, patients
received therapy later than in the French trial and were not also administered mineralocorticoids.
Subsequent meta-analyses of the role of steroids in septic shock reveal no difference in mortality but
improved shock reversal.152,153 Current recommendations advise administration of low-dose,
“replacement” steroids (glucocorticoids) to septic patients who remain hypotensive despite adequate
volume resuscitation, particularly those whose serum cortisol levels are below 20 mcg/dL.20 Still
controversial is whether or not to administer a mineralocorticoid concomitantly to those felt adrenally
insufficient. If fludrocortisone is not administered, then it is important to remember that glucocorticoids
have varied mineralocorticoid potency – none seen with dexamethasone and half seen with
methylprednisolone compared to hydrocortisone. Typically 200 to 300 mg hydrocortisone daily is
administered in intermittent doses, every 8 hours, for 5 to 7 days and then tapered as guided by clinical
response. A parallel to the relative insufficiency of cortisol seen in ICU patients with septic shock is that
of arginine vasopressin. Therapy with low, replacement doses of vasopressin might be considered
analogous to that with glucocorticoids and may, in fact, be complimentary to this therapy.154 A final
point to mention is that the induction agent etomidate is associated with relative adrenal insufficiency.
Etomidate is laudatory because it is not associated with hemodynamic instability and, thus, had been
favored in shock. However, etomidate is a reversible inhibitor of 11-beta-hydroxylase, and thus may
cause transient adrenal insufficiency which theoretically can worsen outcome in sepsis. Studies have not
definitively demonstrated worse outcome between patients intubated using etomidate versus other
induction agents such as ketamine. Practitioners should balance the risks and benefits of etomidate
administration and consider the transient administration of steroids to blunt adverse effects in the
airway management of those with sepsis.155
Thyroid Abnormalities
Thyroid abnormalities occur infrequently in ICU patients. Although the half-life of commonly
administered thyroid medications is long, it is possible that chronically ill patients who eventually
present to the ICU could develop severe hypothyroidism. The typical patient with myxedema coma has
a long-standing need for replacement thyroid medications and is ill after infection or trauma. Patients
325
are hypothermic, bradycardic, and obtunded with low serum sodium and glucose levels. The treatment
includes securing an airway, hydration, warming, and administration of thryoxine and hydrocortisone.
The treatment of thyroid storm is discussed elsewhere in more detail. It occurs in patients with Graves
disease or toxic nodular goiters who become infected, pregnant, traumatized, or undergo surgery.
Supportive treatment includes ICU admission to monitor hemodynamic status and arrhythmias, cooling,
hydration, and beta blockade. Propylthiouracil (PTU) or methimazole is administered both to inhibit the
release of T4 and to block the conversion of T4 to T3. Thereafter, iodine as SSKI or Lugol solution is
given, once hemodynamics have been stabilized to inhibit T4 release. Glucocorticoids may also be
indicated. Finally, there is an entity of pseudohypothyroidism, the so-called sick syndrome, that occurs
in ICU patients who have normal thyroid function but low levels of T3, freeT4, and T4 as T3 is
converted to its isomer reverse T3. Several mechanisms can contribute to the inhibition of 5′-
monodeiodination and therefore to the low serum T3 concentrations in patients with nonthyroidal
illness. These include elevated cortisol levels with glucocorticoid therapy, free fatty acids that inhibit
deiodinase, cytokines, and treatment with drugs that inhibit 5′-monodeiodinase activity such as
amiodarone. No treatment is required. If there is additional evidence to suggest a diagnosis of
hypothyroidism, critically ill patients, should receive cautious thyroid hormone replacement beginning
with approximately half the expected full replacement dose of levothyroxine.
INFECTIOUS DISEASE ISSUES IN THE ICU

Sepsis Guidelines
Evidence-based sepsis resuscitation and global care guidelines are set forth in the Surviving Sepsis
Campaign, now in its third version.20 These guidelines prioritize care for those with the most acute
forms of sepsis – that is, severe sepsis and septic shock. Severe sepsis refers to those infected patients
with hypotension and/or hypoperfusion with organ dysfunction (manifested by oliguria, acute mental
status change, new coagulopathy or thrombocytopenia, or acute lung injury). Septic shock refers to
those who require administration of pressors despite initial volume resuscitation. Care of the septic
patient with severe sepsis and septic shock is suggested to adhere to bundles that optimally should be
completed within 3 and 6 hours (Table 10-2). Resuscitation targets a MAP of >65 mm Hg, a central
venous pressure (CVP) of >8 mm Hg, and a central venous oxygen saturation (ScvO2) of >70%.
Pressors are administered if the initial fluid bolus does not achieve the targets above and inotropes
and/or blood transfusion are given to maintain a hemoglobin >10 g/dL if the ScvO2 goal is not met.
The principal evidence underlying the resuscitation strategy is derived from Emanuel Rivers’ early goal-
directed therapy study (EGDT) published in 2001.156 This single center trial allocated patients to usual
care or CVP-directed intravenous fluid administration with MAP and ScvO2 goals achieved by
administration of dopamine, dobutamine, and packed red blood cells. In this study, Rivers and
colleagues demonstrated a significant difference in mortality between the groups – 30.5% in the study
patients versus 46.5% in the controls. Further, the current surviving sepsis guidelines render several
specific recommendations regarding fluid administration. They advocate for the use of crystalloids as
the initial fluid therapy of choice and against the use of hydroethyl starches and suggest that albumin
may be beneficial if large volume crystalloid resuscitation is required.
12 In the interim, three trials have been conducted that call into question Rivers’ resuscitation
paradigm. The ProCESS trial, a large, multicenter controlled trial randomized patients into three groups
with excellent protocol compliance (90%) and equivalent usage of early antibiotics. The three groups
were the EGDT group (439 patients) exactly as described by Rivers with CVP and ScvO2 monitoring and
administration of dobutamine and packed cells. The second (protocol-based standard care) group (446
patients) was resuscitated to clinical euvolemia within 6 hours. Insertion of a CVC or and ScvO2 catheter
was not mandatory. Finally, a third (usual care) group (456 patients) was resuscitated according to the
clinical judgment of the provider. Approximately half of the protocol and usual group patients received
CVCs. Fluid administration was not clinically different between the protocol- and goal-directed therapy
groups (2.3 L vs. 3.3 L, respectively). However, dobutamine use and packed cell transfusion was
roughly eight times higher and double, respectively, in the EGDT group. Most importantly, there was
no difference in 60-day, 90-day, or 1-year mortality, length of stay, or organ failure.36 The second, the
ARISE trial, randomized patients with early septic shock to receive EGDT (796 patients) or usual care
(804 patients) and corroborated the results of the ProCESS trial. There was no difference in 90-day
mortality, but the EGDT group was twice as likely to receive red blood cell transfusion and was six
326
times as likely to receive dobutamine.37 The third trial – ProMISe from the United Kingdom, still awaits
publication. It is apparent that these studies will result in a de-emphasis on CVP and ScvO2-guided
resuscitation in future iterations. Finally, the guidelines provide an in-depth evidence-based review of
the components of global sepsis care, the evidence for which is described throughout this chapter.
Use of Procalcitonin to Guide Antibiotic Therapy

Procalcitonin, a precursor of calcitonin with a half-life of about 24 hours, is released in response to
bacterial toxins and interleukin-1b and has been identified as a marker of sepsis and bacterial infection
for nearly a decade. Procalcitonin increases within 4 to 6 hours or bacterial infection, is attenuated in
the presence of viral infection and not affected in the presence of fungal infections. Far more important
clinically is the observation that procalcitonin levels halve once bacterial infection is controlled by
antibacterials. Protocols have been developed to stop empiric or therapeutic antibiotics once
procalcitonin levels decrease by 80% or to an absolute level of 0 to 0.5 ng/mL. Seven randomized trials
in ICU patients were subjected to a systematic review and meta-analysis suggesting that procalcitonin
assay reduces antibiotic use by an average of two days per patient without otherwise affecting
outcome.157 An in-depth economic analysis suggests that use of procalcitonin is effective in the ICU
setting.158 More recent studies support the notion that use of procalcitonin is useful in determining
when to stop antibiotics in ICU patients and that these shorter therapeutic courses are not associated
with a difference in outcome.159,160
Central Line Associated Blood Stream Infections

Central line associated blood stream infections (CLABSI) can be an important cause of morbidity,
resource utilization, and even attributable mortality in ICU patients. Infection control measures have
been successful in dramatically lowering the incidence of this infection, defined as 15 colony forming
units (cfu)/mL by semiquantitative or 103 by quantitative means. Perhaps the most successful
intervention to preventing CLABSI is to remove (or not insert) central catheters if they are not needed;
this is the cornerstone of care bundles or checklists (Table 10-3).161 Antiseptic or antibiotic-coated
catheters should be considered in ICUs with a high baseline rate of infection after employing less costly
measures. Chlorhexidine-impregnated dressings lower CLABSI rates as well.162 Routine wire changing of
catheters does not decrease CLABSI rate. In the past the subclavian site was felt to be the least prone to
infection; however, recent studies indicate that internal jugular (and perhaps even femoral) catheters
are not much worse. Further, no randomized controlled trial compares subclavian versus internal
jugular versus femoral insertion in a single study.
Catheter Associated Urinary Tract Infections

Infection control measures have also been undertaken to prevent catheter associated urinary tract
infections (CAUTI), a common cause of morbidity, but rarely of mortality, in surgical ICU patients.
CAUTI are the leading cause of secondary healthcare-associated bacteremia and may be associated with
symptomatic or asymptomatic bacteriuria of >10 cfu/mL.5 Most strategies focus on prompt removal of
indwelling catheters. There may be some role for use of antiseptic- (silver preparations) or antibiotic-
coated catheters (minocycline-rifampin) in high-risk patients, although clinical trials have not been
definitive.164,165
The Use of Selective Oral and Selective Digestive Decontamination (SOD and SDD) and
Other Strategies to Address Resistant Organisms in the ICU
Antibiotic-resistant bacteria are discussed more in detail in this text. Those relevant to ICU patients
include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus, and
multi-drug resistant gram negative pathogens, including carbapenem-resistant enterobacteriaceae.
Various infection control strategies have been promulgated in ICU patients to address these virulent
organisms. We will discuss the use of selective decontamination and MRSA decontamination strategies
here. The practice of selective decontamination was developed many decades ago and is used
extensively in surgical and trauma patients in Europe. Its goal is to minimize ventilator-associated
pneumonia to lessen multiple organ dysfunction and improve outcome in high-risk populations. The
cornerstone of the therapy is the administration of a short course (4 day) of parenteral antibiotics to
address respiratory gram negative pathogens, typically a second generation cephalosporin. SOD
strategies add use of a chlorhexidine mouthwash. SDD employs a nonabsorbable enteral antibiotic (such
327
as colistin) instead. Although there is a more robust experience with selective digestive rather than oral
decontamination, both strategies are associated with a reduction in ventilator-associated pneumonia
without a concomitant change in mortality.165 Another systematic review demonstrated a reduction in
multiorgan failure rates, but not of mortality.166 A large crossover cluster trial of nearly 6,000 ICU
patients in Denmark demonstrated that SOD and SDD both decreased mortality by roughly 15%,
although SOD was markedly less expensive. For whatever reason, perhaps the concern for antibiotic
resistance, the practice of decontamination by either route has not garnered interest in the United
States. The Danish group has noted, however, that antibiotic resistance was actually lower after
institution of decontamination.167 However, another large Danish trial demonstrated that SDD patients
did experience higher rates of aminoglycoside resistance by gram negative organisms.168 Specific
strategies to provide MRSA decontamination are focused on certain principles: that MRSA colonization
can be rapidly identified by aggressive screening protocols using polymerase chain reaction (PCR)
technology, that MRSA colonization ultimately leads to bacteremia and that therapies exist to
successfully decolonize patients. The clinical data are confusing and various society guidelines have
reached different conclusions regarding universal screening. Nonetheless, in the United States, 35% or
more of all precaution days are due to MRSA and screening increases these contact days by 15%. A large
Veterans Affairs initiative involving both ward and ICU patients demonstrated that MRSA screening
decreased infection rates.169 Two other large studies, one of surgical patients170 and another of mixed
ICU patients171 did not show benefit of MRSA screening in lowering infection rate. Several studies have
investigated the role of MRSA-directed decontamination, using such agents as topical chlorhexidine on
washcloths and intranasal mupirocin with or without oral rifampin and doxycycline. This strategy has
been successful in liver transplant patients172 and in mixed ICU patients173 in terms of decreasing
colonization, infection, and bacteremia. A multicenter US study randomized ICUs to MRSA screening
and isolation, targeted decolonization, or universal decolonization with topical chlorhexidine and nasal
mupirocin. Interestingly, the latter strategy was associated with reduced MRSA colonization and all-
cause infections (but not MRSA), suggesting that chlorhexidine is the most efficacious component of the
strategy.173 Chlorhexidine can also decrease colonization, and perhaps infection, with VRE, but its effect
of gram negative organisms is less certain.174
References
1. Health Forum LLC, an American Hospital Association Company. AHA Hospital Statistics 2011. ed.
Chicago, IL: health Forum LLC, an American Hospital Association Company; 2010.
2. Halpern NA, Pastores SM, Oropello JM, et al. Critical care medicine in the United States: addressing
the intensivist shortage and image of the specialty. Crit Care Med 2013;41(12):2754–2761.
3. Malstam J, Lind L. Therapeutic intervention scoring system (TISS)—a method for measuring
workload and calculating costs in the ICU. Acta Anethesiol Scan 1992;36:758–763.
4. Leape LL, Cullen DJ, Clapp MD, et al. Pharmacist participation on physician and adverse drug
events in the intensive care unit. JAMA 1999;282:267–270.
5. Braga JM, Hunt A, Pope J, et al. Implementation of dietitian recommendations for enteral nutrition
results improved outcomes. J Am Diet Assoc 2006;106:281–284.
6. Schweickert WD, Pohlman MC, Pohlman AS, et al. Early physical and occupational therapy in
mechanically ventilated, critically ill patients: a randomized controlled trial. Lancet 2009;373:1874–
1882.
7. Kleinpell, RM, Ely EW, Grabenkort R. Nurse practitioners and physician assistants in the intensive
care unit: an evidence-based review. Critical Care Med 2008;36:2888–2897.
8. Yoo EJ, Edwards JD, Dean ML, et al. Multidisciplinary critical care and intensivist staffing: results
of a statewide survey and association with mortality. J Inten Care Med 2014;1–8.
9. Wilcox, ME, Chong CA, Niven DJ, et al. Do intensivist staffing patterns influence hospital mortality
following ICU admission? A systematic review and meta-analyses. Crit Care Med 2013;41:2253–
2274.
10. Sluis FJ, Slagt C, Liebman B, et al. The impact of open versus closed format ICU admission practices
on the outcome of high risk surgical patients: a cohort analysis. BMC Surg 2011;11:18.
11. Gutsche JT, Kohl BA. Who should care for intensive care unit patients? Crit Care Med 2007;35(2
Suppl):S18–S23.
328
12. Iyegha UP, Asghar JI, Habermann EB, et al. Intensivists improve outcomes and compliance with
process measures in critically ill patients. J Am Coll Surg 2013;216:363–372.
13. The Joint Commission. The 2015 Accreditation Manual for Hospitals: The Official Handbook. Oakbrook
Terrace, IL: Joint Commission Resources; 2014.
14. Burnhan EL, Moss M, Geraci MW. The case for 24/7 in-house intensivist coverage. Am J Respir Crit
Care Med 2010;181:1159–1160.
15. Wilden GM, Schmidt U, Chang Y, et al. Implementation of 24/7 intensivist presence in the SICU:
effect on processes of care. J Trauma Acute Care Surg 2013;74:563-567.
16. Kumar K, Singal R, Manji R, et al. The benefits of 24/7 in-house intensivist coverage for prolonged-
stay cardiac surgery patients. J Thoracic and Cardiovascular Surg 2014;148(1):290–297.
17. Kerlin MP, Small DS, Cooney E, et al. A randomized trial of nighttime physician staffing in an
intensive care unit. N Engl J Med 2013;368:2201–2209.
18. Wallace DJ, Angus DC, Barnato AE, et al. Nighttime intensivist staffing and mortality among
critically ill patients. N Engl J Med 2012;366:2093–2101.
19. Ward NS, Afessa B, Kleinpell R, et al. Intensivist/patient ratios in closed ICUs: a statement from the
society of critical care medicine taskforce on ICU staffing. Crit Care Med 2013;41:638–645.
20. Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for
management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41:580.
21. Vincent JL. Give your patient a fast hug (at least) once a day. Crit Care Med 2005;33(6);1225–1230.
22. Pronovost P, Berenholtz S, Dorman T, et al. Improving communication in the ICU using daily goals.
J Crit Care 2003;18(2):71–75.
23. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related
bloodstream infections in the ICU. N Engl J Med 2006; 355:2725–2732.
24. Ferrer R, Artigas A, Levy MM, et al. Improvement in process of care and outcome after a
multicenter severe sepsis educational program in Spain. JAMA 2008;299:2294–2303.
25. van Zanten AR, Brinkman S, Arbous MS, et al. Guidelines bundles adherence and mortality in
severe sepsis and septic shock. Crit Care Med 2014;42(8):1890–1898.
26. Blot, K, Bergs J, Vogelaers D, et al. Prevention of central line-associated bloodstream infections
through quality improvement interventions: a systemic review and meta-analysis. Clin Infect Disease
2014;59(1):96–105.
27. Carrothers KM, Barr J, Spurlock B, et al. Contextual issues influencing implementation and
outcomes associated with an integrated approach to managing pain, agitation and delirium in adult
ICUs. Crit Care Med 2013;41:S128–S135.
28. Salluh JI, Soares M. ICU severity of illness scores: APACHE, SAPS and MPM. Curr Opin Crit Care
2014;20:557–565.
29. Zimmerman JE, Kramer AA, McNair DS, et al. Acute physiology and chronic health evaluation
(APACHE) IV: hospital mortality assessment for today’s critically ill patients. Crit Care Med
2006;34:1297–1310.
30. Moreno RP, Metnitz PG, Almeida E, et al. SAPS 3 – From evaluation of the patient to evaluation of
the intensive care unit. Inte Care Med 2005;31:1345–1355.
31. Higgins TL, Teres D, Copes WS, et al. Assessing contemporary intensive care unit outcome: an
updated Mortality Probability Admission Model (MPM0-III). Crit Care Med 2007;35:1853–1862.
32. Wysham NG, Abernethy AP, Cox CE. Setting the vision: applied patient-reported outcomes and
smart, connected digital healthcare systems to improve patient-centered outcomes prediction in
critical illness. Curr Opin in Crit Care 2014;20:566–572.
33. Marshall JC, Cook DJ, Christon NV, et al. Multiple organ dysfunction score: a reliable descriptor of
a complex clinical outcome. Crit Care Med 1995;23(10);1635–1652.
34. Moore FA, Sauaia A, Moore EE, et al. Postinjury multiple organ failure: a bimodal phenomenon. J
Trauma 1996;40:501–502.
35. Marik PE, Cavallazzi R. Does the central venous pressure predict fluid responsiveness? An updated
meta-analysis and a plea for some common sense. Crit Care Med 2013;41:1774–1781.
36. The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock. N Engl
J Med 2014;370(18):1685–1693.
329
37. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for
patients with early septic shock. N Engl J Med 2014;371:1496–1506.
38. National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical
Trials Network, Wiedmann HP, Wheeler AP, et al. Comparison of two fluid-management strategies
in acute lung injury. N Engl J Med 2006;354:2564–2575.
39. Lavrentieva A, Kontakiotis T, Kaimakamis E, et al. Evaluation of arterial waveform derived
variables for an assessment of volume resuscitation in mechanically ventilated burn patients. Burns
2013;39(2):249–254.
40. Barbier C, Loubieres Y, Scmit C, et al. Respiratory changes in inferior vena cava diameter are
helpful in predicting fluid responsiveness in ventilated septic patients. Intens Care Med
2004;30:1740–1746.
41. Anantharaman V, Gunasegaran K. Advance Cardiac Life Support guidelines 2011. Singapore Med J
2011;52(8):548–555.
42. Futier E, Constantin JM, Paugam-Burtz C, et al. A trial of intraoperative low-tidal-volume
ventilation in abdominal surgery. N Engl J Med 2013; 369(5):428–437.
43. Levine S, Nguyen T, Taylor N, et al. Rapid disuse atrophy of diaphragm fibers in mechanically
ventilated humans. N Engl J Med 2008;358(13):1327–1335.
44. Bernard GR, Artigas A, Brigham KL, et al. The American-European consensus conference on ARDS.
Definitions, mechanisms, relevant outcomes and clinical trial coordination. Am J Respir Crit Care
Med 1994;149:818–824.
45. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome:
the Berlin Definition. JAMA 2012;307:2526–2533.
46. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as
compared with traditional tidal volumes for acute lung injury and the acute respiratory distress
syndrome. N Engl J Med 2000;342(18):1301–1308.
47. Brower RG, Lanken PN, MacIntyre N, et al. Higher versus lower positive end-expiratory pressures
in patients with the acute respiratory distress syndrome. N Engl J Med 2004;351(4):327–336.
48. Meade MO, Cook DJ, Guyatt GH, et al. Ventilation strategy using low tidal volumes, recruitment
maneuvers and high positive end-expiratory pressure for acute lung injury and acute respiratory
distress syndrome: a randomized controlled trial. JAMA 2008;299:637–645.
49. Mercat A, Richard JM, Vielle B, et al. Positive end-expiratory pressure setting in adults with acute
lung injury and acute respiratory distress syndrome (EXPRESS). JAMA 2008;299:646–655.
50. Santa Cruz R, Rojas JI, Nervi R, et al. High versus low positive end-expiratory pressure (PEEP)
levels for mechanically ventilated adult patients with acute lung injury and acute respiratory
distress syndrome. Cochrane Database Syst Rev 2013;6:CD009098.
51. Young D, Lamb SE, Shah S, et al. High-frequency oscillation for acute respiratory distress
52. Ferguson ND, Cook DJ, Guyatt GH, et al. High-frequency oscillation in early acute respiratory
distress syndrome. N Engl J Med 2013;368(9):795–805.
53. Dart BW, Maxwell RA, Richart CM, et al. Preliminary experience with airway pressure release
ventilation in a trauma/surgical intensive care unit. J Trauma 2005;59(1):71–76.
54. Kaplan LJ, Bailey H, Formosa V. Airway pressure release ventilation increases cardiac performance
in patients with acute lung injury/adult respiratory distress syndrome. Crit Care 2001;5(4):221–226.
55. Putensen C, Zech S, Wrigge H, et al. Long-term effects of spontaneous breathing during ventilator
support in patients with acute lung injury. Am J Respir Crit Care Med 2001;164(1):43–49.
56. Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional
support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR):
a multicenter randomized controlled trial. Lancet 2009;374(9698):1351–1363.
57. Melsen WG, Rovers MM, Koeman M, et al. Estimating the attributable mortality of ventilator-
associated pneumonia from randomized prevention studies. Crit Care Med 2011;39(12):2736–2742.
58. Boyer AF, Schoenberg N, Babcock H, et al. A prospective evaluation of ventilator-associated
conditions and infection-related ventilator-associated conditions. Chest 2014;147(1):68–81.
59. Yang KL, Tobin MJ. A prospective study of indexes predicting outcome of trials of weaning from
mechanical ventilation. N Engl J Med 1991;324(21):1445–1450.
330
60. McCaffrey J, Farrell C, Whiting P, et al. Corticosteroids to prevent extubation failure: a systemic
review and meta-analysis. Intensive Care Med 2009;35(6):977–986.
61. Afshari A, Brok J, Moller AM, et al. Inhaled nitric oxide for acute respiratory distress syndrome
(ARDS) and acute lung injury in children and adults. Cochrane Database Syst Rev 2010;
(7):CD002787.
62. Adhikari NK, Dellinger RP, Lundin S, et al. Inhaled nitric oxide does not reduce mortality in
patients with acute respiratory distress syndrome regardless of severity: systemic review and meta-
analysis. Crit Care Med 2014;42(2):404–412.
63. Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory
distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury)
disease on gas exchange response. Crit Care Med 2001;29(1):57–62.
64. Guerin C, Reignier J, Richard JC, et al. PROSEVA study group. Prone positioning in severe acute
respiratory distress syndrome. N Engl J Med 2013;368:2159–2168.
65. Sud S, Freidrich JO, Adhikari NK, et al. Effect of prone positioning during mechanical ventilation
on mortality among patients with acute respiratory distress syndrome: a systemic review and meta-
analysis. CMAJ 2014;186(10):E381–E390.
66. Lee, SJ, Ramar K, Park JG, et al. Increased fluid administration in the first three hours of sepsis
resuscitation is associated with reduced mortality: a retrospective cohort study. Chest
2014;146:908–915.
67. Sweet D, Marsden J, Ho K, et al. Emergency management of sepsis: the simple stuff saves lives.
BCMJ 2012;54(4):176–182.
68. Bioc JJ, Magee C, Cucchi J, et al. Cost effectiveness of benzodiazepine vs. nonbenzodiazepine –
based sedation regimen for mechanically ventilated, critically ill adults. J Crit Care 2014;29(5):753–
757.
69. Jakob SM, Ruokonen E, Grounds RM, et al. Dexmedetomidine vs. midazolam or propofol for
sedation during prolonged mechanical ventilation. JAMA 2012;307(11):1151–1160.
70. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress
71. Needham CJ, Brindley PG. Best evidence in critical care medicine: the role of neuromuscular
blocking drugs in early severe acute respiratory distress syndrome. Can J Anaesth 2012;59(1):105–
108.
72. Horlander KT, Mannino DM, Leeper KV. Pulmonary embolism mortality in the United States, 1979
– 1998. Arch Intern Med 2003;163:1711–1717.
73. Munoz FJ, Mismetti P, Poggio R, et al. Clinical outcome of patients with upper-extremity deep vein
thrombosis: results from the RIETE registry. Chest 2008;133(1):143–148.
74. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP
Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(3 Suppl):338S–400S.
75. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic
therapy: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):e326S–e 350S.
76. Caprini JA. Risk assessment as a guide to thrombosis prophylaxis. Curr Opin Pulm Med
2010;16:448–452.
77. Christie S, Thibault-Halman G, Casha S. Acute pharmacologic DVT prophylaxis after spinal cord
injury. J Neurotrauma 2011;28(8):1509–1514.
78. Ho KM, Tan JA. Stratified meta-analysis of intermittent pneumatic compression of the lower limbs
to prevent venous thromboembolism in hospitalized patients. Circulation 2013;128(9):1003–1020.
79. Geerts WH, Jay RM, Code KI, et al. A comparison of low-dose heparin with low-molecular-weight
heparin as prophylaxis against venous thromboembolism after major trauma. N Engl J Med
1996;335:701–707.
80. PROTECT investigators for the Canadian critical care trials group and the Australian and New
Zealand intensive care society clinical trials group, Cook D, Meade M, et al. Dalteparin versus
unfractionated heparin in critically ill patients. N Engl J Med 2011;364(14):1305–1314.
81. Dudley RR, Aziz I, Bonnici A, et al. Early venous thromboembolic event prophylaxis in traumatic
brain injury with low-molecular-weight heparin: risks and benefits. J Neurotrauma 2010;27:2165–
331
2172.
82. Jamjoom AA, Jamjoom AB. Safety and efficacy of early pharmacological thromboprophylaxis in
traumatic brain injury: systematic review and meta-analysis. J Neurotrauma 2013;30(7):503–511.
83. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: Anemia and blood transfusion in the
critically ill – current clinical practice in the United States. Crit Care Med 2004;32(1):39–52.
84. Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial to
transfusion requirements in critical care. Transfusion requirement in critical care investigators,
Canadian critical care trials group. N Engl J Med 1999;340:409–417.
85. Hebert PC, Yetisir E, Martin C, et al. Is a low transfusion threshold safe in critically ill patients with
cardiovascular disease? Crit Care Med 2001;29(2):227–234.
86. Leal-Noval SR, Munoz-Gomez M, Jimenez-Sanchez M, et al. Red cell transfusion in non-bleeding
critically ill patients with moderate anemia: is there a benefit?Int Care Med 2013;39:445–453.
87. RELIEVE Investigators, Walsh TS, Boyd JA, et al. Restrictive versus liberal transfusion strategies for
older mechanically ventilated critically ill patients: a randomized pilot trial. Crit Care Med
2013;41(10):2354–2363.
88. Chatterjee S, Wetterslev J, Sharma A, et al. Association of blood transfusion with increased
mortality in myocardial infarction: a meta-analysis and diversity-adjusted study sequential analysis.
JAMA Intern Med 2013;173(2):132–139.
89. Murphy GJ, Reeves BC, Rogers CA, et al. Increased mortality, postoperative morbidity and cost
after red blood cell transfusion in patients having cardiac surgery. Circulation 2007;116:2544–2552.
90. Paone G, Likosky DS, Brewer R, et al. Transfusion of 1 and 2 units of red blood cells is associated
with increased morbidity and mortality. Ann Thorac Surg 2014;97(1):87–93; discussion 93–94.
91. Hajjar LA, Vincent JL, Galas FR, et al. Transfusion requirements after cardiac surgery: the TRACS
randomized controlled trial. JAMA 2010;304(14):1559–1567.
92. Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper gastrointestinal
bleeding. N Engl J Med 2013;368(1):11–21.
93. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on
neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA
2014;312(1):36–47.
94. Holst LB, Haase N, Wetterslev J, et al. Lower versus higher hemoglobin threshold for transfusion in
septic shock. N Eng J Med 2014;371(15):1381–1391.
95. Corwin HL. Erythropoietin use in critically ill patients: forest and trees. CMAJ 2007;177(7):747–
749.
96. Munoz M, Breymann C, Garcia-Erce JA, et al. Efficacy and safety of intravenous iron therapy as an
alternative/adjunct to allogenic blood transfusion. Vox Sanguinis 2008;94:172–183.
97. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of
nutrition support therapy in the adult critically ill patient: society of critical care medicine (SCCM)
and American society for parenteral and enteral nutrition (ASPEN). JPEN J Parenter Enteral Nutr
2009;33:277–316.
Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs. full enteral feeding in patients with
acute lung injury: the EDEN randomized trial. JAMA. 2012; 307:795.
99. McClave SA, Lukan JK, Stefater JA, et al. Poor validity of residual volumes as a marker for risk of
aspiration in critically ill patients. Crit Care Med 2005;33(2):324–330.
100. Heyland DK, Novak F. Immunonutrition in the critically ill patients: more harm than good? JPEN J
Parenter Enteral Nutr 2001;25(2 Suppl):S51–S55; discussion S55–S56.
101. Luiking YC, Engelen MP, Deutz NE. Regulation of nitric oxide production in health and disease.
Curr Opin Clin Nutr Metab Care 2010;13:97–104.
102. Ho KM, Dobb GJ, Webb SA. A comparison of early gastric and post-pyloric feeding in critically ill
patients: a meta-analysis. Intens Care Med 2006;32:639–649.
103. Prelack K, Dylewski M, Sheridan RL. Practical guidelines for nutritional management of burn injury
and recovery. Burns 2007;33(1):14–24.
104. Burlew CC, Moore EE, Cuschieri J, et al. Who should we feed? Western Trauma Association multi-
institutional study of enteral nutrition in the open abdomen after injury. J Trauma Acute Care Surg
332
2012;73(6):1380–1387.
105. Heyland DK, Dhaliwal R, Drover JW, et al. Canadian clinical practice guidelines for nutrition
support in mechanically ventilated, critically ill adult patients. JPEN J Parenter Enteral Nutr
2003;27(5):355–373.
106. Desai SV, McClave SA, Rice TD. Nutrition in the ICU: an evidence-based approach. Chest
2014;145(5):1148–1157.
107. Dhaliwal R, Heyland DK. Nutrition and infection in the intensive care unit: what does the evidence
show? Curr Opin Crit Care 2005;11(5):461–467.
108. Khalid I, Doshi P, DiGiovine B. Early enteral nutrition and outcomes of critically ill patients treated
with vasopressors and mechanical ventilation. Am J Crit Care 2010;19(3):261–268.
109. Yang S, Wu X, Yu W, et al. Early enteral nutrition in critically ill patients with hemodynamic
instability: an evidence-based review and practical advice. Nutr Clin Pract 2014;20(1):90–96.
Trials Network, Rice TW, Wheeler AP, et al. Initial trophic vs. full enteral feeding in patients with
acute lung injury: the EDEN randomized trial. JAMA 2012;307(8):795–803.
111. Casaer MP, Mesotten D, Hermas G, et al. Early versus late parenteral nutrition in critically ill
adults. NEJM 2011;365:506–517.
112. Sena MJ, Utter GH, Cuschieri J, et al. Early supplemental parenteral nutrition is associated with
increased infectious complications in critically ill trauma patients. J Am Coll Surg 2008;207(4):459–
467.
113. Heidegger CP, Berger MM, Graf S, et al. Optimization of energy provision with supplemental
nutrition in critically ill patients: a randomized controlled clinical trial. Lancet 2013;381(9864):385–
393.
114. CALORIES Trial Investigators, Harvey SE, Parrott F, et al. Trial of the route of early nutritional
support in critically ill adults. N Engl J Med 2014; 371(18):1673–1684.
115. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants
in critically ill patients. N Engl J Med 2013; 368(16):1489–1497.
116. Palmer AJ, Ho CK, Ajibola O, et al. The role of omega 3 fatty acid supplemented parenteral
nutrition in critical illness in adults: a systemic review and meta-analysis. Crit Care Med
2013;41(1):307–316.
117. Manzanares W, Dhaliwal R, Juresitsch B, et al. Parenteral fish oil lipid emulsions in the critically
ill: a systemic review and meta-analysis. JPEN J Parenter Enteral Nutr 2014;38(1):20–28.
118. Van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition with immune-modulating
nutrients vs. standard high-protein enteral nutrition and nosocomial infections in the ICU: a
randomized clinical trial. JAMA 2014;312(5):514–524.
119. Al-Omran M, Albalawi ZH, Tashkandi MF, et al. Enteral versus parenteral nutrition for acute
pancreatitis. Cochrane Database Syst Rev 2010;(1):CD002837.
120. Cook DJ, Fuller HD, Guyatt GH, et al. Risk factors for gastrointestinal bleeding in critically ill
patients. Canadian Critical Care Trials Group. N Engl J Med 1994;330(6):377.
121. Marik PE, Vasu T, Hirani A, et al. Stress ulcer prophylaxis in the new millennium: a systematic
review and meta-analysis. Crit Care Med 2010;38(11):2222–2228.
122. Leontiadis GI, Sharma VK, Howden CW. Systemic review and meta-analysis of proton pump
inhibitor therapy in peptic ulcer bleeding. BMJ 2005;330(7941):568.
123. Kasotakis G, Sideris A, Yang Y, et al. Aggressive early crystalloid resuscitation adversely affects
outcomes in adult blunt trauma patients: an analysis of the Glue Grant database. J Trauma Acute
Care Surg 2013;74(5):1215–1221.
124. Bellomo R, Ronco C, Kellum JA, et al. Acute Renal Failure – definition, outcome measures, animal
models, fluid therapy and information technology needs: the Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8(4):R204–R212.
125. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network: report of an initiative to
improve outcomes in acute kidney injury. Crit Care 2007;11(2):R31.
126. KDIGO clinical practice guidelines for acute kidney injury. Kidney Int Suppl 2012;2:8.
127. Au TH, Bruckner A, Mohiuddin SM, et al. The prevention of contrast-induced nephropathy. Ann
Pharmacother 2014;48(10):1332–1342.
333
128. Scharman EJ, Troutman WG. Prevention of kidney injury following rhabdomyolysis: a systemic
review. Ann Pharmacotherapy 2013;47(1):90–105.
129. Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart
failure with renal dysfunction. The ROSE acute heart failure randomized trial. JAMA
2013;310(23):2533–2543.
130. Joannidis M, Drumli W, Forni LG. Prevention of acute kidney inury and protection of renal
function in the intensive care unit. Int Care Med 2010;36:392–411.
131. Wu MY, Chang NC, Su CL, et al. Loop diuretic strategies in patients with acute decompensated
heart failure: a meta-analysis of randomized controlled trials. J Crit Care 2014;29:2–9.
132. Ejaz AA, Mohandas R. Are diuretics harmful in the management of acute kidney injury? Curr Opin
Nephrol Hypertens 2014;23(2):155–160.
133. Algahtani F, Koulouridis I, Susantitaphong P, Dahal K, et al. A meta-analysis of continuous vs.
intermittent infusion of loop diuretics in hospitalized patients. J Crit Care 2014;29(1):10–17.
134. Palazzuoli A, Pellegrini M, Ruocco G, et al. Continuous versus bolus intermittent loop diuretic
infusion in acutely decompensated heart failure: a prospective randomized trial. Crit Care
2014;18(3):R134.
135. Finfer S, Cass A, Gallagher M, et al. The RENAL (Randomised Evaluation of Normal vs. Augmented
Level of Replacement Therapy) study: statistical analysis plan. Crit Care Resus;11(1):58–66.
136. VA/NIH Acute Renal Failure Trial Network, Palevsky PM, Zhang JH, et al. Intensity of renal
support in critically ill patients with acute kidney injury. N Engl J Med 2008;359(1):7–20.
137. Ricci Z, Ronco C. Timing, dose and mode of dialysis in acute kidney injury. Curr Opin Crit Care
2011;17:556–561.
138. Joannes-Boyau O, Honore PM, Perez P, et al. High-volume versus standard-volume hemofiltration
for septic shock patients with acute kidney injury (IVOIRE study): a multicenter randomized
controlled trial. Int Care Med 2013;39:1535–1546.
139. Schneider AG, Bellomo R, Bagshaw SM, et al. Choice of renal replacement therapy modality and
dialysis dependence after acute kidney injury: a systemic review and meta-analysis. Intensive Care
Med 2013;39:987–997.
140. Rauf AA, Long KH, Gajic O, et al. Intermittent hemodialysis versus continuous renal replacement
therapy for acute renal failure in the intensive care unit: an observational outcomes analysis. J
141. Bochicchio GV, Sung J, Joshi M, et al. Persistent hyperglycemia is predictive of outcome in
critically ill trauma patients. J Trauma 2005;58:921–924.
142. Jeremitsky E, Omert LA, Dunham CM, et al. The impact of hyperglycemia on patients with severe
brain injury. J Trauma 2005;58:47–50.
143. Krinsley JS. Association between hyperglycemia and increased hospital mortality in a
heterogeneous population of critically ill patients. Mayo Clin Proc 2003;78:1471–1478.
144. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N
Engl J Med 2001;345:1359.
145. Preiser JC, Devos P, Ruiz-Santana S, et al. A prospective randomized multi-centre controlled trial
on tight glucose control by intensive insulin therapy in adult intensive care units: the Glucontrol
study. Intensive Care Med 2009;35(10):1738–1748.
146. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, et al. Intensive versus conventional
glucose control in critically ill patients. N Engl J Med 2009;360(13):1283–1297.
147. Egi M, Finfer S, Bellomo R. Glycemic control in the ICU. Chest 2011;140(1):212–220.
148. Burry LD, Wax RS. Role of corticosteroids in septic shock. Ann Pharmacother 2004;38(3):464–472.
149. Annane D, Sebille V, Troche G, et al. A 3-level prognostic classification in septic shock based on
cortisol levels and cortisol response to corticotropin. JAMA 2000;283:1038–1045.
150. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and
fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862–871.
151. The CORTICUS Study Group, Sprung CL, Annane D, et al. Hydrocortisone therapy for patients with
septic shock. N Engl J Med 2008;358:111–124.
152. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids in the treatment of severe sepsis and
334
septic shock in adults: a systemic review. JAMA 2009;301(22):2362–2375.
153. Minneci PC, Deans KJ, Eichacker PQ, et al. The effects of steroids during sepsis depend on dose and
severity of illness: an updated meta-analysis. Clin Microbiol Infect 2009;15(4):308–318.
154. Gordon AC, Mason AJ, Perkins GD, et al. The interaction of vasopressin and corticosteroids in
septic shock: a pilot randomized controlled trial. Crit Care Med 2014;42(6):1325–1333.
155. Malerba G, Romano-Girard F, Cravoisy A, et al. Risk factors of relative adrenocortical deficiency in
intensive care patients needing mechanical ventilation. Intensive Care Med 2005;31(3):388–392.
156. Rivers E, Nguyen B, Havsted S, et al. Early goal-directed therapy in the treatment of severe sepsis
and septic shock. N Engl J Med 2001;345:1368–1377.
157. Kopterides P, Siempos II, Tsangaris I, et al. Procalcitonin-guided algorithms of antibiotic therapy in
the intensive care unit: a systematic review and meta-analysis of randomized controlled trials. Crit
Care Med 2010;38(11):2229–2241.
158. Heyland DK, Johnson AP, Reynolds SC, et al. Procalcitonin for reduced antibiotic exposure in the
critical care setting: a systemic review and an economic evaluation. Crit Care Med 2011;39(7):1792–
1799.
159. Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in ventilator-
associated pneumonia: a randomized study. Eur Respir J 2009;34(6):1364–1375.
160. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to
antibiotics in intensive care units (PRORATA trial): a multicenter randomized controlled trial.
Lancet 2010;375(9713):463–474.
161. Tang HJ, Lin HL, Lin YH, et al. The impact of central line insertion bundle on central line-
associated bloodstream infection. BMC Infectious Diseases 2014;14:356.
162. Safdar N, O’Horo JC, Ghufran A, et al. Chlorhexidine-impregnated dressing for prevention of
catheter-related bloodstream infection: a meta-analysis. Crit Care Med 2014;42(7):1703–1713.
163. Lam TB, Omar MI, Fisher E, et al. Types of indwelling urethral catheters for short term
catherisation in hospitalized adults. Cochrane Database Syst Rev 2014;9:CD004013.
164. Srinivasan A, Karchmer T, Richards A, et al. A prospective trial of a novel, silicone-based, silver
ion-impregnated urinary catheters in the prevention of nosocomial urinary tract infections (NUTIs).
Infect Control Hosp Epidemiol 2006;27(1):38–43.
165. Liberati A, D’Amico R, Pifferi S, et al. Antibiotic prophylaxis to reduce respiratory tract infections
and mortality in adults receiving intensive care. Cochrane Database Syst Rev 2009;(4):CD000022.
166. Silvestri L, Weir I, Gregori D, et al. Effectiveness of oral chlorhexidine on nosocomial pneumonia,
causative micro-organisms and mortality in critically ill patients: a systemic review and meta-
analysis. Minerva Anestesiol 2014;80(7):805–820.
167. De Smet AM, Kluytmans JA, Cooper BS, et al. Decontamination of the digestive tract and
oropharynx in ICU patients. N Engl J Med 2009;360:20–31.
168. Oostdijk EA, Kesecioglu J, Schultz MJ, et al. Effects of decontamination of the oropharynx and
intestinal tract on antibiotic resistance in ICUs: a randomized clinical trial. JAMA
2014;312(14):1429–1437.
169. Jain R, Kralovic SM, Evans ME, et al. Veterans’ affairs initiative to prevent methicillin-resistant
staphylococcus aureus infections. N Engl J Med 2011;364(15):1419–1430.
170. Harbath S, Fankhauser C, Schrenzel J, et al. Universal screening for methicillin-resistant
staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA
2008;299(10):1149–1157.
171. Huskins WC, Huckabee CM, O’Grady NP, et al. Intervention to reduce transmission of resistant
bacteria in intensive care. N Engl J Med 2011;364(15):1407–1418.
172. Singh N, Squier C, Wannstedt C, et al. Impact of an aggressive infection control strategy on
endemic staphylococcus aureus infection in liver transplant recipients. Infect Control Hosp Epidemiol
2006;27(2):122–126.
173. Sandri AM, Dalarosa MG, Ruschel de AL, et al. Reduction in incidence of nosocomial methicillin-
resistant staphylococcus aureus (MRSA) infection in an intensive care unit: role of treatment with
mupirocin ointment and chlorhexidine baths for nasal carriers of MRSA. Infect Control Hosp
Epidemiol 2006;27(2):185–187.
174. Haung SS, Septimus E, Kleinman K, et al. Targeted versus universal decolonization to prevent ICU
335
infection. N Engl J Med 2013;368(24):2255–2265.
336
Chapter 11
Fluids, Electrolytes, and Acid–Base Balance

Richard B. Wait, M. George DeBusk, and Jeffry Nahmias
Key Points
1 The human body is conceptualized as being composed of two primary fluid compartments:
extracellular fluid (ECF) and intracellular fluid (ICF). The two compartments are separated by
cellular membranes.
2 The ECF can be further divided into smaller compartments: transcellular fluid, plasma, interstitial
fluid, and bone/connective tissue fluid. Blood is a composite compartment containing both ECF
(plasma) and ICF (red cell volume).
3 Sodium and potassium are the dominant cations of the ECF and ICF, respectively.
4 Extracellular tonicity is under tight regulation by osmoreceptors found in the hypothalamus. As
sodium accounts for the majority of ECF tonicity, these receptors function essentially as ECF
monitors.
5 Effective circulating volume is sensed by volume receptors (capacitance vessels, atria, hepatic, and
central nervous system [CNS]) and pressure receptors (aortic arch, carotid, and intrarenal) that alter
sodium and water balance mediated by renin–angiotensin, aldosterone, atrial natriuretic peptide
(ANP), dopamine, and renal prostaglandins.
6 Water losses are composed of both sensible (i.e., measurable) losses via urine, stool, and sweat and
insensible (i.e., immeasurable) via evaporative loss from the skin, respiratory tract, or open
abdomen.
7 Goals of fluid therapy are to normalize body fluid compartment volumes and electrolyte
concentrations. This can be achieved with crystalloid (preferable) or colloid infusion to correct
deficits and/or match ongoing and expected losses.
8 The major electrolytes (Na+, K+, Ca2+, Mg2+, Cl-, HCO3-, and HPO42-) should be monitored and
replaced, when possible, with respect to the pathophysiology of various disease states.
9 Acid–base balance is carefully buffered within very narrow limits. Acid–base disturbances are
frequently mixed, involving combined respiratory and metabolic derangements.
In this chapter, the normal physiologic mechanisms of fluid and electrolyte homeostasis, inclusive of
acid–base physiology, are reviewed. This will be the starting point for a discussion of fluid and
electrolyte pathophysiology and the management of specific clinical situations. With a thorough
understanding of disease- and injury-related alterations from normal fluid volume and electrolyte
physiology, one can effectively care for all surgical and critically ill patients.
BODY FLUIDS
Total Body Water and Body Fluid Compartments
Total body water (TBW) is defined as the total amount of water contained within the body. The
relationship between TBW and body weight varies according to the percentage of body fat.1 The
average TBW in adult men is 60% of total body weight and 55% in adult women. In infants, water
makes up approximately 75% to 80% of body weight. This figure decreases to approximately 65% by 1
year of age and continues to decrease slowly throughout life, primarily related to decreases in lean body
mass. Estimates of TBW can be empirically adjusted for the obese and thin body habitus. In obesity,
estimates of TBW can be decreased by 10% to 20%. In very thin individuals, estimates can be increased
by up to 10%.1
1 TBW is principally distributed into the intracellular and extracellular compartments which are in
337
dynamic equilibrium (Table 11-1). ICF makes up approximately two-thirds of the TBW, and the
remaining one-third is composed of ECF. Using these techniques, ECF volume estimates range from 30%
to 33% of TBW, or approximately 20% of body weight.2
2 The ECF compartment is subdivided into the interstitial and intravascular spaces. The interstitial
space extends from the blood vessels to the cells. It includes the complex ground substance making up
the acellular tissue matrix. The water in this space exists in free and bound phases. The free phase
contains water that is freely exchangeable with intravascular, lymphatic, and intracellular water. It is in
a constant state of flux. The bound phase is much less freely exchangeable. It is composed of water that
hydrates matrix materials such as glycosaminoglycans and mucopolysaccharides. Interstitial water
volume can be calculated as ECF–intravascular space volume and constitutes approximately 25% of
TBW, or 15% of body weight. The intravascular space accounts for 25% of the ECF and contains the
plasma volume, which is approximately 8% of the TBW or 5% of body weight.
The transcellular space, a third and smaller component of ECF, consists of water that is separated
from other compartments by endothelial and epithelial barriers, including cerebrospinal, ocular, and
synovial fluids, as well as fluid in the gastrointestinal (GI) tract. Under normal circumstances, fluid in
the transcellular space is not easily exchangeable with that in other compartments.3
Composition of Body Fluids

3 Sodium and potassium are the dominant cations in the body. As mentioned above, sodium is restricted
primarily to the ECF. Sodium content in an average adult is approximately 60 mEq/kg. Approximately
25% is confined to bone and is nonexchangeable. Of the exchangeable fraction, approximately 85% is in
the ECF. Potassium, calcium, and magnesium make up the remainder, smaller fraction, of the cations
present in the ECF (Table 11-2).
Table 11-1 Body Fluid Compartments
In the ICF, potassium is the dominant cation. Total body potassium is normally approximately 42
mEq/kg, and most of this potassium is intracellular and freely exchangeable. Magnesium and sodium
ions also contribute to a lesser extent to the cationic component of the ICF. Phosphate, sulfate anions,
bicarbonate, and intracellular proteins balance these cations.
The Gibbs–Donnan equilibrium describes the relationship between charged particles in a solution that
are unevenly distributed across a semipermeable membrane.4 This special type of equilibrium exists
between the ICF and ECF because of the high concentration of protein and nondiffusible phosphates in
the cell. ECF cations are in electrochemical balance with chloride, bicarbonate, phosphate, and sulfate
anions, although chloride is the major contributor to this balance. In addition, anionic proteins
contribute to ion balance in plasma but not in interstitial fluid, which is essentially an ultrafiltrate of
plasma that normally contains little protein. As a result, the content of both cations and anions in
interstitial fluid is slightly higher than in plasma (Table 11-2).
Interstitial fluid, in comparison, contains little protein. These impermeable intracellular negative
charges tend to favor diffusion of permeable anions into the ECF. The Gibbs–Donnan equilibrium also
exists across the capillary endothelial membrane because the concentration of protein is higher on the
blood side of the capillary than on the interstitial fluid side. Thus, the concentrations of diffusible ions
are not necessarily equal across these membranes because of the presence of these complex anions.
Table 11-2 Electrolyte Concentrations of Intracellular and Extracellular Fluid

Compartments
338
Osmotic Activity of Body Fluids
The concentration of solutes in the fluid compartments depends on the osmotic activity generated by the
ion species contained in each compartment. When two solutions are separated by a semipermeable
membrane, water moves across the membrane to equalize the concentration of osmotically active
particles to which the membrane is impermeable. The maintenance of osmotic equilibrium across a
semipermeable membrane is based primarily on the number of solute particles rather than on the molar
concentration of the solution on each side of the membrane due to the flow of water.
The unit of measurement of osmotically active particles is the osmole (Osm) or milliosmole (mOsm)
rather than the conventional units of solute concentration such as milliequivalents per liter (mEq/L). In
solution, osmolarity (mOsm/L) and osmolality (mOsm/kg water) define the osmotic activity of
particles. When 1 mol of NaCl dissociates in water to Na+ and Cl−, it produces 2 Osm. The same
relationship holds true of dissociating salts of multivalent ions such as calcium and magnesium. One mol
of a nondissociating molecule, such as glucose, produces 1 Osm (1,000 mOsm). The measured
osmolality of a solution may not equal the calculated osmolality if the ions do not totally dissociate.
Body fluids are aqueous solutions composed of water and various solutes within the different body
fluid compartments. Because cells are bounded by a semipermeable membrane, adding free water to the
fluid surrounding a cell causes water to move across the cell membrane to equalize the osmolality
differential between the intracellular and extracellular compartments. On a larger scale, adding free
water to the ECF of the body causes an immediate expansion of the extracellular space, followed by a
redistribution of water into the intracellular compartment (Fig. 11-1A). Conversely, loss of free water
from the extracellular space ultimately leads to a shift of water from the intracellular to the
extracellular space (Fig. 11-1B). An osmotic gradient of just 1 mOsm generates a pressure gradient of
19.3 mm Hg.
Colloid Oncotic Pressure (Colloid Osmotic Pressure)

Plasma proteins are confined primarily to the intravascular space and contribute to the osmotic pressure
developed between the plasma and the interstitial fluid. Normal plasma protein levels of 7 g/dL
contribute approximately 0.8 mOsm/L.
Figure 11-1. A: The equilibration of water from the extracellular to the intracellular space after the addition of free water to the
339
extracellular fluid compartment. Osmolality transiently decreases in the extracellular compartment, causing water to move across
the cell membranes into the intracellular space. B: Similar shifts after free water loss from the extracellular compartment. Water
moves from the intracellular space to the extracellular space in response to the osmolal gradient that is established.
Osmoregulation
4 Osmolality of body fluids stays fairly constant at approximately 285 to 295 mOsm/L as the result of
tightly regulated water balance. Osmoreceptor cells in the paraventricular and supraoptic nuclei of the
hypothalamus exert central control over the thirst mechanism and antidiuretic hormone (ADH) secretion
from the posterior pituitary.5 In the presence of excess free water, ECF osmolality falls toward 280
mOsm/kg H2O, thirst is inhibited, and ADH levels decline. In the absence of ADH, the permeability of
renal collecting tubules to water is decreased, causing free water reabsorption to decrease and excretion
to increase. Urine osmolality (Uosm) can decline to 50 mOsm/kg H2O (Fig. 11-2). As excess free water is
eliminated, Posm begins to rise. Conversely, free water depletion causes an increase in Posm. As Posm
approaches 295 mOsm/kg H2O, thirst is stimulated as is ADH secretion. As ADH levels rise to
approximately 5 pg/mL, the renal collecting tubules become maximally permeable to water. Water is
reabsorbed from the collecting ducts in response to the concentration gradient developed in the renal
medullary interstitium. Thus, the final concentration of urine depends on both the permeability of the
collecting ducts (controlled by ADH secretion) and the concentration of the medullary interstitium.5
Maximal Uosm may approach 1,200 mOsm/kg H2O. The net effect of these mechanisms is to promptly
return high or low Posm to normal. The high sensitivity of the osmoreceptors and the responsiveness of
the ADH feedback system ensure that even small changes in Posm result in marked alterations in urine
concentration. This relation can be expressed as follows:
Urine osmolality = 95 × Plasma osmolality
Thus, a 1-mOsm change in Posm results in a 95-fold change in Uosm.
Angiotensin II and neural input from medullary baroreceptors can also influence ADH secretion and
thirst, thus tying water balance to hemodynamic alterations. Relatively small changes in pressure have
little effect on ADH secretion, but large decreases in pressure can cause tremendous increases in ADH
release. Therefore, ADH release as a response to changes in serum osmolality is regulated by a very
sensitive system (only small changes in serum osmolality outside its normal range lead to dramatic
changes in ADH release), while the nonosmotic release of ADH occurs in the setting of profound
hypotension for the purposes of preserving volume homeostasis with the subsequent effect of water
retention regardless of serum osmolality (Fig. 11-3).
Tonicity of Body Fluids

Tonicity refers to the effect of the particles on cell volume. (NB: Osmolality defines the concentration of
osmotically active particles in solution.) Permeable solutes can freely cross cell membranes, whereas
impermeable solutes cannot. Although permeable solutes contribute to the osmolality of a solution, they
have no effect on tonicity because they contribute neither to oncotic gradients across cell membranes
nor to alterations in cell volume. Sodium is an example of an impermeable solute that affects both
osmolality and tonicity. Urea and ethanol are permeable solutes that contribute to osmolality but have
little effect on tonicity because they distribute equally across membranes.
340
Figure 11-2. The relation of plasma antidiuretic hormone (arginine vasopressin [AVP]) secretion to plasma (A) and urine (B)
osmolality in healthy adults in varying states of water balance. (Reproduced with permission from Robertson GL, Berl T. Water
metabolism. In: Brenner BM, Rector FC Jr, eds. The Kidney. Philadelphia, PA: WB Saunders; 1986:392.)
Figure 11-3. Effect of acute changes in blood volume or pressure on the osmoregulation of antidiuretic hormone (ADH;
vasopressin). The heavy oblique line in the center represents the relation between plasma ADH and osmolality under
normovolemic, normotensive conditions. The lines to the left and right show the shift in the relation when blood volume or blood
pressure is acutely decreased or increased by the percentage indicated in the circles. (Reproduced with permission from Robertson
GL. Physiology of ADH secretion. Kidney Int 1987;32(Suppl 21):520.)
Both impermeable and permeable solutes can contribute to hyperosmolar and hypoosmolar states.
However, hypoosmolar states are always accompanied by hypotonicity, whereas hyperosmolar states
are not always associated with hypertonicity. There may be marked hyperosmolality without
hypertonicity with elevation of blood urea nitrogen (BUN) levels because urea is a freely permeable
molecule. In contrast, elevated levels of plasma glucose in diabetic patients are associated with
hyperosmolarity and associated hypertonicity. Insulin increases the transport of glucose across cell
membranes, rendering these osmoles ineffective and reducing hypertonicity. Plasma hyperglycemia is
associated with the movement of intracellular water to the extracellular space. This causes expansion of
ECF and plasma volume and a consequent decrease in the concentration of plasma sodium. For every
100 mg/dL elevation in blood glucose, measured serum sodium is calculated to fall 1.5 mEq/L, without
an actual alteration of body sodium content. The osmotic diuresis caused by the elevated glucose level
tends to normalize the serum sodium if adequate hydration is maintained. Some patients with
uncontrolled diabetes also have marked hyperlipidemia. Because of this, the concentration of measured
sodium falls. This condition is termed pseudohyponatremia, an artifactual hyponatremia most commonly
caused by severe hypertriglyceridemia, or by severe hyperproteinemia.
Plasma osmolality (Posm) is an excellent measure of total body osmolality. Osmolality differentials
between fluid compartments are only transient because fluid shifts maintain isosmotic conditions.
Sodium is the predominant extracellular cation; thus, estimates of Posm can be made by simply doubling
the serum sodium concentration (serum [Na+]):
Posm (mOsm/L) = 2 × serum [Na+]
Because glucose and BUN may make significant contributions to Posm in certain disease states, this
formula is modified for glucose and for BUN:
Posm (mOsm/L) = 2 × Serum [Na+] - Glucose/18 − BUN/2.8
Discrepancies of greater than 15 mOsm/L between calculated Posm and Posm measured in the clinical
laboratory may be the result of the presence of other osmotically active particles, such as mannitol,
ethanol, or ethylene glycol, or of a reduced fraction of plasma water secondary to high levels of
myeloma proteins or hypertriglyceridemia.
FLUID BALANCE
Sodium Concentration and Water Balance
Abnormalities in serum sodium are usually indicative of abnormal TBW content. This is due to sodium
being the primary extracellular cation. As potassium is the predominant intracellular cation, the serum
[Na+] approximates the sum of the exchangeable total body sodium (Na+e) and total body
341
exchangeable potassium (K+e) divided by TBW:
Serum [Na+] = (Na+e − K+e)/TBW
Because the sum of total body solute content (Na+e − K+e) remains relatively stable over time, changes
in TBW content is, therefore, inversely proportional to changes in the serum [Na+] (Fig. 11-4).
Volume Control
5 Changes in volume (i.e., hypovolemic/nonosmotic stimuli) are detected by both osmoreceptors and
baroreceptors.3 The osmoreceptors are responsible for the day-to-day fine-tuning of volume by
responding to changes in tonicity, whereas the baroreceptors contribute relatively little to the control of
fluid balance under normal conditions. As mentioned previously, large changes in circulating volume
(10% to 20% blood volume loss) can modify the osmoregulation of ADH secretion. Cardiac atrial
baroreceptors control volume by means of sympathetic and parasympathetic neural mechanisms,
whereas ANP released by atrial myocytes in response to atrial wall distention may influence sodium-
linked volume control by inhibition of renal sodium reabsorption.6–8
Figure 11-4. Relation between serum [Na+] and the ratio of (Na+e + K+e) to total body water (TBW). (Reproduced with
permission from Edelman IS, Liebman J, O’Meara MP, et al. Interrelationships between serum sodium concentration, serum
osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J Clin Invest 1958;37:1236.)
Osmoreceptors
Specialized cells in the hypothalamus that respond to changes in extracellular tonicity are known as
osmoreceptors. It is believed that the activity of ion channels in the cell membrane, aquaporins, and
changes in cell volume contribute to the function of these receptors. As the majority of the ECF tonicity
is contributed by sodium, under normal physiologic conditions, these receptors function as “osmo-
sodium” receptors. Osmoreceptors can respond to changes in tonicity as small as a few percent. In
effect, these receptors monitor water balance by monitoring the tonic effect of changes in water
volume. Therefore, ECF [Na+] is an effective monitor of TBW.
Baroreceptor Modulation of Volume Control

Effective circulating volume describes that portion of the extracellular volume that perfuses the organs of
the body and affects the baroreceptors. The effective circulating volume normally corresponds to the
intravascular volume.
Changes in the effective circulating volume are sensed by volume receptors in the intrathoracic
capacitance vessels and atria, pressure receptors of the aortic arch and carotid arteries, intrarenal
baroreceptors, and hepatic and cerebrospinal volume receptors.8,9 These stretch receptors respond to
changes in pressure and circulating volume and, through a complex system of neural and hormonal
actions, alter sodium and water balance in the kidneys. Hormonal effects are mediated by the renin–
angiotensin system, aldosterone, ANP, dopamine, and renal prostaglandins.
Baroreceptor Function
The low-pressure baroreceptors of the intrathoracic vena cava and atria are located in vessels that are
distensible and not affected by sympathetic stimulation; thus, they are ideally situated to detect changes
in venous volume.8 These receptors send continuous signals through vagal afferent nerves to the
cardiovascular control centers of the medulla and hypothalamus, which, in turn, send signals through
parasympathetic and sympathetic fibers to the heart and kidneys. Changes in stretch of these vessels
342
result in changes in the frequency of signal output from these receptors. Increases in atrial distention
cause decreased nerve signal traffic, which ultimately causes increased sympathetic tone to the heart,
which results in tachycardia and inhibition of sympathetic tone to the kidney. This leads to increased
renal blood flow and decreased tubular sodium reabsorption. Conversely, low volume in the
intrathoracic vessels results in increased sympathetic tone to the kidneys, decreased renal blood flow,
and increased sodium reabsorption.
The effects of sympathetic activity on renal sodium reabsorption are probably mediated both by
direct tubular innervation and by β-adrenergic stimulation of renin production. Whether this effect is
crucial to fine regulation of sodium balance under normal physiologic conditions is unclear. Renal
denervation in conscious, unstressed animals results in minimal alteration of either blood flow or
sodium reabsorption. The effects of renal denervation become much more marked with anesthesia
administration or hypotension, suggesting that sympathetic effects on renal function may be important
during periods of physiologic stress.
Arterial baroreceptors are located in the aortic arch and carotid arteries. They respond to changes in
heart rate, arterial pressure, and the rate of rise in the arterial pressure. Arterial baroreceptors are
important during periods in which there are extremes in the changes in arterial pressure characteristics,
as occur during hemorrhage. They are probably not involved in controlling subtle volume or pressure
changes. In addition to large-vessel baroreceptors, there are arterial baroreceptors in the afferent
arterioles of the kidneys. These baroreceptors modulate renin secretion. Increases in transmural
pressure cause suppression of renin release, and decreases in transmural pressure stimulate renin
release.
Hormonal Mediators of Volume Control

Renin–Angiotensin System. Renin is a proteolytic enzyme that is released from the juxtaglomerular
cells of afferent arterioles in the kidney in response to several stimuli. These include changes in arterial
pressure, changes in sodium chloride delivery to the macula densa of the distal convoluted tubule,
increases in β-adrenergic activity, and increases in cellular cyclic adenosine monophosphate.
Renin cleaves angiotensin I from circulating angiotensinogen, produced by the liver. Angiotensin I is
cleaved to the octapeptide angiotensin II by angiotensin-converting enzyme (ACE), which is produced
by vascular endothelial cells. One pass through the pulmonary microvasculature converts most
angiotensin I to angiotensin II. Angiotensin II acts both locally and systemically to increase vascular
tone. It also stimulates catecholamine release from the adrenal medulla, increases sympathetic tone
through central effects, and stimulates catecholamine release from sympathetic nerve terminals.
Angiotensin II affects sodium reabsorption by decreasing renal blood flow and glomerular filtration.
This results in altered tubuloglomerular feedback, the mechanism by which changes in distal tubular
NaCl delivery alter glomerular blood flow. Finally, angiotensin II increases sodium reabsorption by
direct tubular action as well as by stimulation of aldosterone release from the adrenal cortex. The
multiplicity of actions of angiotensin is depicted in Figure 11-5.
Aldosterone. Aldosterone is a mineralocorticoid produced in the zona glomerulosa of the adrenal cortex.
Aldosterone increases renal tubular reabsorption of sodium. Aldosterone acts directly on the distal
tubule cells by modifying gene expression and stabilizing the epithelial Na+ channel in the open state
and by increasing the number of channels in the apical membrane of these cells.5 By increasing protein
production in these tubular cells, aldosterone induces an influx of sodium, which causes an increase in
cellular Na+-K+-adenosine triphosphatase activity. The net result is increased sodium reabsorption and
the obligate loss of potassium via the renal outer medullary potassium (ROMK) channel. Although the
primary regulator of aldosterone secretion is angiotensin II, aldosterone release is also stimulated by
increased potassium levels, adrenocorticotropic hormone, endothelins, and prostaglandins.10
343
Figure 11-5. Multiple effects of increased angiotensin II release in response to the stimulus of decreased extracellular volume.
Atrial and Renal Natriuretic Peptides. ANP is synthesized and released by atrial myocytes in
response to atrial wall distention. As mentioned previously, small changes in right atrial pressure
produce large increases in plasma levels of ANP.7,8 There is evidence that ANP has a direct inhibitory
effect on renal sodium reabsorption, which is probably maximal at the level of the medullary collecting
tubules. Although pharmacologic doses of ANP can cause changes in both renal blood flow and
glomerular filtration rate (GFR), physiologic levels do not appear to have any major effect on these
parameters. Other active fragments of the ANP prohormone have been found to have natriuretic
activity. The best described is urodilatin, also known as renal natriuretic peptide. Urodilatin is a peptide
with ANP-like activity that was first isolated from human urine. It is synthesized and luminally secreted
by cortical collecting tubule cells. Like ANP, it is released in the kidney tubules in response to atrial
distention and saline loading. It is at least twice as potent as ANP, acting in the distal nephron to cause a
rise in intracellular cyclic guanosine monophosphate, leading to sodium, chloride, and water diuresis.
ANP and other peptides may play an important role in controlling intravascular volume and water and
electrolyte secretion.
Renal Prostaglandins. Renal prostaglandins appear to play a role in volume control, although under
normal physiologic conditions, this role may be minimal. Disease states such as sepsis and jaundice, or
the induction of anesthesia, may make the contribution of the prostaglandins more pronounced.9
Prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) appear to be the predominant prostaglandins
produced in the kidney. PGE2 is produced primarily by the interstitial cells of the renal medulla. The
release of PGE2 has been shown to depend on increases in interstitial pressure, which can be induced by
changes in renal perfusion, ureteral obstruction, or alterations in oncotic pressure. Under these
conditions, PGE2 increases sodium excretion in the absence of changes in GFR. PGE2 antagonizes the
action of vasopressin (ADH) and inhibits ADH-induced sodium reabsorption along the medullary
collecting duct and thick ascending limb. PGI2 is produced by the glomeruli and endothelial cells of the
kidney and is present in the greatest concentrations in the renal cortex. PGI2 is a vasodilator, and its
effects on renal vascular resistance increase both renal blood flow and GFR. PGI2 production is
augmented by increases in angiotensin, catecholamines, and sympathetic tone and may act to
counterbalance their vasoconstricting effects. Although under normal physiologic conditions inhibition
of prostaglandin production has little effect on renal function, administration of nonsteroidal anti-
inflammatory agents, which inhibit cyclooxygenase, to patients with conditions known to cause renal
dysfunction (e.g., cirrhosis) can precipitate renal failure, presumably because of loss of the protective
effects of the renal prostaglandins.
Endothelins. Endothelins are peptide vasoconstrictors that are involved in volume and pressure
regulation.10 Endothelin is produced and released by endothelial and other cells to act on adjacent
smooth muscle cells. In addition to increasing peripheral resistance, endothelin infusion has a direct
inotropic effect on the myocardium. In contrast to its vasoconstrictive effects, endothelin stimulates the
release of other vasoactive mediators, particularly endogenous vasodilators like nitric oxide, which act
to limit its intense vasoconstrictor effect.
Endothelin exerts a complex influence on sodium and water exchange through varied interactions
with many other hormones that govern fluid and electrolyte balance. One net effect of endothelin is a
decrease in the filtered load of sodium in the kidney. This results in inhibition of water reabsorption and
344
decreased sodium excretion. Endothelin increases ANP secretion, activates ACE, and inhibits renin
release by the juxtaglomerular apparatus. At low doses, endothelin-1 produces natriuresis and diuresis.
Endothelin also modulates the biosynthesis of aldosterone, thereby inhibiting water reabsorption
through aldosterone-controlled mechanisms. Vasopressin-mediated water reabsorption is also inhibited.
Endothelin appears to have complex interactions with other regulators of renal perfusion and handling
of water and electrolytes, which has stimulated research to evaluate the contribution of endothelin to
the pathophysiology of various renal diseases.11
Nitric Oxide. Nitric oxide is a short-lived free radical produced from l-arginine by nitric oxide
synthases.11 This substance has numerous biologic functions, including regulation of vascular tone and
tissue blood flow. Nitric oxide is produced in renal smooth muscle cells, mesangial cells, tubules, and
endothelial cells and participates in the regulation of renal hemodynamics and renal handling of water
and electrolytes. Nitric oxide and PGI2 each independently cause renal vasodilation in response to a
variety of stimuli. Nitric oxide contributes to tubuloglomerular feedback, which modulates the delivery
and reabsorption of sodium and chloride in the renal tubules. Nitric oxide also regulates renin release by
the juxtaglomerular apparatus. Nitric oxide produced in the proximal tubule may mediate the effects of
angiotensin on tubular reabsorption.11
Normal Water and Electrolyte Exchange

Surgical patients are prone to fluid and electrolyte abnormalities. It is important to recognize that
disease states, trauma, and stress-related abnormalities – especially those caused by a surgical procedure
– alter many of the body’s fundamental homeostatic mechanisms. It is therefore important to
understand normal fluid and electrolyte balance to avoid additional iatrogenic perturbations of these
mechanisms.
Normal Water Exchange

6 Water losses are both sensible (measurable) and insensible (unmeasurable). Measurable losses include
urinary and intestinal. Table 11-3 summarizes the normal sensible and insensible losses encountered in a
24-hour period. The volumes of these losses may vary considerably especially in disease states. Under
normal conditions, the minimal amount of water needed to excrete normal metabolic waste products is
approximately 300 to 500 mL/day.
The GI tract has a net secretory action down to the level of the jejunum. After that, the resorptive
capacity of the remainder of the small and large bowel acts to keep further water loss to a minimum.
Fecal water loss is usually trivial: ∼150 mL/day. In disease conditions like bowel obstruction, severe
diarrhea, and enterocutaneous fistulas, GI losses of water and electrolytes can be significant causing
secondary pathophysiologic conditions.
Table 11-3 Body Fluid Compartments
Sweating and diaphoresis are active processes involving the secretion of a hypotonic mixture of
electrolytes and water. Sweating functions to allow the convective dissipation of heat. Diaphoresis is a
similar effect, but is a pathophysiologic state stemming from a disease process.
These aforementioned conditions are distinct from the immeasurable, evaporative loss of water from
the skin under normal conditions (Table 11-3). Evaporative skin losses are increased with an increase in
body surface area (especially infants and small children), patient temperature, and the relative humidity
of the environment. Evaporation through the skin functions through convective heat loss and is
proportional to calories expended. Approximately 30 mL of water is lost for every 100 kcal expended.
Respiratory exchange depends on ambient temperature, relative humidity, and on the amount of air
345
flow. Overall, normal insensible water losses average approximately 8 to 12 mL/kg/day. Insensible
water loss increases 10% for each degree of body temperature above 37.2°C (99°F). In addition, patients
who breathe unhumidified air lose additional free water. Conversely, patients who are on respirators or
who breathe air that is 100% humidified have no respiratory losses and may gain free water.
FLUID AND ELECTROLYTE THERAPY

Parenteral Solutions
Crystalloids
7 The most widely used parenteral solutions are composed most commonly of sodium and chloride.
They are collectively referred to as crystalloids (based on the solid, room temperature form of the
primary ingredient sodium chloride). Crystalloids are inexpensive and highly effective for fluid
maintenance and rapid volume replacement. They also have excellent safety profiles. Although
crystalloid-induced hypercoagulability has been reported, its causes are multifactorial and poorly
understood.12–15 Clinically, this does not represent a significant problem.
The most commonly used crystalloid solutions available for parenteral administration are found in
Table 11-4. Selection of the appropriate fluid requires assessment of the patient’s maintenance fluid
needs, existing fluid deficits and anticipated ongoing fluid losses. When a single solution does not
accurately replace the required electrolyte components, bolus administration of specific replacement
solutions is commonly performed. It is commonplace to use more than one type of crystalloid solution.
This is commonly seen with parenteral medication formulations that may have specific carrier-fluid
requirements. Ions such as potassium, magnesium, or calcium may be necessary and can be added to
parenteral solutions to suit the patient’s requirements.
Table 11-4 Electrolyte Content of Commonly Used Intravenous Crystalloid

Solutions
Isotonic saline (0.9% sodium chloride or normal saline) contains 154 mEq of both sodium and chloride.
Although this solution can be useful in patients with hyponatremia or hypochloremia, the excess of both
sodium and chloride can lead to acid–base disturbances. For example, infusion of large volumes of 0.9%
saline can lead to a hyperchloremic metabolic acidosis. In addition, the pH of normal saline and of the
related solutions (0.45%, 0.33%, and 0.2% saline) is 4.0 to 5.0 further decreasing the blood pH.
Lactated Ringer solution is a buffered solution composed of the conjugate-base lactate. It was created
in the 1930s by an American pediatrician, Alexis Hartmann, as a treatment for metabolic acidosis. The
solution has a lower sodium and chloride content (130 mEq/L) and adds a very small amount of
potassium and calcium (4 mEq/L each). It is ideal for the replacement of acute fluid losses where serum
electrolyte concentrations are initially normal. Normal renal function usually ensures that any extra free
water from this solution is excreted. Hyponatremia can occur with extended use of lactated Ringer
solution. Furthermore, the presence of potassium in lactated Ringer solution has been a concern when
used in patients with acute kidney injury, although more recent data has suggested that normal saline
(with no potassium in solution) may actually be more likely to cause hyperkalemia in this population
due to metabolic acidosis-induced cellular shifts of potassium from the cell. Although the lactate anion
in lactated Ringer solution is metabolized to bicarbonate in the liver, this does not appear to contribute
to acidosis in normal hepatic function. Work comparing the D,L-racemic mixture of lactate has implicated
the D-isomer in leukocyte activation.16 There are no compelling data to suggest that resuscitation with
346
this solution increases the inflammatory response. Utilization of only the L-isomer is presumed to
eliminate this concern.16 Ringer solution is not used as a diluent in blood transfusions given the concern
of calcium being chelated by citrate (an anticoagulant in blood products), which may promote clotting
in donor blood.
For maintenance fluid therapy especially prior to an operation with nil per os status or following
correction of any existing deficits, less concentrated saline solutions are more appropriate to replace
ongoing fluid losses (e.g., nasogastric tube losses). The specific crystalloid selected is best determined
by calculated requirements. These fluids are hypoosmotic and hypotonic with respect to plasma. In
theory, rapid infusion of very hypotonic solutions can result in red blood cell lysis. For this reason, 5%
dextrose (50 g of dextrose per liter) has traditionally been added to these solutions to increase tonicity.
The addition of dextrose is beneficial in pediatric patients who are unable to adequately control glucose
homeostasis due to immature livers. A 5% dextrose solution represents 200 kcal per liter of solution.
Hypertonic saline solutions (HTSs) (3% NaCl and 5% NaCl) are generally used to replace sodium
deficits in patients with symptomatic hyponatremia. These and even more concentrated (7.5% and 23%
NaCl) solutions have also been used for resuscitation of hemorrhagic shock, head trauma, and burn
patients.17–19 Hypertonic saline appears to increase intravascular volume in these patients more quickly
than isotonic solutions. It is believed that the osmotic gradient produced redistributes fluids from the
perivascular and intracellular spaces to the intravascular space with consequent plasma volume
expansion (up to fourfold). This, in turn, may decrease the total resuscitation volume requirement.
When HTS is used for resuscitation of patients with severe sepsis, it has been shown to result in
improvements in oxygen transport, cardiac output, and pulmonary capillary wedge pressure.17 The
systemic and mesenteric oxygen extraction coefficient improves without worsening of other markers of
perfusion. This is achieved by rapid mobilization of fluids from the intracellular compartment to the
extracellular compartment. These cardiovascular and hemodynamic effects are short-lived, in general
lasting from 60 to 120 minutes.
The osmotic effect of hypertonic saline may benefit patients with acute severe brain injury.19 By
reducing the water content of the brain, HTS can help to control intracerebral pressure after injury. In
addition, HTS has immunomodulatory effects, which are well documented.20 HTS reduces the systemic
inflammatory response syndrome and may attenuate multiple organ dysfunction syndrome. HTSs are
not without adverse effects, however. Patients are at risk for electrolyte abnormalities such as
hypernatremia, hyperchloremia, and consequent metabolic acidosis. Extravasation into the soft tissues
can produce significant soft tissue edema and even necrosis.
Colloids
Colloids are composed of large molecules (e.g., albumin) that have a greater tendency to stay in the
intravascular space. They appear to be more effective at enhancing the plasma volume than do
crystalloid fluids. Colloid solutions offer the potential benefits of promoting fluid retention in the
intravascular space and reducing excess interstitial fluid (edema). Worldwide, albumin and artificial
colloids are relied on to a varying degree in fluid management of the surgical patient. In the United
States, concerns regarding the effectiveness, cost, and potential complications of colloid administration
have limited their use to specific clinical situations.
Albumin
Albumin (69 kD) is the primary protein in plasma responsible for oncotic pressure. Exogenous human
albumin is derived from human plasma and heat-treated to reduce the risk of infection. It is available in
a 5% (50 g/L) and a 25% solution (250 g/L) in isotonic saline. These act by increasing plasma oncotic
pressures and theoretically slowing or even reversing movement of water into the interstitial space.
Albumin has an approximate intravascular half-life of 4 hours in conditions of normal physiological
capillary permeability. However, many of the conditions associated with edema are also associated with
abnormalities in microvascular permeability (e.g., systemic inflammatory disease). For example, the
pulmonary circulation in the adult respiratory distress syndrome, regional circulatory beds in
postoperative patients, burns or infections, and the systemic circulation in sepsis all lead to conditions
resulting in increased microvascular permeability. It is, therefore, believed that exogenously
administered protein in colloid solutions quickly extravasate into the interstitial space and paradoxically
intensify – rather than decrease – interstitial edema. The SAFE trial (Saline vs. Albumin Fluid
Evaluation) found no overall difference in organ dysfunction or survival when comparing saline
administration to albumin infusion.21 However, the SOAP trial (Sepsis Occurrence in Acutely Ill
347
Patients) demonstrated increased mortality in intensive care unit patients treated with colloids.22,23 As
mentioned above, albumin solutions are heat-treated to negate viral and bacterial contamination.
Allergic reactions are rare. The primary concern with albumin administration is cost; the infection risk is
negligible.
Hetastarch
Hydroxyethyl starches (HES) are synthetic colloids derived from hydrolyzed amylopectin. In the United
States, it is available as a 6% solution of high–molecular-weight (150 to 450 kD), highly hydroxyethyl
substituted HES in normal, isotonic saline. The average molecular weight of the starch molecules is
equivalent to that of albumin. However, HES is slightly more effective than 5% albumin as a colloid – it
has a higher colloid oncotic pressure than 5% albumin. The main advantage of hetastarch is its lower
cost compared to albumin.
Hetastarch has been used as a resuscitative solution in a variety of clinical settings with variable
results. Coagulopathy and bleeding complications have been widely reported after administration of
highly substituted, high–molecular-weight HES.24,25 This appears to be associated with reduced factor
VIII and von Willebrand factor levels, a prolonged partial thromboplastin time, and impaired platelet
function.26 It also has a long elimination half-life (17 days). Because of its long half-life, the
coagulopathy does not rapidly reverse after cessation of HES administration. Also, serum amylase
enzymes continually degrade HES molecules before renal clearance. It is common for serum amylase
levels to be elevated for the first few days after HES infusion. In order to differentiate this from
pancreatitis, serum lipase levels should be checked and are usually normal.
The above observations and reports of renal insufficiency after HES administration prompted a
prospective study, with results published in 2012.27,28 The results of these trials were so significant that
the FDA and the Pharmacovigilance Risk Assessment Committee, the European equivalent of the FDA,
recommended suspending marketing authorization of all HES products and issued warnings to its
use.29,30 The Surviving Sepsis Campaign recommends against HES administration in septic patients.31
Dextrans
First introduced in the 1940s, dextrans are glucose polymers synthesized by Leuconostoc mesenteroides
bacteria. These are available as synthetic plasma expanders in both 40 kD (dextran 40) and 70 kD
(dextran 70) solutions. Although neither is used frequently for volume expansion, dextran 70 has been
preferred because of its significantly longer half-life and better retention in plasma. It is degraded to
glucose and water by cells. The use of dextrans involves risks of anaphylaxis, hyperglycemia, renal
dysfunction and failure, coagulopathy (e.g., erythrocyte and platelet dysfunction), and increased
thrombosis rates. The use of dextran solutions is no longer favored given a higher relative risk of
mortality compared to HESs.32
Gelatins
Gelatin solutions produced from bovine collagen are effective as plasma volume expanders. These are
currently only available outside the United States in urea-linked (Gelofusin) and succinate-linked
(Haemaccel) formulations. Gelofusin has been used in similar clinical settings to HES, with similar
clinical results.33 Uniquely, coagulopathy does not appear to be an issue with gelatins. Renal
impairment has been reported with these colloids as having allergic reactions ranging in severity from
pruritus to anaphylaxis with both gelatin formulations.34
Artificial Oxygen Carriers

Recent clinical trials and subgroup analyses using temporary hemoglobin-based oxygen-carrying
solutions (e.g., PolyHeme, Northfield Laboratories, Inc.) have been encouraging albeit with some
controversy.35 PolyHeme is made from polymerized human hemoglobin. It originally began as a
military project following the Vietnam war. PolyHeme’s primary use is in trauma situations with
massive blood loss when fresh, whole blood is not readily available for transfusion. On May 9, 2009,
Northfield Laboratories, Inc. shut down operations after it failed to secure a biologic license application
for PolyHeme from the FDA. However, with further studies, solutions like PolyHeme may prove
beneficial in the future when volume expansion in conjunction with increased oxygen-carrying capacity
is required.
348
GOALS OF FLUID AND ELECTROLYTE THERAPY
Maintaining homeostasis – body fluid and electrolyte concentrations – and normal hemodynamic
parameters are the goals of fluid and electrolyte therapy. This is accomplished by first understanding
the general maintenance fluid required by an idealized 70-kg male patient to account for normal daily
losses. Thereafter, it is imperative to correct existing volume and electrolyte abnormalities and any
ongoing losses associated with disease states and surgical treatments.
Table 11-5 Calculation of Maintenance Fluid Requirements
Maintenance Fluid Therapy

Maintenance fluid volume requirements can be calculated based on body weight taking into account a
larger per kilogram volume requirement of smaller body weight individuals (Table 11-5). A 10-kg child
requires 100 mL/kg/day or 1,000 mL/day. A 70-kg man requires 1,000 mL/day for the first 10 kg (100
mL/kg × 10 kg), plus 500 mL/day for the second 10 kg (50 mL/kg × 10 kg), plus 1,000 mL/day for
the last 50 kg (20 mL/kg × 50 kg), for a total daily water requirement of 2,500 mL/day. In patients
who may be intolerant of hypervolemia (i.e., cardiac disease, elderly patients), the requirement per
kilogram over 20 kg is decreased to 15 mL/kg/day.
Maintenance Electrolyte Therapy

One to 2 mEq/kg/day of sodium is required, with any administered excess managed by urinary sodium
excretion. Potassium requirements are approximately 0.5 to 1 mEq/kg/day. If sodium is replaced at 2
mEq/kg/day and potassium is replaced at 1 mEq/kg/day, a 70-kg patient requires 2,500 mL of water
containing 140 mEq of sodium and 70 mEq of potassium. Each liter of parenteral solution would contain
56 mEq of sodium and 28 mEq of potassium. The solution that best fits this patient’s daily maintenance
requirements is 0.33% saline solution (56 mEq/L Na+). Potassium chloride can be added to each liter of
solution (20 to 30 mEq/L), with appropriate adjustments for the patient’s electrolyte and renal
functional status.
Additional Electrolyte Therapy

Short-term maintenance therapy generally does not require addition of calcium, phosphate, or
magnesium. In patients with acute and/or chronic disorders, patients who experience significant volume
shifts, or patients who require long-term parenteral fluid therapy, these electrolytes should be measured
and corrected by the most practical, physiologically natural route. In general, the enteral route is
preferred given normal physiology. If the enteral route is unavailable, these additional electrolytes are
administered in parenteral nutrition solutions along with trace elements, vitamins, and appropriate
caloric sources. Corrections and allotment must be made for disease states that may alter the need or
absence of electrolytes (e.g., potassium in renal failure patients) in replacement solutions.
CORRECTION OF VOLUME ABNORMALITIES

Volume Deficits
States of subphysiologic volume (i.e., hypovolemia) are common among surgical and trauma patients.
This may be related to direct blood loss or other fluids. Large volumes of fluid can be sequestered in
extravascular spaces (third-space losses) as a consequence of inflammation, sepsis, or shock-related
endothelial injury and increased endothelial permeability.36 This situation is characterized by a
movement of proteins and fluid from the intravascular to the interstitial compartment. Examples of
disorders that cause third-space losses include bowel obstruction with edema of the bowel wall and
349
transudation of fluid into the bowel lumen, pancreatitis (especially with retroperitoneal fluid
extravasation) and extensive tissue destruction in trauma. While the disease state exists, normal
homeostasis is altered and cannot be maintained. With the resolution of the pathologic condition and
normalization of microvascular permeability, these fluid losses abate. Sequestered extravascular fluid
returns – albeit at variable rates – to the intravascular space.
Volume deficits can manifest either acutely or over time. Chronic volume deficits may manifest with
decreased skin turgor, sunken eyes, oliguria, weight loss, hypothermia, tachycardia, and orthostatic
hypotension. In addition, serum BUN and creatinine values may be elevated, with a high
BUN/creatinine ratio (above 15:1). The absolute hematocrit level has been shown to be a poor predictor
of intravascular volume status. The hematocrit may be measured during dialysis as a way to indirectly
measure volume status.37 Optical measurements of absolute red cell mass and oxygen saturation are
measured as blood passes through the dialysis tubing while a patient is undergoing dialysis treatment.
The hematocrit is then determined by both the absorption properties of hemoglobin and the scattering
properties of red blood cells passing through the blood chamber.37
Acute volume losses usually manifest by changes in vital signs. In an attempt to provide sufficient
cardiac output for end-organ perfusion, the heart rate may increase. At the extreme, blood pressure will
drop resulting in hypotension. Urine output is usually low by this point.
Fluid resuscitation for hypovolemia is initiated with an isotonic solution such as normal saline or
lactated Ringer solution. Once routine laboratory values (e.g., chemistries) are measured, tailoring the
type of solution can be done. Urine flow in critically ill patients is monitored with an indwelling Foley
catheter with a goal of at least 0.5 mL/kg/hr output. In addition, a thorough history and physical
examination will help determine the origins of the volume deficits, specifically addressing underlying
causes and resultant losses.
Volume Excess
Volume excess may occur with significant resuscitative fluid, blood product administration, or excessive
parenteral volume administration. Volume overload will occur if adjustments to fluid therapy are not
made as the clinical status of the patient changes. Possible manifestations of volume overload are
weight gain, truncal and peripheral edema and pulmonary congestion (identified by rales on pulmonary
auscultation and/or radiographic chest imaging). Intravascular volume excess is treated by a
combination of volume restriction and diuresis. At the extreme, volume overload may be treated by
ultrafiltration of the blood (often done concurrently during hemodialysis).
REPLACEMENT OF ONGOING FLUID LOSSES

Ongoing losses from stomas, fistulae, open body compartments (e.g., abdomen, chest) and all tubes
(e.g., nasogastric) and drains – are recorded during the course of care. Once the net “ins and outs” have
been calculated, any existing volume deficits should be replaced with fluid replacement. The electrolyte
content of these fluids can be estimated or measured and used to guide the choice of replacement fluid
type (Table 11-6). As the disease state changes, the overall fluid balance of the patient can be estimated
and replaced beyond what is considered to be maintenance.
Table 11-6 Electrolyte Concentrations in Gastrointestinal Secretions
Intraoperative Fluid Therapy
350
Fluid losses during operative procedures result from evaporative losses in open wounds, blood loss, and
extravascular, third-space sequestration. Relative operative blood loss can frequently be measured.
Evaporative losses as well as shifts of intravascular fluid to the extravascular space are difficult to
measure, but should be anticipated. Intraoperative replacement with crystalloid solutions is usually
accomplished at rates of 500 to 1,000 mL/hr as this is roughly equivalent to the hourly insensible loss
rate during open celiotomy cases. The choice of intraoperative fluid is dependent on many factors.
Administration of buffered solutions (e.g., Ringer lactate solution) is as efficacious and safe as
nonbuffered, saline-based fluids and may prevent postoperative hyperchloremia and metabolic acidosis.
Close monitoring of blood pressure, blood loss, urine output, and invasive monitoring techniques aids
the surgeon and anesthesiologist in gauging fluid shifts and potential problems associated with
intraoperative volume depletion.
Postoperative Fluid Therapy and Monitoring

Routine monitoring of intraoperative and postoperative fluid status consists of serial vital signs (e.g.,
blood pressure and heart rate), measurements of all tubes, lines, and drains (e.g., urine output) and
inclusive of all intravenous and enteral drips. These are recorded in the patient’s medical record and
used to plan ongoing fluid management. The net gains (all inputs) minus the losses allow daily and
length-of-stay volume assessments to be made. Daily weight should also be recorded and compared to
the patient’s starting or “dry” weight prior to their surgery, if possible. In the postsurgical patient, rapid
fluctuations in weight are generally related to changes in TBW. In the absence of any extenuating
circumstances (e.g., renal dialysis, kidney transplantation), adequate fluid is usually given to maintain a
urine output of greater than 0.5 mL/kg/hr in adult patients.
Urine specific gravity can also be measured and serves as an indicator of both volume status and renal
ability to concentrate and dilute the urine. A urine specific gravity of greater than 1.010 to 1.012
indicates that the urine is being concentrated (relative to plasma), and a urine specific gravity of less
than 1.010 indicates that dilute urine is being produced.
Renal failure in the postoperative period may be accompanied by low urine volume (oliguric renal
failure, <0.5 mL/kg/hr, or <500 mL/day). Additionally, normal or high urine volumes (nonoliguric or
high-output renal failure) may also indicate renal dysfunction. Measuring the fractional excretion of
sodium compared to creatinine (i.e., FeNa) can help delineate the potential etiology of renal dysfunction
by discerning prerenal states (FeNa usually <1%) from acute tubular necrosis (FeNa usually >2%).
FeNa = (UrineNa)(SerumCreat)/(UrineCreat)(SerumNa)
Central venous pressures (CVPs) have also been extensively used to gauge fluid status and
responsiveness. Normal CVP may range from 5 to 12 mm Hg. Higher pressures usually indicate volume
overload or cardiac failure, whereas pressures below this range indicate intravascular volume depletion.
However, the use of CVP measurements alone has been shown to be highly variable and inaccurate in
assessing intravascular volume and venous return. This is especially true in critically ill patients where
abnormalities of cardiac performance and vascular tone may confound interpretation of CVP
measurements.
More recently, assessments of fluid status, responsiveness, and overall tissue perfusion are being
accomplished by the use of (1) bedside echocardiography (e.g., transthoracic) to measure function
through ventricular filling and ejection, (2) ultrasound of the vena caval diameter, and (3) peripheral
arterial pulse-volume variability calculations. The latter measures the stroke volume variability (SVV)
during the ventilatory cycle via a peripherally placed arterial line. SVV is the calculated percentage of
the difference between the maximal and minimal stroke volumes (SVs) divided by the mean SV. This is
usually calculated over a time period between 20 to 30 seconds.38 Use of the SVV has been shown to be
a reliable indicator of fluid responsiveness.
It is important to note that the efficacy of these techniques may be altered in abnormal right and/or
left ventricular compliance, increased intrathoracic pressure (via elevated levels of positive end
expiratory pressure and intra-abdominal pressure), valvular heart disease (e.g., mitral stenosis) and
cardiac dysrhythmias (e.g., atrial fibrillation). In order to solve any serious questions of volume status,
the gold standard technique remains pulmonary artery catheterization in the critically ill patient.
ELECTROLYTES
8 An electrolyte is defined as a substance that ionizes when dissolved in an appropriate solvent, the
351
most common example being water. Some of the most common physiologic electrolytes include: sodium
(Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), chloride (Cl-), and hydrogen phosphate
(HPO42-). The + or – designates the charge of the ion.
In order to maintain homeostasis, the human body has a complex yet stable arrangement of
electrolytes in different concentrations in the intracellular and extracellular environments (Table 11-7).
In clinical practice, only measurements of serum values (extracellular space excluding the interstitial
space) are performed and used to infer disruptions of homeostasis, which cause organ damage. For
instance, with hyperkalemia, the serum concentration itself does not directly cause injury. It initiates
depolarization leading to impairment of cardiac conduction resulting in an end pathway of ventricular
fibrillation or asystole.
Given that serum derangements can only be discovered if lab evaluation or symptoms are present, it
is important to try to anticipate potentially life-threatening electrolyte abnormalities. This is especially
important in surgical patients in whom the loss of electrolyte-rich GI fluids occurs and can cause
predictable serum derangements (Table 11-8). For example, an infant with hypertrophic pyloric stenosis
who vomits nonbilious gastric secretions will develop a predictable hypochloremic metabolic alkalosis
due to the loss of hydrochloric acid. It is therefore of the utmost importance to recognize circumstances
that cause predictable electrolyte derangements in order to decrease the risk of morbidity and
mortality.
Table 11-7 Electrolyte Concentrations in Plasma and Intracellular Compartments
Where Sodium Goes, Water Follows

Although the relationship between sodium and water is far more complex than the above adage, there is
a distinct correlation between sodium and fluid status. This relationship can help establish both the
etiology and treatment of various derangements. For example, when thinking about hyponatremia, it is
clinically important to assess the patient’s volume status as well as check laboratory studies. These
include serum sodium, serum osmolality, and urine electrolytes. Other values such as serum glucose,
serum protein, and serum lipids may also help to differentiate hyponatremia from
pseudohyponatremia.40
Pseudohyponatremia
Marked elevations in serum lipid or protein result in a reduction in the fraction of serum that is
water/sodium and thus causes a “dilutional” hyponatremia. Examples include hyperlipidemia,
hyperproteinemia (e.g., multiple myeloma), hyperglycemia, and mannitol administration. In the case of
hyperglycemia, the serum sodium concentration should fall 1.6 mEq/L for every 100 mg/dL rise in
serum glucose concentration.
Hyponatremia
The most common pathophysiology is retention of water, which most commonly stems from oral intake
or iatrogenic use of intravenous hypotonic fluid. The body has an innate ability to produce up to 10
L/day of urine, providing an enormous range of protection against the development of hyponatremia.
However, in most surgical/trauma patients who experience hyponatremia, there is an inability to
suppress ADH, as it is normally elevated during a stress response. In this case the sodium rarely falls
below 130 mEq/L because the hyponatremia itself, as well as volume expansion, decreases the effects of
ADH on the renal collecting tubules.
Table 11-8 Electrolyte Concentrations in Gastrointestinal Secretions

352
In significant cases (i.e., serum sodium <130 mEq/L) it is helpful to take a more systematic
approach. This entails assessing serum and urine osmolality as well as urine sodium (Algorithm 11-1).
Symptoms of hyponatremia occur in multiple organ systems including the CNS, GI, and
musculoskeletal (Table 11-9). In acute hyponatremia, symptoms often start when serum sodium is less
than 130 mEq/L; whereas in chronic hyponatremia symptoms typically do not occur until serum sodium
is less than 120 mEq/L.
Treatment. Treatment depends on the patient’s volume status. Hypovolemic patients are treated by
rehydration with isotonic saline, with caution not to correct serum sodium faster than 0.5 mEq/L/hr and
less than 10 mEq/L over 24 hours. If correction is faster than this rate the patient may develop central
pontine myelinolysis. This can lead to “locked in” syndrome, which consists of quadriplegia, dysarthria,
and dysphagia. In order to best prevent this rare, yet highly morbid complication, use of the following
calculation is recommended:
Na+ required (in mEq) = (Desired Na+ - Actual Na+) × TBW
TBW = 0.6 × Weight (kg)
Rapid correction with 3% or higher-concentration solutions should be avoided unless significant CNS
symptoms such as coma or seizures are present and should be done using the calculation above to
prevent overcorrection. A reasonable initial dose in an emergent situation would be 100 mL of 3%
saline given as a bolus; this can be repeated in 10 minute intervals with definite need for follow-up
laboratory evaluation to prevent overly rapid correction.
Cerebral Salt Wasting and Syndrome of Inappropriate Antidiuretic Hormone

Cerebral salt wasting (CSW) and syndrome of inappropriate antidiuretic hormone (SiADH) are both seen
in the setting of CNS disease, which is especially pertinent to trauma patients. CSW is much rarer and
typically occurs within the first 10 days of CNS insult/injury. The pathophysiology is likely related to
impaired sodium reabsorption leading to volume depletion, followed by increased ADH release causing
hyponatremia from water retention. Laboratory findings are nearly identical amongst CSW and SiADH.
Both have elevated urine osmolality compared to serum. However, CSW is associated with ECF
depletion and thus hypotension and/or elevated hematocrit, whereas SiADH patients are often net
positive in fluid balance. Given the volume status associated with CSW the treatment is usually isotonic
fluids which will suppress the release of ADH. On the contrary if isotonic fluid is given for SiADH it can
actually worsen the hyponatremia. Other options to treat CSW include salt tablets and if needed
fludrocortisone.
The initial treatment for SiADH is often fluid restriction of <800 mL/day. For more significant cases
the use of oral salt tablets or 3% hypertonic saline is recommended. Finally, vasopressin receptor
antagonists such as Conivaptan (IV) and Tolvaptan (PO) can be used; however these do carry risks such
as hepatotoxicity and can rapidly overcorrect serum sodium levels. Furthermore, they are fairly
expensive in the United States and hence should only be used in select cases.39–41
353
Algorithm 11-1. Hyponatremia.
Hypernatremia
Although a less common problem in surgical patients, hypernatremia has a variety of etiologies which,
like hyponatremia can be categorized based on the patient’s volume status (Table 11-10). The most
common scenario is excessive free water loss associated with hypovolemia.
Symptoms of hypernatremia typically do not develop until serum sodium exceeds 160 mEq/L or
serum osmolality is higher than 320 to 330 mOsm/kg. Also, akin to hyponatremia the degree of acuity
is a factor. Acute hypernatremia can cause symptoms at lower levels than chronic hypernatremia. The
majority of symptoms experienced are CNS related with early signs being irritability, restlessness, and
spasms. Later symptoms include ataxia and seizures.
The treatment of hypernatremia, like hyponatremia should not occur too rapidly, otherwise
complications can ensue. A rate >0.7 mEq/L is considered dangerous as it can lead to cerebral edema
and brainstem herniation. The most judicious way to correct hypernatremia involves calculating the free
water deficit to obtain a desired sodium level.
Table 11-9 Symptoms of Hyponatremia
Water requirement = (Desired change in Na+ × TBW)/Desired Na+

TBW = 0.6 × Weight (kg)
A caveat to this equation is that it does not take into account ongoing free water losses such as urinary
or GI loss. Further calculations can be done to quantify urine losses if this is a major concern.
Table 11-10 Causes of Hypernatremia
354
Algorithm 11-2. Acute hyperkalemia.
Potassium
Potassium is the most abundant intracellular cation with a normal intracellular concentration of 150
mEq/L as opposed to an extracellular level ranging from 3.5 to 5 mEq/L. This large gradient produces a
strong membrane potential especially in cardiac, skeletal, and smooth muscles. The overall potassium
balance is determined by potassium intake and renal/extrarenal excretion. Renal excretion accounts for
90% of excreted potassium. Thus, renal failure leads to hyperkalemia. Humoral factors such as
aldosterone, vasopressin, and β-agonists stimulate renal excretion of potassium. Intracellular shifting is
another strong causative agent for extracellular potassium change. For instance, insulin and alkalosis
both cause K+ to shift intracellular, one for glycolysis, the other in exchange for H+ as a buffer.
Conversely, acidosis causes K+ to shift extracellular in exchange for H+, again to buffer serum pH.
Hyperkalemia
Renal insufficiency is the leading cause of hyperkalemia in surgical patients. Hyperkalemia can occur
even in the setting of nonoliguric renal failure. Potassium-rich intravenous fluids, especially blood
transfusions can also lead to hyperkalemia. Disease processes associated with cellular injury such as
crush injuries, reperfusion syndrome, tumor lysis syndrome, and burns are all potential causes of
hyperkalemia. Additionally, medications such as succinylcholine and ACE inhibitors can worsen existing
hyperkalemia.
Regardless of the etiology, the common pathway for clinical manifestations is dysfunctional
membrane depolarization, the most lethal scenario effecting cardiac membrane depolarization. On an
electrocardiogram (EKG) this can be seen in the mildest form with peaked T waves, in a more severe
state with flattened P waves, prolongation of the QRS, or deep S waves. The final pathway can yield
ventricular fibrillation with or without cardiac arrest.
The initial medication of choice for hyperkalemia is intravenous calcium for membrane stabilization,
which lasts approximately 30 to 60 minutes. Subsequent therapy can include insulin coadministered
with dextrose, β2 agonist, and sodium bicarbonate, which are designed to shift extracellular potassium
355
into the intracellular space. Resin-binding agents such as Kayexalate act to decrease potassium
absorption and thus are more important in the management of chronic hyperkalemia.42,43 Loop diuretics
can assist by promoting renal potassium excretion, but should only be used if the patient is not
hypovolemic. A last resort in situations of complete renal failure or critical levels of potassium is
hemodialysis. The treatment utilized depends upon the laboratory value, but more importantly the
clinical scenario and EKG findings (Algorithm 11-2).
Hypokalemia
Similar to hyperkalemia, manifestations of hypokalemia result from the disturbance in the gradient
between intracellular and extracellular potassium. The reference level of 3.5 mEq/L is often cited as the
lowermost level of normal serum potassium. Below this level minor disturbances including intestinal
ileus, premature ventricular complexes, and nonfatal arrhythmias can occur. Severe cardiac and muscle
manifestations often do not occur until levels fall below 2.5 mEq/L. Findings at this dangerous level
include significant muscle weakness and major EKG changes. Possible changes include prolonged QT,
flattened T waves, ST depression, prominent U waves, and most dangerously ventricular arrhythmias.
Initial treatment consideration must include elucidation of possible etiologies (Table 11-11); certain
etiologies are especially important, as without correction of the underlying cause, the hypokalemia
itself may not be correctable. Examples of this include hypomagnesemia, acute alkalosis,
hyperaldosteronism, and mucus secreting villous adenoma. The mainstay of initial treatment for
hypokalemia is enteral or intravenous potassium replacement. If the patient is symptomatic, then the
replacement or at least a portion of it should be given intravenously to achieve a more rapid effect.
Limiting the rate of intravenous potassium infusion is necessary to prevent caustic injury to veins.
Maximal recommended rates include 10 to 20 mEq/hr via a peripheral IV or up to 40 mEq/hr via
central access.
Table 11-11 Causes of Hypokalemia
Figure 11-6. Effects of hypocalcemia (A) and hypercalcemia (B) on the mediators of calcium homeostasis. PTH, parathyroid
356
hormone.
Calcium
Calcium (Ca2+) is essential for human life. Calcium participates in numerous processes including cardiac
membrane depolarization, muscle contraction, enzymatic reactions, coagulation, and formation of
bone/teeth. Approximately 99% of total body calcium is located in bone. Ionized calcium, which makes
up approximately 45% of total calcium, is responsible for most of the physiologic actions of calcium in
the body. Normal serum concentration of ionized calcium is approximately 4.5 mg/dL and this level is
tightly regulated. Both pH and plasma protein level can affect the proportion of calcium in the ionized
state. A change in albumin concentration of 1 g/dL changes protein-bound calcium by 0.8 mg/dL in the
same direction. The fundamentals of the regulation of calcium homeostasis are depicted in Figures 11-6
and 11-7. The effect of pH on calcium will be discussed later in this chapter.
Hypercalcemia
The most common causes of hypercalcemia are hyperparathyroidism and malignancy (Table 11-12).44,45
Primary hyperparathyroidism occurs when one or more parathyroid glands inappropriately produce
increased amounts of PTH. Parathyroid adenomas are responsible for ∼85% of cases. Chief cell
hyperplasia accounts for an additional 15% of cases, while parathyroid cancer is the cause in less than
1% of cases of primary hyperparathyroidism.
Secondary hyperparathyroidism occurs when there is elevated PTH due to another organ system,
namely renal failure. This occurs because of poor renal excretion of phosphate and decreased intestinal
absorption of calcium secondary to impaired renal hydroxylation of vitamin D.
Tertiary hyperparathyroidism is parathyroid hyperplasia with autonomous PTH production. Most
commonly, patients who had renal failure with secondary hyperplasia then undergo renal transplant and
still have hypercalcemia. This occurs in up to 30% of patients with prerenal transplantation
hyperparathyroidism (Table 11-13).
Figure 11-7. Vitamin D synthesis.
Table 11-12 Other causes of Hypercalcemia
Regardless of cause, hypercalcemia has characteristic clinical manifestations that affect various organ
systems. Classically taught as “stones, moans, and psychiatric undertones,” meaning renal,
abdominal/GI, and neuropsychiatric manifestations (Table 11-14). The earliest symptoms are usually
357
neuromuscular and mild GI symptoms. Cardiac and renal complications typically occur later in disease
progression.
Treatment. Serum calcium concentration >14 mg/dL requires prompt treatment. If combined with
hyperphosphatemia, this situation is even more concerning due to the potential for metastatic
calcification. Initial treatment should include aggressive hydration with 0.9% normal saline with 20
mEq/L potassium with a goal of hydration to promote a urine output greater than 200 mL/hr. Once the
patient is adequately hydrated a trial of furosemide can be performed as long as a positive fluid balance
is maintained and potassium and magnesium are adequately replaced. Other adjuncts include calcitonin
(especially for inhibition of bone resorption), bisphosphonates (especially to treat malignancy), and in
patients with renal failure the use of low-calcium dialysate. Patients with hematologic malignancies and
granulomatous disease can be considered for treatment with steroids. Lastly, for those with
hyperparathyroidism, parathyroidectomy of some form is clearly indicated, with operation type
dependent upon whether the etiology is adenoma or hyperplasia. In medically refractory secondary or
tertiary hyperparathyroidism, total parathyroidectomy with parathyroid autotransplantation or sub-total
parathyroidectomy should be considered.46
Hypocalcemia
There are many causes of hypocalcemia (Table 11-15). Other factors can affect the serum calcium level
as mentioned previously, namely pH and albumin. In critically ill patients the incidence of hypocalcemia
can be up to 85%. From a surgical perspective the most common causes are postsurgical, including
hungry bone syndrome and loss of calcium from circulation.
Table 11-14 Signs and Symptoms of Hypercalcemia
Postsurgical hypocalcemia can occur in any neck surgery, although the incidence is higher with
parathyroidectomy. In non-neck surgery hypocalcemia can occur because of hypoalbuminemia; this does
not affect ionized calcium levels. Other postsurgical causes of hypocalcemia include atrophy of the
remaining parathyroid glands (i.e., after removal of a large parathyroid adenoma), venous congestion,
devascularization or hungry bone syndrome. Transient hypoparathyroidism is seen in up to 20% of
thyroid cancer surgery; this is permanent in 1% or less of cases.
Other surgery-related etiologies include pancreatitis, small bowel fistula, renal failure, massive
transfusion of blood, and severe hypomagnesemia. Pancreatitis-induced hypocalcemia occurs due to
calcium precipitation in peripancreatic tissue. Small bowel fistula can lead to hypocalcemia by loss of
calcium-rich effluent and vitamin D deficiency from malnutrition. Renal failure hypocalcemia is due to
deficiency in 1,25-dihydroxyvitamin D and hyperphosphatemia. Massive transfusion hypocalcemia does
not affect total calcium but decreases ionized calcium as a result of citrate binding to ionized calcium.
Symptoms typically do not occur until calcium levels are below 8 mg/dL. Chronic symptoms include
cataracts, dental changes, and extrapyramidal disorders. Symptoms of acute hypocalcemia are tetany,
papilledema, and seizures. Tetany is defined as repetitive discharges after a single stimulus. Tetany
usually does not occur until ionized calcium is less than 4.3 mg/dL or serum total calcium is less than
7.0 mg/dL. Alkalosis also plays a strong role in the development of tetany, even beyond its association
with hypocalcemia, as tetany is rarely seen in renal failure patients despite low calcium levels. This is
likely due to the protective effect of concurrent metabolic acidosis. The earliest symptoms of
hypocalcemia are perioral and acral paresthesias. Motor symptoms such as Trousseau sign (induction of
carpopedal spasm by inflation of sphygmomanometer above systolic pressure for 3 minutes) and
Chvostek sign (tap facial nerve and ipsilateral facial muscles twitch) occur later. Of note, Chvostek sign is
seen in up to 10% of normal patients. The last findings to occur are cardiac, in the form of ST segment
358
prolongation (Table 11-16).44
Table 11-13 Differential Diagnosis of Hypercalcemia
Table 11-15 Causes of Hypocalcemia
Asymptomatic hypocalcemia needs no treatment as it is most commonly attributed to

hypoalbuminemia with normal ionized calcium. Symptomatic hypocalcemia is best treated with
intravenous infusion of calcium gluconate or calcium chloride. Calcium chloride is faster acting as it
does not require hepatic metabolism to dissociate into an active form, hence is usually the drug of
choice if severely symptomatic. A study during the anhepatic stage of liver transplantation found
equally rapid increase in calcium after administration of calcium chloride and gluconate.47 Calcium
chloride carries a higher risk of irritation of veins and tissue damage should extravasation occur; hence
calcium gluconate should be the drug of choice except in emergent situations. In order to minimize
caustic damage to veins, any form of calcium should be administered at a rate not to exceed 1.5
mEq/min. If prolonged calcium replacement is needed it is recommended to check vitamin D levels and
replace any deficiency with calcitriol, in addition to giving an oral form of calcium such as calcium
carbonate, calcium citrate, or calcium lactate.
Table 11-16 Clinical Manifestations of Hypocalcemia
Magnesium
359
Half of the total body magnesium is confined to bone. Most of the remaining magnesium is
intracellular, with less than 1% of total body magnesium found extracellular. Magnesium is primarily
absorbed in the small intestine and is influenced by 1,25-dihydroxyvitamin D3. The other source of
magnesium is bone.
Hypermagnesemia
Outside of renal failure, hypermagnesemia is rare, as the kidneys have a strong ability to excrete large
amounts of magnesium. Instances do occur with severe burns, crush injuries, or other causes of
rhabdomyolysis but usually in the setting of renal insufficiency. Symptoms of hypermagnesemia include
loss of deep tendon reflexes at levels greater than 8 mg/dL. Once levels are greater than 12 mg/dL
paralysis can occur. Cardiac arrest can occur if levels exceed 18 mg/dL. The mainstay of treatment is
intravenous calcium to antagonize the effect of magnesium, volume expansion or loop diuretic
depending on volume status, correction of acid–base disturbances and if needed, hemodialysis.
Hypomagnesemia
Kidneys are also able to conserve magnesium quite well with about 40% reabsorption in the proximal
tubule. Most instances of hypomagnesemia occur with chronic malnutrition, prolonged intravenous fluid
replacement without magnesium, and loop diuretics. Other causes include pancreatitis and diabetic
ketoacidosis (DKA). Magnesium functions as a cofactor for many neuromuscular functions, thus
deficiency can lead to muscle fasciculation or tetany. The treatment depends on the severity, which
includes taking into account symptoms and magnesium level. For instance, if serum magnesium level is
less than 1 mEq/L or if the patient is hemodynamically unstable or is in a torsade de pointes arrhythmia
then immediate infusion of intravenous magnesium sulfate is indicated. The maximum recommended
rate would be 150 mg/min excluding the above emergent situations where it can be given as IV push or
over 5 minutes for torsade de pointes. If the patient has chronic or mild hypomagnesemia, oral doses of
magnesium should be used, with options including magnesium oxide, magnesium chloride, and
magnesium hydroxide (milk of magnesia) depending on side-effect profiles. It should be noted that
doses greater than 80 mEq/day can become cathartic.
ACID–BASE
An acid is defined as a chemical that can donate a hydrogen ion (H+), for example, HCl and H2CO3. A
base is a chemical that can accept an H+, for example, OH− and HCO3−. Ampholytes are both acids and
bases; an example is H2PO4−, which can donate an H+ to become HPO42− but can also accept H+ to
become H3PO4. Bases are commonly anions, but neutral substances can also function as bases (e.g.,
ammonia and creatinine). Some chemicals do not fit the classic definition of an acid, although they
retain acidic properties when dissociated in water. For example, when CaCl2 is dissolved in water, the
Ca2+ accepts OH− to form Ca(OH)2.
The concentration of hydrogen ions [H+] determines the acidity of a solution. The pH is the negative
logarithm of [H+] expressed in moles per liter (mol/L). The concentration of H+ in biologic systems is
in the range of nanomoles (10−9 mol) per liter (nmol/L). The degree to which an acid dissociates
determines its strength.
Table 11-17 HCO3− and PCO2 Derangements in Primary and Secondary Acid–Base
Disturbances
The Henderson–Hasselbalch equation describes pH as a measure of acidity in a biologic system.

pH = pKa + log10 ([A-]/[HA])
pKa = Negative log of the acid dissociation constant
360
A- = Conjugate base
HA = Acid–base pair
Buffer Systems
Buffers are chemicals in solution that tend to minimize changes in pH that would otherwise occur after
the addition of acid or alkali. For instance, if a strong base is added to a weak acid, the base is
neutralized:
NaOH - H2CO3 → NaHCO3 + H2O
One type of buffer is a mixture of a weak acid and its salt. The presence of such buffer systems in the
body is crucial in minimizing changes in pH, which can be deleterious to cell function.
The principal intracellular buffers are organic phosphates, bicarbonate, and peptides. In addition,
hemoglobin functions as a significant buffer in red blood cells. The major extracellular buffer is
bicarbonate. An approximation of the total body buffer capacity is 15 mEq/kg. More than half of the
total body alkaline buffer content is located outside the ECF and may in large part reside in bone.50 The
buffer pair carbonic acid/bicarbonate (H2CO3/HCO3−) is the primary buffer system of the body.
From a chemical point of view, the ideal buffer should have a pKa that allows normal physiologic pH.
The H2CO3/HCO3− buffer system has a pKa of only 6.1, which is not the normal body pH. That said,
this buffer system is efficient because of the presence of large amounts of bicarbonate, the conversion of
its acid H2CO3 to CO2 that is rapidly excreted through the lungs, and an inexhaustible supply of CO2
from metabolism.
Acid–Base Disturbances
9 There are four primary acid–base disturbances, each of which are related to changes in either
[HCO3−] or PCO2. These are categorized as metabolic and/or respiratory (Table 11-17). A metabolic
acidosis is a decrease in pH as a result of a relative decrease in [HCO3−], whereas a metabolic alkalosis
is an increase in pH caused by a relative increase in [HCO3−]. A respiratory acidosis is a decrease in pH
secondary to a relative increase in PCO2, and a respiratory alkalosis is an increase in pH caused by a
relative decrease in PCO2. In each of these disorders, compensatory changes occur to minimize changes
in the relative ratio of [HCO3−] to PCO2 and thereby blunt the effect of the primary disturbance on
pH.48,49
Metabolic Acidosis
Anion Gap
The difference in the measured serum cations and anions yields the anion gap. This can be utilized to
identify the etiology of a metabolic acidosis. The most common equation used in practice is as follows:
Anion gap = [Na+] - ([Cl-] + [HCO3])
The normal value of serum anion gap is approximately 3 to 10; however, each laboratory should
establish its own normal. If one includes potassium in the equation then the normal value should be
increased by about 4 mEq/L. The differential for an elevated anion gap acidosis includes: lactic acidosis,
salicylate poisoning, acute or chronic kidney disease, chronic acetaminophen ingestion, ketoacidosis
(i.e., diabetic), and acute or chronic kidney disease. A common mnemonic used to address etiologies is
the acronym: MUDPILES: methanol, uremia, diabetic ketoacidosis, propylene glycol, isoniazid, lactic
acidosis, ethylene glycol, and salicylates.
Mechanisms of Metabolic Acidosis

Four mechanisms result in a decrease in extracellular bicarbonate concentration and metabolic acidosis:
1. Dilutional acidosis. Rapid infusion of an alkali-free solution results in dilution of the bicarbonate
concentration.
2. Increased acid generation (e.g., lactic acidosis, ketoacidosis, salicylate poisoning).
3. Diminished renal acid excretion (e.g., renal failure or type I renal tubular acidosis [RTA]).
4. Decreased body bicarbonate content (e.g., severe diarrhea, fistula, type II RTA).
Table 11-18 Compensatory Mechanisms
361
The most common example of a dilutional acidosis is large resuscitation with normal saline, which
causes a hyperchloremic acidosis. Clinically significant metabolic acidosis in surgical patients is most
commonly related to net loss of bicarbonate. One means of classification would be renal acidosis versus
extrarenal acidosis. Renal acidosis is not as readily compensated because by definition the kidney’s
ability to regulate acid/base is compromised. Extrarenal acidosis can be further subdivided into
increased acid production (e.g., lactic acidosis in shock) or increase bicarbonate loss (e.g., fistula).
Increased Production of Organic Acids

Increased protein intake and tissue catabolism resulting in greater metabolism of sulfur-containing
amino acids can lead to generation of increased amounts of sulfuric acid. With normal kidney function,
any decline in serum bicarbonate concentration stimulates renal acid excretion, which can compensate
almost completely for the increase in acid production.
Nonrenal Loss of Bicarbonate

Diarrhea, intestinal or pancreatic fistulas, and burns can cause metabolic acidosis secondary to loss of
bicarbonate. Urinary diversion with segments of GI tract (ureterosigmoidostomy and ureteroileostomy)
can result in loss of bicarbonate with reabsorption of NH4Cl from the urine. The potential for fistulas to
result in metabolic acidosis depends on the concentration of bicarbonate in the fluid and the rate of
external drainage. For instance, metabolic acidosis is less common with biliary fistulas than pancreatic
fistulas. Biliary fistulas typically have only modest volumes with a bicarbonate concentration of
approximately 50 to 60 mEq/L, whereas pancreatic fistulas can have profuse output with a
concentration of 150 mEq/L.
Ketoacidosis
Normally, free fatty acids generated from breakdown of triglycerides in adipose tissue are either used as
an energy source by tissues such as muscle or carried to the liver, where they are reesterified to
triglycerides. Ketoacids are produced by mitochondrial metabolism of free fatty acids to acetyl CoA,
with subsequent formation of acetoacetate and β-hydroxybutyrate (redox forms of the same compound).
Under normal conditions, a small amount of ketoacid is produced. During prolonged starvation,
production of ketoacid increases to modest levels, providing an important source of energy to
nonhepatic tissues, particularly the brain. In DKA, the ketoacid production is excessive because of
insulin deficiency, which drives ketoacid production by increasing free fatty acid release from adipose
tissue, increasing transport of free fatty acids into hepatic mitochondria, promoting conversion of acetyl
CoA to ketoacids, and impairing extrahepatic use of ketoacids. Insulin deficiency also contributes to
hyperglycemia by decreasing the metabolism of glucose by extrahepatic tissues and increasing hepatic
production of glucose. The resulting osmotic glucose diuresis causes increased renal excretion of sodium
and water. Additional losses of sodium and potassium occur as a result of renal excretion of the excess
ketoacid anions. Potassium excretion is further enhanced by hyperaldosteronism due to increased
delivery of sodium to the distal tubule that occurs in association with the osmotic diuresis. Despite total
body potassium depletion, serum potassium concentration is often increased in DKA secondary to
metabolic acidosis, renal insufficiency, insulin deficiency, and hyperosmolality. These pathophysiologic
changes result in the typical clinical presentation, which includes dehydration, polyuria, polydipsia,
hyperglycemia, hyperventilation, and metabolic acidosis with an increased anion gap.
Lactic Acidosis
Lactic acidosis can be characterized as type A (caused by tissue hypoxia) or type B (other causes). The
generation of lactic acid is the final step of anaerobic glycolysis. Lactic acid is normally produced by
muscle, blood elements, intestine, and skin and is used by the liver and kidney. Normal serum lactate
concentration is below 2 mEq/L. Lactic acidosis secondary to hypoxia is usually due to increased
362
production of lactate as well as decreased use, and exists when serum lactate concentration is greater
than 6 mEq/L.
The most common cause of type B lactic acidosis is ethanol intoxication. Lactic acidosis is caused by
increased generation of NADH by the metabolism of alcohol, which interferes with hepatic
gluconeogenesis and, therefore, lactate use.
In lactic acidosis, the L-isomer is usually elevated because of the specificity of mammalian lactate
dehydrogenase. Various bacteria found in colonic flora are capable of generating large amounts of D-
lactic acid. D-lactic acidosis has been reported in humans only in the presence of short-gut syndrome
because the small bowel normally absorbs the dietary substrate for bacterial D-lactic acid production. In
addition, the colon must be selectively colonized by bacteria that possess D-lactate dehydrogenase.
Typically, the patient has short-gut syndrome, and the acidosis is preceded by food ingestion and is
accompanied by characteristic neurologic findings, including mental confusion, slurred speech,
staggering gait, and nystagmus. These neurologic manifestations are secondary to bacterial neurotoxins.
The acidosis is accompanied by an increased anion gap, but L-lactate and ketone levels are normal.
Treatment includes oral antibiotics, recolonization of the colon with non–D-lactate dehydrogenase–
forming bacteria, and a low-carbohydrate diet.
Renal Acidosis
The most common renal-associated acidosis in surgical patients is that of acute or chronic renal failure.
One of the kidney’s many important functions is to excrete acid. When GFR decreases so does the ability
to excrete acid, thus causing a metabolic acidosis.
The impaired ability of the kidney to excrete acid may be secondary to a decrease in the number of
functioning nephrons and is termed RTA. Type I (distal) RTA is most commonly caused by autoimmune
diseases (e.g., Sjogren disease or rheumatoid arthritis) and hypercalciuria in adults. Distal RTA leads to
impaired distal acidification.
Type II (proximal) RTA is caused by a reduction in proximal bicarbonate reabsorption – the most
common cause in adults being monoclonal gammopathies or medications such as carbonic anhydrase
inhibitors.
Clinical Features of Acute Metabolic Acidosis

The major cardiovascular effects of acute metabolic acidosis are peripheral arteriolar dilatation,
decreased cardiac contractility, and central venous constriction. These can lead to cardiovascular
collapse and pulmonary edema. Catecholamine secretion is stimulated by metabolic acidosis, and in
mild cases (pH >7.1), heart rate may be increased. In more severe metabolic acidosis (pH <7.1), the
direct effects of acidosis override the catecholamine effects and result in bradycardia and decreased
contractility. These depressive effects are magnified by β-blockers. In addition to these cardiovascular
effects, metabolic acidosis can increase oxygen delivery by shifting the oxygen–hemoglobin dissociation
curve to the right. In more prolonged metabolic acidosis, this may be partially offset by decreased
production of 2,3-diphosphoglycerate in red blood cells because of a slower rate of glycolysis. Metabolic
acidosis can also cause gastric distention, abdominal pain, nausea, and vomiting.
Algorithm 11-3. Guidelines for the treatment of diabetic ketoacidosis.
363
Renal Compensation
The kidney is extremely sensitive to changes in serum bicarbonate concentration and responds by
increasing net acid excretion primarily in the form of ammonia excretion. Maximal renal compensation
requires 2 to 4 days. In addition, the maximal amount of ammonia excreted during acidosis depends on
factors such as glutamine delivery, GFR, and the type of anion that accompanies the acid, because renal
acid secretion is stimulated to varying degrees by different anions. Although renal compensation is
effective in achieving normal net acid excretion with extrarenal causes of metabolic acidosis, variable
results are seen with renal acidosis, especially distal RTA.
Respiratory Compensation
A decrease in blood pH causes an immediate stimulus to hyperventilate. Although effective in promptly
raising blood pH, early ventilatory compensation is only partial. Full respiratory compensation can
occur in 12 to 24 hours. The magnitude of the decrease in PCO2 in response to a given degree of
metabolic acidosis can be used to determine whether the metabolic acidosis is complicated by coexisting
respiratory acidosis or respiratory alkalosis. There are multiple equations that can describe this
relationship; whichever is easiest remembered can be utilized:
Arterial PCO2 = Serum HCO3- + 15
Arterial PCO2 = 1.5 × Serum HCO3- + 8 ± 2 (Winter equation)
The PCO2 can fall no lower than 8 to 12 mm Hg in response to a severe metabolic acidosis and this
compensation can only be maintained for a limited period of time due to respiratory muscle fatigue.
Treatment of Acute Metabolic Acidosis

In surgical and trauma patients, metabolic acidosis is often the result of inadequate tissue perfusion and
consequent lactic acidosis. Volume resuscitation alone may be enough to correct this acidosis. Attempts
to correct acidosis with exogenous bicarbonate without addressing inadequate tissue perfusion will be
unsuccessful. Furthermore, exogenous administration of bicarbonate may cause a superimposed
respiratory alkalosis and a deleterious left shift of the oxygen–hemoglobin dissociation curve, by not
allowing reversal of 2,3-diphosphoglycerate depletion, hence resulting in tissue hypoxia.
Diabetic Ketoacidosis
Initial therapy must include four components: intravenous fluid, insulin, potassium, and the need for
bicarbonate. Intravenous fluid should be given in the form of normal saline. On average 4 to 5 L of fluid
are required within the first 24 hours. While doing this, serum sodium levels should be monitored. The
initial dose of insulin is typically 0.1 unit/kg intravenous or 0.3 unit/kg subcutaneously administered.
Insulin should be redosed every 1 hour intravenously or every 2 hours subcutaneously until serum
glucose reaches 200 mg/dL. In terms of potassium replacement, it is paramount to ensure adequate
renal function (i.e., urine output of at least 0.5 mL/kg/hr). Once adequate urine output is assured,
potassium repletion is dosed. If the serum potassium is >5.3 then no further potassium should be given,
whereas if serum potassium is 3.5 to 5.3, 20 mEq is added to each liter of fluid. If the serum potassium
is <3.5 then 20 mEq/hr of potassium can be administered until serum potassium is in the ideal 3.5 to
5.3 range. Determination for bicarbonate therapy is largely based on pH. If the pH is <7 then it is
reasonable to dilute sodium bicarbonate (100 mmol) in 400 mL water and infuse over 2 hours, then
rechecking the pH (Algorithm 11-3).51,52
Metabolic Alkalosis
Sustained metabolic alkalosis occurs only if extracellular bicarbonate concentration is increased and
renal excretion of excess bicarbonate is inhibited. Extracellular bicarbonate concentration increases can
occur through several mechanisms. In surgical patients, loss of HCl is a frequent cause of metabolic
alkalosis, most commonly due to vomiting or nasogastric drainage in the presence of gastric outlet
obstruction. External loss of gastric acid results in a net gain in bicarbonate (generated by equimolar
gastric secretion of HCl), which causes alkalosis. Although the kidney can excrete excess bicarbonate,
this must be accompanied by excretion of sodium. Renal excretion of sodium is limited in the presence
of the volume depletion that occurs with external losses of gastric secretion. As volume depletion
progresses, sodium is conserved in exchange for hydrogen, and urine will become acidic, even in the
presence of severe metabolic alkalosis. This phenomenon is referred to as paradoxical aciduria.
364
Increased extracellular bicarbonate concentration can occur with administration of either bicarbonate
or precursors of bicarbonate, such as lactate, citrate, or calcium carbonate, or as a result of increased
renal production of bicarbonate. Conditions in which acid excretion exceeds endogenous acid production
and in which the renal threshold for bicarbonate reabsorption is increased can result in metabolic
alkalosis. Such conditions include moderate potassium depletion, excess mineralocorticoids, and high
PCO2.
Hypokalemia and cellular exchange of potassium for hydrogen can also lead to metabolic alkalosis.
Hypokalemia results in enhanced proximal tubular bicarbonate reabsorption and distal tubular acid
excretion. When potassium leaves the cell, it is exchanged for either sodium or hydrogen to maintain
electrical neutrality. Loss of potassium from the body then results in a net gain in bicarbonate in the
ECF.
Maintenance of elevated extracellular bicarbonate concentration can occur by a number of
mechanisms. Volume contraction leads to decrease in renal blood flow and GFR thus reducing the
filtered load of bicarbonate. This, in addition to increased proximal tubular reabsorption of bicarbonate,
maintains high extracellular concentrations of bicarbonate. High PCO2 causes an increase in renal
threshold for bicarbonate secondary to decreased intracellular pH of the renal tubular cell. The net
result is increased bicarbonate reabsorption.
Diuretics can cause or exacerbate metabolic alkalosis by both causing rapid contraction of
intravascular volume and increasing renal excretion of acid. Chloride deficiency is another common
factor that maintains an alkalotic state. In some instances of metabolic alkalosis, urinary excretion of
chloride is markedly reduced. Reversal of metabolic alkalosis in these cases can be readily achieved by
administration of chloride-containing solutions. Metabolic alkalosis can be categorically divided into
chloride-responsive and chloride-resistant types.
Clinical Features
Clinical signs of metabolic alkalosis may not be prominent because the condition usually develops
slowly. If acute, CNS manifestations of confusion, obtundation, stupor, and coma may be present as well
as tetany or neuromuscular irritability.
Respiratory Compensation
Respiratory compensation for metabolic alkalosis should raise the PCO2 by 0.7 mm Hg for every 1
mEq/L elevation in serum HCO3-. Typically the arterial PCO2 does not go above 55 mm Hg. Among the
four major acid–base disorders, this compensatory mechanism is the least effective.60
Treatment
Correction of the underlying cause is the mainstay of treatment in this disorder. In general, correction
of potassium depletion and volume depletion corrects the metabolic alkalosis. Renal excretion of
bicarbonate cannot occur in the face of persistent volume depletion. Volume depletion should be
corrected with chloride-containing solutions. In patients without intravascular volume deficits, renal
excretion of bicarbonate can be enhanced by administration of the diuretic, carbonic anhydrase inhibitor
acetazolamide. In extremely rare circumstances where renal excretion of bicarbonate cannot be
increased because of underlying renal insufficiency or if the metabolic alkalosis is severe, acid may be
administered to titrate in opposition the excess extracellular bicarbonate. Acids that can be used include
ammonium chloride, arginine hydrochloride, lysine hydrochloride, or dilute hydrochloric acid (0.1N).
Partial correction of the alkalosis is the initial goal and a specialist should be involved prior to
instituting this care. In the face of frank renal failure, dialysis may be necessary to remove excess
bicarbonate.
Respiratory Alkalosis
Respiratory alkalosis is defined as increased extracellular pH secondary to decreased PCO2 with
hyperventilation. Hyperventilation and the ensuing fall in PCO2 may be secondary to hypoxia, reflex
stimulation from decreased pulmonary compliance, drugs, mechanical ventilation, or other causes.
Hypoxia stimulates ventilation through peripheral chemoreceptors in the carotid and aortic bodies.
Decrease in arterial partial pressure of oxygen (pO2), rather than in oxygen content, is the main
stimulus. Acute drops in arterial pO2 result in sustained hyperventilation only when the PCO2 decreases
below 60 mm Hg. Although hyperventilation occurs with even slight degrees of hypoxia, the resulting
365
increase in brain pH suppresses the stimulus for hyperventilation unless severe hypoxia is present. In
contrast, chronic hypoxia results in hyperventilation even with mildly decreased PCO2 because brain pH
is lowered by metabolic compensation. The two most common causes of hypoxia resulting in respiratory
alkalosis are pulmonary disease and exposure to high altitudes.
Clinical Features
Chronic respiratory alkalosis is usually asymptomatic because compensatory mechanisms are successful
in maintaining pH close to normal. Acute respiratory alkalosis may cause sensations of breathlessness,
dizziness, and nervousness and can result in circumoral and extremity paresthesias, altered levels of
consciousness, and tetany. These signs are related to decreased cerebral blood flow secondary to the
decreased PCO2 and decreased ionized calcium concentration secondary to the increased blood pH.
Compensatory Mechanisms
Tissue buffering is the initial response to a decrease in PCO2. Red blood cells provide one-third of the
buffering. Consumption of bicarbonate results from cellular liberation of H+. The magnitude of tissue
buffering is weak compared with renal compensation. This is accomplished not by increasing
bicarbonate excretion but by decreasing net acid excretion, namely ammonia. Acute compensation is not
as strong as chronic compensation, which takes at least 3 days to occur.
Acute compensation: Decrease serum HCO3- by 2 mEq/L per 10 mm Hg reduction in PCO2
Chronic compensation: Decrease serum HCO3- by 4 to 5 mEq/L per 10 mm Hg reduction in PCO2
Treatment
The underlying stimulus for the hyperventilation should be addressed. The cause of hypoxemia should
be determined and corrected. In acute symptomatic respiratory alkalosis, rebreathing or breathing 5%
CO2 temporarily relieves symptoms. If the condition is secondary to mechanical ventilation, decreasing
tidal volume or respiratory rate should result in resolution of respiratory alkalosis.
Respiratory Acidosis
Respiratory acidosis is defined by a decrease in extracellular pH from a primary increase in PCO2, due
to inadequate ventilation. Causes of hypoventilation include CNS depression, impaired pulmonary
mechanics, airway obstruction, and chronic obstructive pulmonary disease (COPD). In addition,
inappropriate ventilator settings may result in respiratory acidosis in patients on mechanical ventilation.
Clinical Features
The magnitude of clinical manifestations depends on the chronicity and rate of development of
respiratory acidosis. Acute increases result in cerebral acidosis, manifested by drowsiness, restlessness,
and tremor, as well as stupor or coma in more severe cases. Cerebral vasodilation occurs in response to
acidosis, resulting in increased cerebral blood flow. This may, in turn, result in increased intracranial
blood pressure, headache, and papilledema. Systemic acidosis results in peripheral vasodilatation,
depressed cardiac contractility, and insensitivity to catecholamines.
366
Figure 11-8. Acid–base nomogram. Shown are the 95% confidence limits of the normal respiratory and metabolic compensations
for primary acid–base disturbances. (Reproduced with permission from Cogan MG, Rector FC Jr. Acid–base disturbances. In:
Brenner BM, Rector FC Jr, eds. The Kidney. Philadelphia, PA: WB Saunders; 1986:473.)
Compensatory Mechanisms
Increased pCO2 results in increased H2CO3, which dissociates into H+ and HCO3-. Cellular exchange of
Na+ and K+ for H+ allows the reaction to continue in this direction with increased extracellular
bicarbonate. This tissue buffering is accomplished within minutes. Persistently elevated PCO2 also
stimulates increased renal acid excretion, primarily the chloride salt of ammonia, and results in
increased renal generation of HCO3-. Full renal compensation occurs over 3 to 5 days.
Acute compensation: 1 mEq/L HCO3- per 10 mm Hg PCO2
Chronic compensation ~4 mEq/L for every 10 mm Hg PCO2
Treatment
Treatment should be directed to the underlying cause of hypoventilation. Endotracheal intubation to
achieve adequate ventilation is paramount to the treatment of acute respiratory acidosis of any cause. In
select cases of respiratory acidosis, namely patients with COPD, noninvasive positive pressure
ventilation (i.e., CPAP/BiPAP) has proven effective. However, patients must be able to protect their
airway and have no major concern for aspiration (i.e., not appropriate in the setting of a bowel
obstruction). Furthermore, there must be close follow-up to ensure the acidosis is resolving.
The treatment of chronic, compensated respiratory acidosis may be complicated by the accompanying
hypoxemia. In chronic hypercapnia, the central chemoreceptors may be insensitive, and the
accompanying hypoxemia may supply the main respiratory drive through stimulation of peripheral
chemoreceptors. In such patients, complete correction of the hypoxemia may further suppress
respiration and worsen the respiratory acidosis. In addition, PCO2 should not be normalized rapidly.
Equilibration of cerebral bicarbonate concentration lags behind systemic changes. Thus, even if PCO2 is
normal, cellular and cerebral metabolic alkalosis may develop.
Mixed Acid–Base Disorders

Combinations of two or more of the four primary acid–base disorders may occur and should be
suspected when blood pH approaches normal despite abnormal PCO2 and [HCO3-], or when
compensatory changes appear to be either excessive or inadequate (Fig. 11-8). Familiarity with the
acid–base disorders associated with various clinical situations and the expectation of mixed
abnormalities allows appropriate interpretation of arterial blood gases and serum electrolyte
determinations.
References
1. Forbes G. Body composition: overview. J Nutr 1999;129(1):270S–272S.
2. Briggs JP, Sawaya BE, Schnerman J. Disorders of salt balance. In: Kokko JP, Tannen RL, eds. Fluid
and Electrolytes. Philadelphia, PA: WB Saunders; 1990:70.
3. Thompson CA, Tatro DL, Ludwig DA, et al. Baroreflex responses to acute changes in blood volume
in humans. Am J Physiol 1990;259:R792–R798.
4. Le Fevre P. Gibbs-Donnan Effect: A Computer Simulation.
http://www.philippelefevre.com/icu_medicine/gibbs_donnan. Accessed January 5, 2015.
5. Stockand JD. New ideas about aldosterone signaling in epithelia. Am J Physiol Renal Physiol
2002;51:F559–F576.
6. Boland DG, Abraham WT. Natriuretic peptides in heart failure. Congest Heart Fail 1998;4:23–33.
7. Falcao LM, Fausto P, Luciano R, et al. BNP and ANP as diagnostic and predictive markers in heart
failure with left ventricular systolic dysfunction. J Renin Angiotensin Aldosterone Sys 2004;5:121–
129.
8. Schrier R, Abraham W. Mechanisms of disease: hormones and hemodynamics in heart failure. N
Engl J Med 1999;341:577–585.
9. Wait RB, Kahng KU. Renal failure complicating obstructive jaundice. Am J Surg 1989;157:256–263.
367
10. Naicker S, Bhoola KD. Endothelins: vasoactive modulators of renal function in health and disease.
Pharmacol Ther 2001;90(1):61–68.
11. Roland CB, Aihua D, Mark L, et al. The complex role of nitric oxide in the regulation of glomerular
filtration. Kidney Int 2002;61:782–785.
12. Ruttmann TG, James MF, Lombard EM. Haemodilution induced enhancement of coagulation is
attenuated in vitro by restoring antithrombin III to predilution concentrations. Anaesth Intensive
Care 2001;29:489–493.
13. Ng KF, Lam CC, Chan LC. In vivo effect of haemodilution with saline on coagulation: a randomized
controlled trial. Br J Anaesth 2002;88:475–480.
14. Ruttmann TG, James MF, Finlayson J. Effects on coagulation of intravenous crystalloid or colloid in
patients undergoing peripheral vascular surgery. Br J Anaesth. 2002;89:226–230.
15. De Lorenzo C, Calatzis A, Welsch U, et al. Fibrinogen concentrate reverses dilutional coagulopathy
induced in vitro by saline but not by hydroxyethyl starch 6%. Anesth Analg 2006;102:1194–2000.
16. Koustova E, Standon K, Gushchin V, et al. Effects of lactated Ringer’s solution on human
leukocytes. J Trauma 2002;53:872–878.
17. Hanneman L, Reinhart K, Korrel R, et al. Hypertonic saline in stabilized hyperdynamic sepsis. Shock
1996;5:130–134.
18. Wade CE, Kramer GC, Grady JJ, et al. Efficacy of 7.5% saline and 6% dextran-70 in treating
trauma. A meta-analysis of controlled clinical studies. Surgery 1997;122:609–616.
19. Doyle J, Davis D, Hoyt D. The use of hypertonic saline in the treatment of traumatic brain injury. J
Trauma 2001;50:367–383.
20. Rizoli SB, Rhind SG, Shek PN, et al. The immunomodulatory effects of hypertonic saline
resuscitation in patients sustaining traumatic hemorrhagic shock. Ann Surg 2006;243:47–57.
21. Finfer S, Bellomo R, Boyce N, et al. The SAFE Study Investigators. A comparison of albumin and
saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004;350:2247–2256.
22. Vincent JL, Sakr Y, Reinhart K, et al. Is albumin administration in the acutely ill associated with
increased mortality? Results of the SOAP study. Crit Care 2005;9:R745–R754.
23. Greg M. Conflicting clinical trial data: a lesson from albumin. Crit Care 2005; 9:649–650.
24. Alexey AS, Raili S, Anne HK, et al. Rapidly degradable hydroxyethyl starch solutions impair blood
coagulation after cardiac surgery: a prospective randomized trial. Anesth Analg 2009;108:30–36.
25. Martin G, Bennett-Guerrero E, Wakeling H, et al. A prospective, randomized comparison of
thrombelastographic coagulation profile in patients receiving lactated Ringer’s solution, 6%
hetastarch in a balanced-saline vehicle, or 6% hydroxyethyl starch in saline during major surgery. J
Cardiothorac Vasc Anesth 2002;16:441–446.
26. Omar MN, Shouk TA, Khaleq MA. Activity of blood coagulation and fibrinolysis during and after
hydroxyethyl starch (HES) colloidal volume replacement. Clin Biochem 1999;32:269–274.
27. Perner A, Haase N, Guttormsen AB, et al.; 6S Trial Group; Scandinavian Critical Care Trials, Group.
Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med 2012;367:124–
134.
28. Myburgh JA, Finfer S, Bellomo R, et al. Hydroxyethyl starch or saline for fluid resuscitation in
intensive care. N Engl J Med 2012;367:1901–1911.
29. Public Workshop: Risks and Benefits of Hydroxyethyl Starch Solutions. Vaccines, Blood & Biologics
(U.S. Food and Drug Administration), September, 2012.
30. Solutions for infusion containing hydroxyethyl starch: Hydroxyethyl-starch solutions (HES) should
no longer be used in patients with sepsis or burn injuries or in critically ill patients. PRAC
recommendations, European Medicines Agency, October 10, 2013.
31. Dellinger R, Phillip L, Mitchell M, et al. The Surviving Sepsis Campaign Guidelines Committee
including the Pediatric Subgroup (February 2013). Surviving Sepsis Campaign: International
Guidelines for Management of Severe Sepsis and Septic Shock: 2012. Crit Care Med 2012;41(2):580–
637.
32. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients.
Cochrane Database Syst Rev 2012;6:CD000567.
33. Allison KP, Gosling P, Jones S, et al. Randomized trial of hydroxyethyl starch versus gelatine for
trauma resuscitation. J Trauma 1999;47:1114–1121.
368
34. Russell WJ, Fenwick DG. Anaphylaxis to Haemaccel and cross reactivity to Gelofusin. Anaesth
Intensive Care 2002;30:481–483.
35. Bernard AC, Moore EE, et al.; PolyHeme Study Group. Postinjury resuscitation with human
polymerized hemoglobin prolongs early survival: a post hoc analysis. J Trauma 2011;70(5
Suppl):S34–S37.
36. Fleck A, Raines G, Hawker F, et al. Increased vascular permeability: a major cause of
hypoalbuminaemia in disease and injury. Lancet 1985;1:781–784.
37. Rodriguez HJ, Domenici R, Diroll A, et al. Assessment of dry weight by monitoring changes in
blood volume during hemodialysis using Crit-Line. Kidney Int 2005;68(2):854–861.
38. McGee WT. A simple physiologic algorithm for managing hemodynamics using stroke volume and
stroke volume variation: physiologic optimization program. J Intensive Care Med 2009;24(6):352–
360.
39. Androgue HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581–1589.
40. Katz MA. Hyperglycemia-induced hyponatremia—calculation of expected serum sodium depression.
N Engl J Med 1973;289:843–844.
41. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med
2007;356:2064–2072.
42. Scherr L, Ogden DA, Mead AW, et al. Management of hyperkalemia with a cation-exchange resin. N
Engl J Med 1961;264:115–119.
43. Magnus Nzerue C, Jackson E. Intractable life-threatening hyperkalaemia in a diabetic patient.
Nephrol Dial Transplant 2000;15:113–114.
44. Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336:1298–1302.
45. Hannan FM, Thakker RV. Investigating hypocalcaemia. BMJ 2013;346:f2213.
46. Tohme JF, Bilezikian JP. Hypocalcemic emergencies. Endocrinol Metab Clin North Am 1993;22:363–
375.
47. Martin TJ, Kang Y, Robertson KM, et al. Ionization and hemodynamic effects of calcium chloride
and calcium gluconate in the absence of hepatic function. Anesthesiology 1990;73(1):62–65.
48. Javaheri S, Shore NS, Rose B, et al. Compensatory hypoventilation in metabolic alkalosis. Chest
1982;81:296–301.
49. Polak A, Haynie GD, Hays RM, et al. Effects of chronic hypercapnia on electrolyte and acid-base
equilibrium. Adaptation. J Clin Invest 1961;40:1223–1237.
50. Lemann J Jr, Lennon EJ. Role of diet, gastrointestinal tract, and bone in acid-base homeostasis.
Kidney Int 1972;1(5):275–279.
51. American Diabetes Association. www.diabetes.org. Accessed November 3, 2014.
52. Kitabchi AE, Wall BM. Management of diabetic ketoacidosis. Am Fam Physician 1999;60(2):455–
464.
369
Chapter 12
Burns
Benjamin Levi, Mark R. Hemmila, and Stewart C. Wang
Key Points
1 Burn reconstruction remains a challenge given the increased survival of burn patients.
2 Most chemical injuries should be treated with dilution of the chemical rather than neutralization.
3 Frostbite outcomes are improved if patients with threatened extremities are treated with tPA within
24 hours of injury.
4 Resuscitation is of crucial importance for burn patient outcome and physicians must be aware when
to begin resuscitation (>20% TBSA) and to monitor the patient’s response to avoid
overresuscitation.
5 Early excision and grafting within 72 hours of the injury remains a pillar of burn care.
6 Order of burn coverage can affect patient outcome and can help prevent the patient from needing a
tracheostomy.
7 In addition to surgical treatment of hypertrophic scars, new laser technologies allow for scar
rehabilitation improving the quality and pain associated with these scars.
INTRODUCTION
Burn injuries represent a major source of trauma, subsequent scarring and debility throughout the
world. Improved worker safety programs, fire prevention efforts, and fire detection systems have
significantly decreased the prevalence of major burn injuries. Burn patients have also benefited from
recent improvements in surgical critical care in areas such as lung protective ventilation, blood glucose
control, and antibiotic stewardship. Overall, survival after burn injuries remains high, leading to a large
need for improved reconstructive treatment options for burn scar rehabilitation.
EPIDEMIOLOGY
1 Based on the American Burn Association (ABA) National Burn Repository, 450,000 people receive
medical treatment for burns annually. There are 40,000 hospital admissions and 3,400 deaths per year
from fire and smoke inhalation.1 Of these patients, 69% are male, 59% are Caucasian, 20% are African
American, and 15% are Hispanic. The cause of these burn injuries varies with 43% from fire or flame
burns, 34% from scald burns, 9% from contact burns, and 7% are electrical and chemical burns. With
increased safety emphasis in the workplace, only 9% of these injuries occur at work. The majority of
chemical, electrical, and molten burns occur at home and 72% of all burn injuries happen at home. As in
other trauma populations, children are affected to a greater degree. Children under 8 years of age
typically suffer from scald burns caused by spilling of hot liquids. With improved surgical critical care
and understanding of burn injury physiology, over 96% of burn patients survive. Thus, with improved
treatments and survival, there has also been an increased focus on burn reconstruction and scar
management.
Children
Infants and children up to 4 years old comprise almost one-third of burns. Burns are the fifth leading
cause of unintentional nonfatal injury in infants and the third leading cause of fatal injury for newborns
to children 9 years of age. Scald burns caused by hot liquids are the most common cause of pediatric
burns and occur most often in the home.2–5 The number of burns decreases from age 9 until adolescence
and increases again after the age of 15, presumably due to greater exposure to hazards,
370
experimentation, risk-taking, and employment.6 Intentional burns account for around 10% of all cases of
child abuse.7 Scalds from hot bath immersion are the most frequent cause of these cases. Other common
etiologies of intentional burns include contact with heated objects including cigarettes, irons, and heated
kitchen utensils.
Adults
In contrast to the pediatric population, flame burns are the most common cause of burns in adults and
the elderly. Flame burns account for 35% to 42% of hospital admissions in adults, while scald burns
account for 15% to 18% of hospital admissions related to burn injuries.3 Cigarette ignition of
upholstered furniture or bedding accounts for 47% of fires and alcohol appears to be a significant
contributor.8
Elderly
The elderly (defined by age greater than 65 years) suffer a disproportionately higher percentage of
hospitalizations due to burns in comparison to the general adult population. A 10-year analysis from
1995 to 2005 using data from the National Burn Repository showed that individuals over the age of 65
comprised 12% of all burn unit admissions and that the average age of those admitted was 76 ± 7
years.9 The most frequent cause of burns that led to death in elderly women was a result of clothing
ignition during cooking.10 Elderly burn patients treated for scald burns had relatively small burns
(<13% of total body surface area [TBSA]) but high mortality rates (30%).11–13 Overall, burns are the
fourth leading cause of mortality in the elderly population. Together, these results suggest that the
medical, economic, and social burdens of burn will likely increase as the general population continues to
age.
Race and Ethnicity

Differences also exist in the susceptibility to burns by race and ethnicity. Burns are the leading cause of
injury-related death in Black children between the ages of 1 and 9 and the rates are 2.7 times higher
than in White, Hispanic, and Asian/Pacific Islander children.14 Likewise, in adults, the rate of nonfatal
burns in Black Americans aged 35 to 39 years was 221 per 100,000 Blacks, which is remarkably higher
than the 135 per 100,000 Whites with burns in the same age group.3 The emergency room visit rate for
burns from 1993 to 2004 in the United States was 62% greater among Black Americans (340 per
100,000 Black Americans) than White Americans (210 per 100,000 White Americans).15 The age-
adjusted death rate from burns of all causes in the United States in 2006 was highest in Blacks (2.4 per
100,000) and lowest in Asians (0.4 per 100,000), with Native Americans (1.5 per 100,000), White non-
Hispanics (1.1 per 100,000), and Hispanics (0.8 per 100,000) falling in between this range.3 These
trends can be translated to the elderly population, as the mortality rate for burn-related injuries in the
elderly was 4.6 times greater in Black Americans than in White Americans.16
There are also significant differences in the gender distribution of burns between age groups. Adult
men more frequently seek care in the emergency department (69%). This may be due to the increased
severity of their burns caused by industrial accidents, compared to women (31%).6 Elderly are also
more highly represented among older burn victims than in younger populations.17,18 The greater
preponderance of older women with burn injuries reflects the decrease in workplace-related injuries
among the geriatric population.
Socioeconomic Status
Socioeconomic status (SES) factors such as low household income, crowded household living conditions,
and unemployment also increase the risk of burns. In the metropolitan Oklahoma City, Oklahoma, the
overall fire-related hospitalization and death rate was 3.6 per 100,000.19 Stratification of the data based
on household income, property values, and quality of housing demonstrated that the injury rate in
lower SES was 15.3 per 100,000.20 The proportion of children in the lowest SES groups requiring
hospitalization for treatment in US burn centers is twice the proportion of all children in the general
population.3 Furthermore, the incidence of house fires was eight times greater in low income families
compared to high incomes.21 The higher incidence of house fires has been attributed to the frequent
absence of functioning smoke detectors.21 Together, these results highlight the increased need for
education and prevention campaigns for lower SES groups to reduce household fires and burn injuries.
371
ETIOLOGY
Numerous modalities, including fire or flame, scalds, contact, electrical conduction, and chemicals can
produce burns. Between 2002 and 2011, 44% of burns were produced by fire or flame, 33% by scald,
9% by contact, 4% by electricity, 3% by chemical, and 7% defined as other.
Burns are caused by contact of heat, cold, or chemicals with the cutaneous surface of the skin. The
depth of the burn injury is proportional to the temperature and duration of exposure. Burn depth is also
dependent on the body region due to differences in skin thickness and blood flow.
Scald burns are most commonly caused by water in the community. Once the water temperature
exceeds 156°F, only 1 second is needed for a full-thickness burn injury. The difference in contact time
underlines the importance of making sure hot water heaters are set at a low enough temperature to
minimize childhood bath and shower scald injuries (120°F). It takes 3 minutes for a burn to occur from
120°F whereas it takes only 1 second for a burn to occur from 156°F water.
Though water scalds do not always cause full-thickness injury due to the variation in temperature,
grease burns almost uniformly cause a deep partial- or full-thickness burn. Grease is usually 400°F and
thus even minimal exposure will cause significant thermal injury. Tar and asphalt also exceed 400°F to
500°F making them a high burn injury risk for industrial workers. Water and grease injury sites should
be cleansed with aqueous solutions. Tar, however, requires a petroleum-based solution to remove it
from the burn wound.
Flame Burns
Thermal injuries, caused by fire or flames, are the most common burn etiology reported over the past
decade.22 These injuries usually occur as a result of flammable liquids, motor vehicle crashes, cooking
fires, or if bedding/clothes ignite. Despite improved fire safety at home with smoke detectors as well as
improved safety at industrial sites, flame injuries are still relatively common and frequently cause
partial- and full-thickness burn injuries. Flame injuries are associated with the highest risk of death and
complications compared to all other burn etiologies. Flame burns most commonly occur at home (64%),
while work fires and recreational fire burns account for 12% and 6% of flame burns, respectively. When
evaluating thermal injuries, it is important to consider the possibility of smoke inhalation as its presence
significantly impacts the morbidity and mortality of patients with flame burns. Inhalation injury occurs
in 17% of patients with flame burns. The presence of smoke inhalation in burn patients is associated
with an overall mortality rate of 24%, compared to the mortality rate of 4% in patients without smoke
inhalation.
Contact Injuries
Contact burns occur as the result of direct contact with hot surfaces and material, most frequently glass,
metal, or plastic. The depth of the injury will depend on the heat of the material and the length of
contact. Frequent sites of injury include the palms of the hands as people, especially toddlers, often fall
with outstretched hands. Other commonly seen contact injuries are due to hot metal devices such as
space heaters, curling irons, or motorcycle exhaust systems.
Electrical Burns
Electrical injuries occur more frequently in adults than children since most result from occupational
exposure. As one of the most devastating and debilitating injuries cared for in burn centers, electrical
injuries comprise 4% of all reported etiologies. Patients who have high-voltage electrical injuries,
defined as greater than 1,000 V, are at elevated risk of spine fracture injury due to tetany and require
complete immobilization until vertebral injury is excluded. Providers must also evaluate patients with
high-voltage injuries for cardiac damage. Direct muscle injury from current flow may cause gross
myoglobinuria, requiring more aggressive fluid resuscitation.23 Patients with gross myoglobinuria often
require fasciotomy of affected limbs and a severe electrical injury often requires monitoring in the ICU.
Bone has the highest conductance and electricity flows along the skeleton cause significant muscle
necrosis adjacent to the bone. TBSA involved is not necessarily associated with prognosis and it does not
quantify damage to deep tissues in electrical injuries.
Thermal injuries occur as electricity can generate temperatures over 100°C. Electroporation occurs as
electrical force drives water into lipid membrane causing cell rupture. Tissue resistance in decreasing
order includes bone, fat, tendon, skin, muscle, vessel, and nerve. Bone heats to a high temperature and
burns surrounding structures such as muscle which is the reason why muscle swelling and compartment
372
syndrome are common in high-voltage electrical injuries.
Alternating current causes tetanic muscle contraction and the “no let-go” phenomenon. This occurs
due to simultaneous contraction of (stronger) forearm flexors and (weaker) forearm extensors. Current
flow through tissue can cause burns at entrance/exit wounds and hidden injury to deep tissues. Current
will preferentially travel along low-resistance pathways. Current will pass through soft tissue, contact
high-resistance bone, and travel along bone until it exits to the ground. Vascular injury to nutrient
arteries and damage to intima and media can result in thrombosis.
Electrical exposure can cause significant injuries to other organ systems besides the skin and
musculoskeletal system. From a cardiac standpoint, arrhythmias are common at the scene (any voltage)
or in the hospital (high voltage ≥1,000). Heart rhythm should be monitored continuously for at least
24 hours if cardiac injury is suspected at the scene or if a high-voltage injury has occurred. Ventricular
fibrillation and asystole are the most common and Advanced Cardiac Life Support should be instituted
immediately. Coronary artery spasm and myocardial injury and infarction have also been described. A
normal cardiac rhythm on admission, however, means dysrhythmia is unlikely and thus 24-hour
monitoring is not needed.24 Additionally, injury to solid organs, acute bowel perforation, and gallstones
after myoglobinuria have been described. Myoglobinuria occurs due to the disruption of muscle cells.
Myoglobinuria from other causes requires increased fluid administration, however, burn resuscitation
usually provides adequate fluid. Cataracts are also a long-term adverse effect of electrical injury
necessitating ophthalmology evaluation and follow-up.
When taking the patient to the operating room for debridement and grafting of electrical injuries, the
physician should perform serial debridements and allow the tissue to completely declare itself. These
injuries will often evolve with progressive muscle necrosis over time, thus early grafting (within the
first week) often fails to fully close the burn wound. These injuries have similarities to crush injuries
and thus multiple trips to the operating room for debridement should not be viewed as failure.
Chemical Burns
General Approach to Chemical Burn Treatment

2 Healthcare providers should use personal protective equipment – always considering that the
chemicals are still present and must be neutralized or temporized. With few exceptions (see below), all
chemical burns should be copiously irrigated with water. Water dilutes but does not neutralize the
chemical and cools the injured area. Neutralization of the chemical is generally contraindicated because
neutralization may induce a hyperthermic reaction leading to further thermal injuries. Water irrigation,
however, is contraindicated or ineffective following exposure to elemental sodium, potassium, and
lithium (precipitates an explosion). Dry lime should be brushed off, not irrigated. Phenol is water
insoluble and should be wiped from the skin with polyethylene glycol-soaked sponges.
Types of Chemical Burns

Alkali causes liquefaction necrosis and protein denaturation and is found in oven and drain cleaning
products, fertilizers, and industrial cleaners. Alkali injuries extend deeper into tissues following
exposure and are especially disruptive to the eye. Acids cause damage tissue via coagulation necrosis
and protein precipitation. Acid burns tend to be self-limited secondary to pain as the patient will quickly
react to the offending agent. Organic compounds (phenol and petroleum) cause damage due to fat
solvent action (cell membrane solvent action) and systematic absorption with toxic effects on the liver
and kidneys. These agents can also cause significant erythema in the surrounding areas that can be
mistaken for cellulitis.
Specific Types of Chemical Burns

Hydrofluoric acid is a potent and corrosive acid used for rust removal, glass etching, and to clean
semiconductors. It is a weak acid but the fluoride ion is toxic as it leaches calcium from cells.
Hydrofluoric acid causes severe pain and local necrosis and should be treated with copious water
irrigation. The fluoride ion is neutralized with topical calcium gel (one ampule of calcium gluconate in
100-g lubricating jelly). If symptoms persist intra-arterial calcium infusion (10-mL calcium gluconate
diluted in 80 mL of saline, infused over 4 hours) and/or subeschar injection of dilute (10%) calcium
gluconate solution should be administered. Fluoride ion binds free serum calcium and thus it is crucial
to make sure to check the serum calcium and replace with intravenous (IV) calcium as needed.
Phenol is commonly used in disinfectants and chemical solvents, it is an acidic alcohol with poor
water solubility. Phenol causes protein disruption and denaturation resulting in coagulation necrosis.
373
Systemically, phenol can cause cardiac arrhythmias and liver toxicity. Thus patients should have cardiac
and liver functions monitored. Additional adverse effects include renal injury and demyelination. Given
phenol’s anesthetic effect, pain is not a reliable indicator of injury. Treatment is copious water irrigation
and cleansing with 30% polyethylene glycol or ethyl alcohol.
Tar is used in the paving and roofing industry and can be heated to 260°C (∼500°F) prior to
application. Tar causes thermal injury and then solidifies as it cools, often becoming enmeshed with hair
and skin. Patients with tar injuries should be cooled with copious water irrigation to stop the burning
process. Tar removers promote micelle formation to break the tar – skin bond. Sterile surfactant
mixture (De-Solv-it or Shur-Clens) allows tar to be wiped away quickly. Wet dressings using polysorbate
(Tween 80) or Neomycin cream for 6 hours prior to tar removal can also be effective.
White phosphorus is used to manufacture military explosives, fireworks, and methamphetamine.
Obvious particles should be brushed off. Skin should be irrigated with 1% to 3% copper sulfate solution.
Copper sulfate stains the particles black for identification. Copper sulfate will also prevent ignition
when particles are submerged in water. After copper sulfate irrigation, the exposed area should be
placed in a water bath and the white phosphorous removed.
Anhydrous ammonia is an alkali used in fertilizer. Skin exposure is treated with irrigation and local
wound care. Exposure is associated with rapid airway edema, pulmonary edema, and pneumonia. It is
important to consider early intubation for airway protection in these cases.
Methamphetamine injuries have been on the rise. In addition to these compounds being highly
flammable, exposure to methamphetamines causes tachycardia (greater than expected with a similar
size burn), hyperthermia, agitation, and paranoia. Any suspicion of chemical injury to the globe should
be treated with prolonged irrigation with Morgan lenses. Eyelids may need to be forced open due to
edema or spasm. Utilize topical ophthalmic analgesic and consult an ophthalmologist.
Frostbite
Frostbite injuries frequently result in severe ischemic damage of distal extremities. Frostbite
classification is similar to that of burn injury with first degree demonstrating hyperemia and no blisters
with no tissue loss expected; second degree having blisters and edema but still no tissue loss; third
degree with hemorrhagic blisters, throbbing pain, and likely tissue loss; and fourth degree with mottled
or cyanotic skin, hemorrhagic blisters, and frozen deeper tissues.
3 Historically, these patients have been managed expectantly with long periods of observation
followed by amputation of devitalized tissue. Recent advances with interventional radiology,
thrombolytic therapy, and nuclear medicine have changed the treatment paradigm and protocol for
these patients (Algorithm 12-1). Current treatment paradigms for patients with frostbite include rapid
rewarming of affected area in 104°F to 108°F water bath, not radiant heat as well as ibuprofen 400 mg,
elevation of the limb, tetanus prophylaxis, and appropriate referral. If the patient has severe frostbite
within the last 24 hours, the patient should be transferred to a center with interventional radiology
expertise. Once they arrive, these patients should receive an arterial line (usually brachial or femoral)
and intra-arterial tPA which treat the microvascular thrombosis.25 Additionally, patients might benefit
from nitroglycerin to treat vasospasm. Patients should return to the interventional radiology suite after
12 hours to evaluate progress and potentially treat again. In general, tPA is stopped after 48 hours.
After 5 to 7 days, a nuclear bone scan can help assess the extent of deeper tissue necrosis as the more
superficial tissue will often appear worse than the actual extent of the injury.
374
Algorithm 12-1. Protocol for frostbite injury.
PHYSIOLOGY OF BURNS
Burn Shock
Most patients with large burn or inhalation injuries will meet criteria for systemic inflammatory
response syndrome (SIRS) (body temperature less than 36°C [96.8°F] or greater than 38°C [100.4°F],
heart rate greater than 90 beats per minute, tachypnea greater than 20 breaths per minute, arterial
partial pressure of carbon dioxide less than 4.3 kPa [32 mm Hg], blood leukocyte count less than 4,000
cells/mm3, or greater than 12,000 cells/mm3); or the presence of greater than 10% immature
neutrophils (band forms). SIRS with infection is defined as sepsis and sepsis in addition to hypoperfusion
is defined as “septic shock.” Burn shock does not equate to septic shock in the acute setting as true
sepsis from a burn injury with subsequent infection usually does not occur until after the first 48 to 72
hours.
Burn shock is unique in the degree of vascular permeability coupled with increased hydrostatic
pressure.26 This increased permeability is thought to result from the release of histamine from mast cells
in burned skin following burn injury.27 Histamine interferes with the venous tight junctions and thereby
allows efflux of fluid and proteins causing intravascular hypovolemia despite total volume
hypervolemia.
Platelet activation products such as eicosanoids and serotonin also act to increase pulmonary vascular
resistance and amplification of the vasoconstrictive effects of norepinephrine and angiotensin II.28 In
addition to the increased vascular leak, platelet-activating factor and clotting factor dysregulation
creates a hypercoagulable state with bleeding that resembles disseminated intravascular coagulation.
This coagulation disorder is further amplified if patients become hypothermic during their
resuscitation.29 Thus, patient temperature monitoring and maintenance is crucial during resuscitation.
Arachidonic acid metabolism products such as eicosanoids also play a role in burn edema. Eicosanoids
increase prostaglandins such as PGE2 and prostacyclin which cause arterial dilation and increased blood
375
flow and hydrostatic pressure in regions of injury resulting in increased edema.
Changes in cardiac output are also seen acutely in burn patients as these patients often have an
increase in heart rate, and systemic vascular resistance but hypovolemia. Though not defined as
“cardiogenic shock,” cardiac function is altered due to inflammatory mediators.30–33 With appropriate
burn resuscitation, cardiac output should return to normal levels within 24 to 72 hours.
Metabolic Response to Burn Injury

Hypermetabolism is a physiologic response unique to burn injury. Hypermetabolism is characterized by
increased body temperature, glycolysis, gluconeogenesis, proteolysis, lipolysis, and prolonged substrate
cycling.34,35 The degree of the hypermetabolic response is proportional to the size of burn injury and
appears to plateau at 70% TBSA. Overall the basal level of glucose is elevated despite a high insulin
state which can complicate outcomes and exacerbate muscle catabolism.
Lipolysis also occurs at a rate that is higher than normal due to abnormal substrate cycling. This
results in hepatic accumulation of triglycerides causing steatosis. Recent work to combat peripheral
lipolysis has had some success using propranolol.36
Proteolysis is also increased in burn patients compared to nonburn patients. This is due to a
combination of increased muscle breakdown and increased plasma protein production by the liver.
Wound healing requires an increase in protein synthesis leading to the recommendation of enteral
nutrition with elevated protein levels.
There are three ways to influence hypermetabolism: nutrition, medication, and surgery. Current
protocols preferentially recommend continuous enteral nutrition with a high-carbohydrate diet
consisting of 82% carbohydrate, 3% fat, and 15% protein. This diet is thought to stimulate protein
synthesis, increase endogenous insulin production, and improve overall lean body mass when compared
to standard formulas.35
Catecholamines are significantly elevated following a burn injury and are thought to play a role in the
hypermetabolic response. This elevation is one reason why propranolol administration is thought to be
helpful. Interestingly, growth hormone levels have been shown to be decreased in burn shock leading
clinicians to supplement patients with the anabolic steroid oxandrolone in large burn injuries. Positive
results to avoid or reduce the loss of muscle mass with oxandrolone have made its use standard in most
burn units for large TBSA burn patients.37–44 With regard to thyroid hormone, total thyronine and
thyroxin (T3 and T4) are reduced whereas reverse T3 is elevated. Burn injuries also cause alterations in
diurnal glucocorticoid levels leading to persistent hypercortisolemia.
Surgery represents the last way to combat hypermetabolism as early debridement and grafting is the
mainstay to mitigate the hypermetabolic syndrome.
Immunologic Response to Burn Injury

The immune system in burn patients demonstrates significant dysregulation that may explain increased
risk of infection. Serum levels of IgA, IgG, and IgM are decreased indicating decreased B-cell function.
T-cell function or cell-mediated immunity is also impaired which is why prolonged homograft and
xenograft take is seen. Interleukin 2 (IL-2) production is also decreased whereas IL-10 is increased.
Similar to other types of nonthermal trauma, burn patients also have elevated tumor necrosis factor
alpha and IL-6. Polymorphonuclear neutrophils have impaired chemotaxis as well as decreased oxygen
consumption and impaired bactericidal capabilities.
EMERGENCY CARE
Initial care in the field and emergency room is similar to that of any trauma patient. The airway should
be stabilized, IV access should be obtained, concomitant life-threatening injuries should be excluded,
and escharotomies should be performed if there are any circumferential areas of full-thickness injury.
Escharotomies should be placed on the lateral aspects of the extremities avoiding the sites of potential
nerve and large vessel injury (Fig. 12-1). Escharotomies should be extended across the chest if there is
full-thickness injuries and if difficult ventilation arises. Abdominal escharotomies can also help with
ventilation.
376
Figure 12-1. Incision lines for escharotomies. In general incisions should be kept on the lateral aspect of extremities to avoid
damage to neurovascular structures. (From Holzman RS, Mancuso TJ, Polaner DM, eds. A Practical Approach to Pediatric Anesthesia,
2e. Philadelphia, PA: Wolters Kluwer; 2016.)
Table 12-1 Burn Center Referral Criteria45
Guidelines from the American College of Surgeons Advanced Trauma Life Support and the ABA
Advanced Burn Life Support programs have standardized the care of trauma patients and have improved
overall patient outcomes. A complete history and physical should be performed with specific focus
placed on the cause and timing of the injury, risk of smoke inhalation injury, concomitant injuries, and
377
treatments including IV fluids received prior to patient arrival. The primary goal is to stabilize the
patient, ensure standard injury assessment, and transfer to a burn center as necessary. The ABA has
published criteria to follow regarding when to transfer a patient to a verified burn center (Table 12-1).
Airway Assessment
Primary survey assessment should begin with evaluation of the airway. Inhalation injuries occur in
approximately 10% of all burn patients, but are present in 70% of those who eventually die of their
burn injury.46 Thus, it is important to specifically note such findings as soon as the patient presents. Risk
for inhalation injury can be first assessed by the history. In general, patients burned outside (not in an
enclosed space) very rarely suffer inhalational injuries. If, however, the patient was in a burning home
or a burning building, one’s suspicions should be raised. Close physical examination should note facial
burns, changes in voice, shortness of breath, singed nasal vibrissae, carbonaceous sputum, and intraoral
swelling. If these findings are present and the patient appears to be in distress, oral intubation should be
performed immediately by an experienced airway physician. In addition to a laryngoscope, the trauma
team should have a video laryngoscope available and a surgeon present in case a surgical airway is
required. If the patient is not in extremis and the level of inhalation injury is unknown, nasoendoscopy
or bronchoscopy should be performed to directly visualize the airway and vocal cords. If significant
swelling exists and the patient is expected to receive large volume IV fluid resuscitation, the airway
should be immediately secured. If a patient is transferred with an endotracheal tube that the accepting
physician feels is no longer needed, a spontaneous breathing trial should be performed followed by
direct laryngoscopy to assess for cord swelling and assessment for a cuff leak should be performed
before removing the endotracheal tube.
Oxygenation in a burned patient may be altered by carbon monoxide (CO) poisoning. Physical
examination findings include red lips and altered mental status. Formal diagnosis should be based on
history and evidence of CO levels in the blood. CO binding is assessed by measuring the level of
carboxyhemoglobin in a peripheral arterial blood gas sample. Symptoms of CO poisoning typically
begin with headaches at levels around 10%, while CO in the blood becomes lethal at around 50% to
70%. The half-life of CO is normally 4 hours when breathing room air, however, half-life is shortened
considerably with administration of supplemental oxygen. Treatment with 100% oxygen (FiO2 100%)
reduces the half-life of CO to 30 to 90 minutes. Hyperbaric oxygen treatment can reduce the half-life of
CO to 15 to 23 minutes. However, if the patient has additional burn injuries or is unstable, the patient
should not be placed in a hyperbaric chamber. Also, the time needed to transfer patients to hyperbaric
facilities and the subsequent difficulty of resuscitating a critically ill patient in a closed chamber make
hyperbaric oxygen an impractical option. Prompt and aggressive evaluation and maintenance of the
airway is the most important initial step in management of a burn patient.
Fluid Resuscitation
It is important to have large bore IV access with 16- or 18G peripheral IVs. IV access catheters should
preferentially be placed in nonburned areas of skin although this is not always possible. If the patient
will require invasive hemodynamic monitoring, a central line should be placed under sterile conditions.
Peripherally inserted central catheter (PICC) lines can be used in burn patients, however, their infection
rate remains high. If a central line is used, this does not need to be changed out at a certain timepoint
but rather should be monitored daily for signs of infection. Ideally, burn and critical care surgeons
would have access to a minimally invasive monitor of cardiac output. Though several technologies exist
including esophageal Dopplers, arterial waveform monitors, and thermodilution modalities, the trend of
these values is more useful than the absolute values. If a PiCCO device (Pulsion Medical Systems AG,
Munich, Germany) is used to monitor the patient, it is best to have the central venous line located in the
internal jugular vein and the arterial line in the femoral artery. This technology uses thermodilution to
determine cardiac performance. Studies have demonstrated efficacy of this technology when compared
to use of a pulmonary artery catheter.47 Burn injury and soft tissue edema make noninvasive blood
pressure measurement difficult and inaccurate, hence arterial line placement is frequently necessary.
The Parkland or Consensus formula is most commonly used to estimate fluid requirements for the
first 24 hours and should be used to guide initial fluid infusion rates. This is a start point and should not
be construed as a dogmatic prescription of the total fluid volume to be given during the first day after
injury.48 It is extremely important to note that the original time of the injury is used in the calculation,
not the time of initial presentation to care providers. Partial- and full-thickness burns are totaled to
calculate burned TBSA.
378
Consensus formula: First 24-hour requirement= 2–4 cc × %TBSA × weight (kg)
Half of this fluid volume is planned to be administered in the first 8 hours after burn injury and the
second half is administered over the next 16 hours. For example, if a 70-kg patient with 20% TBSA burn
sustained at 10 AM presents 2 hours later, the crystalloid fluid to be administered in the first 8 hours is
calculated using the following formula: ([4 cc × 20% × 70 kg]/2)/6 hours. Lactated Ringers crystalloid
solution is recommended as the first choice fluid to avoid complications associated with metabolic
acidosis.48 Currently data do not support hypertonic saline, dextran, or albumin during the first 24 hours
of resuscitation in standard clinical situations.49,50 Studies have suggested that limited albumin usage
may play a role in reducing the rate of abdominal compartment syndrome when the patient requires
substantially more fluid administration than estimated by the Parkland formula (>1.5 times).51
Additionally, D5/LR is commonly used for maintenance of fluid in children under 1 year of age to avoid
hypoglycemia. Once the Parkland formula is begun, the patient’s vital signs and urine output should be
closely monitored and laboratory studies should be drawn frequently. Although such formulas exist, it is
important to note that proper fluid resuscitation should be guided by overall clinical response and the
trend of vital signs and laboratory values. IV fluid infusion rate should be increased or decreased based
on the response of the patient on an hourly basis with fluid administration titrated to maintain urine
output goals of 0.5 to 1 mL/kg/hr in adults and 1 to 1.5 mL/kg/hr in children. Blood pressure and heart
rate should be monitored; burn patients are often tachycardic regardless of the degree of resuscitation.
Though urine output is considered a “gold standard,” it often lags the fluid status and thus clinicians
must be cautious not to reflexively increase fluids with low urine output but rather consider the entire
clinical picture. In addition, close monitoring of the patient’s laboratories is necessary to determine the
trend in organ perfusion. Laboratory values that help assess organ perfusion include lactate, base deficit,
central venous O2, and/or pH. Although any one of these values alone does not provide a sensitive
marker of the patient status, trending these values during resuscitation can help direct resuscitation
adjustments if the current fluid rate is causing a positive trend. If the end organs are adequately
perfused, decrease in lactate and base deficit as well as increase in central venous O2 and normalization
of pH should be observed.
In the second 24 hours, all patients should receive crystalloid sufficient to maintain urine output and
to maintain parameters of perfusion including lactate, pulse volume variation, and cardiac output.
Infusion rate will often be at a maintenance rate plus adjustment for losses of fluid into the burn wound.
Nutritional support should be started enterally within 24 hours. After 24 to 36 hours, providers can cut
fluids by 1/3 if the patient continues to make adequate urine. One may decrease fluids again by 1/3 for
hours 36 to 48 (assuming urine output does not drop off). Colloid can be given after initial crystalloid
resuscitation (5% albumin at 0.3 to 0.5 mL/kg per %TBSA over 24 hours).
After 48 hours, fluid infusion rate should maintain urine output at 0.5 to 1 mL/kg body weight per
hour. Insensible losses and hyperthermia are associated with hyperdynamic states and increase fluid
requirements. Daily patient weights can be helpful to determine insensible fluid loss or retention.
Pediatric fluid resuscitation does have some differences with regard to fluid management. Due to the
limited reserve in children under 20 kg, a glucose-based maintenance fluid is recommended.
Additionally, fluid requirements may be as high as 6 mL/kg per TBSA and their urine output should be
1.0 to 1.5 mL/kg/hr.52 Since burn resuscitation should be considered in the setting of a 10% TBSA in
children, transfer to a burn center is recommended.
Pulmonary status is also an indicator of fluid status but in a delayed fashion. Complications such as
pulmonary edema result from fluid overload and necessitate daily evaluation of oxygen requirements
and ventilator settings.
Difficult to Resuscitate Patients

If the fluid resuscitation required during the first 24 hours is 1.5 times greater than initially estimated,
the physician should reassess the clinical picture. Giving excessive crystalloid fluids and failure to use
appropriate early resuscitation adjuncts are associated with significantly worse outcomes. Physicians
often will give additional fluid due to low urine output not realizing that the kidney, like other organs
during burn shock, often lags behind the clinical picture. Specific complications associated with
excessive resuscitation include compartment syndrome of both the extremities and the abdomen. Signs
of abdominal compartment syndrome include abdominal distention, decreased urine output, elevated
ventilator pressures, and desaturation. Surgeons should have a low threshold to assess for this
devastating complication in any patient requiring resuscitation above the Parkland formula. Diagnosis
379
can be made both by observing clinical signs as well as by assessment of bladder pressure transduced
through a Foley catheter. Pressures over 20 mm Hg are considered abnormal and pressures greater than
25 mm Hg with evidence of organ failure indicate the urgent need for intervention. Strategies to
intervene should begin with decreasing the rate of fluid administration. If the patient has full-thickness
burns on the abdomen or torso, escharotomies should be performed. The bed should be reclined and a
chemical paralytic can be given to relax the musculature. If elevated bladder pressures remain despite
these maneuvers, a decompressive laparotomy is often required. Some surgeons will attempt
decompression with a suprapubic peritoneal drainage catheter; however, the morbidity of these
procedures is significant in burn patients. Therefore, attempts should be made to minimize fluid
overload with early vigilant monitoring of fluid administration.
When patients are difficult to resuscitate, additional monitoring devices can be used including
monitors of cardiac output and cardiac index. Examples include esophageal Doppler, bedside echo as
well as transthoracic echo. Serial echo examinations after providing a fluid bolus allow monitoring of
cardiac filling, IVC variation, and wall motion changes.53,54
Tetanus Prophylaxis
Burns are considered tetanus-prone wounds and therefore tetanus status should be obtained upon
presentation. Previous immunization within 5 years requires no treatment whereas immunization within
10 years requires a tetanus toxoid booster and unknown immunization requires both.
Escharotomies
Thoracic escharotomy is rarely required, however, if a patient has early respiratory distress, this may be
due to compromised ventilation caused by chest wall inelasticity. If chest wall compliance is limited due
to eschar, thoracic escharotomies should be performed bilaterally in the anterior axillary lines with
additional release under the costal margin. Extremity eschartomy can be limb or digit saving. Edema of
the underlying tissue under the thick, stiff eschar can produce vascular compromise. Though Doppler
and pulse oximeters can be used to follow perfusion, once perfusion is lost, it is often too late to
intervene. Thus, patients with circumferential full thickness extremity burns should have an
escharotomy as soon as their airway is stable and vascular access has been obtained. Extremity
eschartomy should be carried out medially and laterally and should extend the entire area of the full
thickness burns. Additional compartments to assess include the orbital compartment. Opthomology
should be consulted in large volume fluid resuscitation to assess intra-ocular pressure. If abnormally
elevated, a lateral canthotomy should be performed.
BURN SEVERITY
For full-thickness burns and partial-thickness burns, identifying the extent of the burn injury is crucial.
TBSA is useful to guide fluid resuscitation administration and defines the overall prognosis of patients.
Only partial- and full-thickness burns are totaled to calculate TBSA.
Figure 12-2. Rule of 9s used to estimate percent burns in adults (A), children (B), and infants (C). (From Stedman’s Medical
Dictionary for the Health Professions and Nursing, Illustrated, 6e. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.)
If small areas in various distributions are affected, it may be easier to use the patient as a ruler with
380
one palm size (patient’s) representing 1% TBSA. Another useful guide is the rule of 9s, where the adult
body is partitioned into several areas that each constitutes 9% of the TBSA (Fig. 12-2). Regions on the
adult that constitutes 9% of the TBSA include the head and arms, while the legs, anterior trunk, and
posterior trunk account for 18% of TBSA each. In children and infants, the body surface area of the
lower extremities constitutes a lower percentage while the head is higher. Careful estimation of TBSA is
essential for proper early management of burn patients, as patients who have burns of more than 20%
TBSA commonly require IV fluid resuscitation.
Acute burn injuries require prompt intervention and serial examinations. On initial evaluation, it is
important to recognize and treat constrictive circumferential burns that can lead to tissue ischemia and
subsequent necrosis by limiting perfusion to the distal tissues.46 The overarching concept, however, in
acute burn care is early debridement and grafting. All blisters and nonviable tissue must be debrided
upon presentation. After the initial debridement, dressing changes are initiated while the patient is
stabilized from a systemic standpoint. If patients suffer from full-thickness or deep partial-thickness
injuries, debridement and grafting within 72 hours should be the standard of care.
First degree or epidermal burns. These burns only involve the epidermis and therefore do not blister.
They do, however, have erythema and can cause pain. These burns will often desquamate by days 4 to
5.
Superficial partial thickness (second degree). Superficial partial thickness burns include the upper
layers of the dermis and usually form blisters at the interface of the epidermis and dermis. When the
blisters are removed, the wound is pink and wet and often is the site if significant pain. The wound
should blanch with pressure and the hair follicles should be visible. Assuming no infection sets in, these
burns should heal on their own in 3 to 4 weeks. They can be treated with xenograft to decrease pain.
Deep partial thickness (second degree). Deep partial thickness burns extend into the deep or reticular
dermis. These will also blister, but appear a “lobster” red. The patient often has some pain and there is
slow to absent capillary refill with applied pressure. The wound is often dry and if hair is present, it is
usually easily depilated. These burns usually require debridement and grafting.
Full thickness (third degree). Full thickness burns involve all layers of the dermis. These burns appear
white, insensate, and without capillary refill. The skin may appear depressed and leathery compared to
surrounding tissues. These burns require debridement and grafting as nondebrided eschar forms a nidus
for infection and inflammation.
Fourth degree. Fourth degree is used to describe burn into the deeper subcutaneous structures such as
muscle, fat, fascia, and bone. These are common in electrical burns and patients who were either
unconscious or insensate.
CRITICAL CARE OF THE BURN PATIENT

Hemodynamic Monitoring
Ideally, a critical care physician would be able to assess real time responses to fluid administration
through accurate cardiac output readings. Unfortunately, no such noninvasive devices to directly assess
cardiac output exist and those invasive devices that estimate cardiac output lack definitive studies
supporting their use. Some centers use a PiCCO device which provides cardiac output based on
temperature changes and use of the Fick equation, however, this requires a femoral arterial line and a
large bore IJ or SVC catheter which introduce potential for complications. Some surgeons use pulse
volume variation (>25% being abnormal), however, this too lacks accuracy. Though goal-directed
therapies with a pulmonary artery catheter, esophageal Doppler, transesophageal echo, or CVP monitor
have demonstrated promising results in some critical care populations, their use in burn patients has
been mixed.55,56 Frequently, the output of monitors such as pulmonary artery catheters or CVP monitors
fails to reflect the actual resuscitation of the patient.57,58
Ventilator Strategies
Treatment for Inhalational Injury

Manifestations of inhalation injury include wheezing and air hunger. Within a few hours, the
tracheobronchial epilthelium slughs and hemorrhagic tracheobronchitis develops. In cases with thermal
injury interstitial edema can cause acute respiratory distress syndrome (ARDS) and oxygenation
difficulty. If inhalation injury is suspected, the patient should undergo urgent airway assessment and be
381
placed on supplemental oxygen. Inhalation injury has three components that must be considered: (1)
upper airway thermal injury which can cause swelling and obstruction, (2) CO poisoning, and (3) lower
airway chemical injury from toxic agents found in smoke. Upper airway thermal injury is treated by
intubation of the airway and CO poisoning is treated by 100% oxygen administration. Lower airway
injury is diagnosed by evidence of soot or mucosal irritation on bronchoscopy. Airway mucosal injury
from chemical pneumonitis leads to increased secretions while compromising the patient’s ability to
clear those secretions. This leads to increased risk of mucous plugging. Airway mucosal sloughing can
also result in bleeding and clot formation that further obstruct airways. The use of aerosolized heparin,
albuterol, and Mucomyst (HAM) following smoke inhalation to promote airway clearance is advocated
in some centers, however, larger studies are needed to validate these treatments.53,54,59–61
Early endotracheal intubation and mechanical ventilator support are important in patients with
inhalation injury or in large TBSA burns expected to receive large volume resuscitation. Ventilator
management should follow ARDSnet protocol recommendations.62,63 Low volume protective lung
ventilation is used to avoid barotrauma: 4 to 6 mL/kg tidal volume, peak airway pressures should not
exceed 30 cm H2O. Assess best positive end expiratory pressure (PEEP) to determine an optimal setting,
but a PEEP of at least 5 should be used to avoid lung derecruitment. Consider esophageal monitor to aid
in settings if the patient is obese. Recruitment maneuvers may be needed to improve oxygenation
and/or ventilation. Permissive hypercapnia is preferred over large tidal volumes to avoid lung
barotrauma. Limited studies have shown a potential role for high-frequency percussive ventilation in
burn patients.64 Elevating the head of bed to 45 degrees helps decrease airway swelling, prevents
aspiration and ventilator-associated pneumonia (VAP) for ventilated patients. Daily mouth care with
chlorhexidine should be used for ventilated patients.
Pulmonary infection occurs in 30% to 50% of patients. Patients with three of the following five
clinical criteria should be assessed for pneumonia with culture samples and placed on empiric antibiotic
therapy; purulent sputum production, fever, elevated white blood cell count, infiltrate on chest
radiograph, and increasing supplemental oxygen requirements. If the patient has pneumonia and been in
the hospital for over 48 hours, he should be treated for hospital-acquired pneumonia. Sputum or a
bronchoalveolar lavage samples should be sent for aerobic, anaerobic, and quantitative cultures.
Empiric antibiotics including coverage of Pseudomonas sp. should be started until culture results
become available. Empiric treatment should also cover methicillin resistant staphylococcus aureus and
thus vancomycin or linezolid is preferred. If vancomycin is used, drug levels should be followed to
adjust dosage and avoid renal toxicity.
Ventilator-Associated Pneumonia
Staphylococcus aureus and Streptococcus are common causes of early VAP. Pseudomonas aeruginosa is
the most common cause of late VAP. The usual signs of pneumonia (fever, purulent sputum, or
leukocytosis) are not helpful in burn patients since almost all patients are febrile, tachypneic, and have
elevated white blood cell counts. The best diagnostic test is bronchoscopy-obtained bronchial alveolar
lavage sample with quantification of bacteria. Bacterial counts of >103 colony forming units (CFU) are
considered positive. ABA recommendations for length of VAP treatment are 8 days of antibiotic therapy
for antibiotic-sensitive organisms and 15 days of therapy for multidrug-resistant organisms.65
Consideration should be given to antifungal therapy (Diflucan) if the patient does not respond to
prolonged broad-spectrum antibiotics.
Electrolyte Abnormalities and Acute Renal Failure

The immediate effects of burn injury on kidney function are secondary to hypovolemia and circulating
inflammatory mediators. The diuresis phase occurs at 48 to 72 hours after “third space” fluid is
reabsorbed. Hyponatremia is often seen due to large volume resuscitation with hypotonic IV fluids and
will usually self-correct. Open burn wounds or the use of topical silver nitrate can also cause
hyponatremia. Renal hypoperfusion exacerbates hyponatremia by decreasing glomerular filtration.
Hypernatremia may also occur due to insensible and evaporative water losses. Hypophosphatemia can
result from dilution or refeeding syndrome. Hypocalcemia can result from use of silver nitrate.
Acute Kidney Injury

4 Risk factors include sepsis, large TBSA burns, organ failure, and antibiotic administration. Renal
function is compromised by hypoperfusion, pharmacologic nephrotoxic insult, and sepsis which are all
common following major burn injury. Physiologically there is a decrease in renal perfusion, glomerular
382
filtration rate, and renal blood flow. The renal medulla is the most sensitive to hypoxia with damage to
renal tubular cells. Patients present with oliguria and decreased creatinine clearance. Early renal failure
often results from hypovolemia-induced ischemic injury. However, overresuscitation can also
compromise renal perfusion by causing abdominal compartment syndrome. Late renal failure occurs
after the fifth postburn day and is frequently caused by sepsis or nephrotoxic antibiotics. Continuous
renal replacement therapy and pharmacologic treatments such as dopamine have not definitively been
shown to improve outcomes.
The initial care of acute renal failure patients should focus on reversing underlying causes and
correcting any fluid and electrolyte imbalances. The physician should ensure adequate volume status,
avoid nephrotoxins, and dose medications appropriately.
Metabolic Response and Nutrition

Early nutrition is now the cornerstone of burn care. Tube feeding should begin soon after admission.
Attempts to feed postpyloric should be done, however, gastric feeding is also acceptable. Tube feeds are
often needed even in patients who are able to feed themselves due to the need to enable wound healing
and keep up with the hypermetabolic response to burn injuries. Feedings can be continued during
surgery as long as prone positioning is not planned.
The metabolic rate is significantly greater in burn patients than in other critically ill patients and
leads to accelerated lean body mass wasting. Positive nitrogen balance is key to prevent skeletal muscle
breakdown and highlights the importance of early nutritional support. The general composition of
enteral feeding should include at least 60% calories from carbohydrates not exceeding 1,600 kcal/day,
12% to 15% from lipids and essential fatty acids, and 20% to 25% from protein. Failure to meet large
energy and protein requirements can impair wound healing and alter end-organ function. Even though
adequate nutrition is crucial, overfeeding must be avoided. A randomized, double-blind, prospective
study demonstrated that aggressive high-calorie feeding with enteral and parenteral nutrition was
associated with increased mortality.66 The daily caloric requirements can be calculated using the Curreri
formula: ([25 kcal] [body wt kg]) + ([40] [% TBSA area burn]) 1 to 2 g/kg/day of protein for synthetic
needs of the patient. Burn patients should receive a small proportion of calorie requirements from fat
than other ICU patients. The liver in a burn patient produces less very low density lipoprotein causing
hepatic triglyceride elevation. Increased fat leads to increased complications including fatty liver,
infection, hyperlipidemia, hypoxia, and mortality. Decreased gastrointestinal absorption and increased
urinary losses can also lead to deficiencies in vitamin C, E, zinc, iron and selenium. Burn patients, like a
subset of trauma and gastrointestinal surgery patients have been shown to benefit from glutamine
supplementation.
5 Acute response to thermal injury is biphasic with the hypodynamic shock state at 24 to 72 hours
and hyperdynamic catabolic state beginning on the fifth postburn day. Patients have supraphysiologic
cardiac output, elevated body temperature, supranormal oxygen consumption, supranormal glucose
consumption and altered glucose metabolism, increased CO2 production, and accelerated tissue
catabolism. This response is thought to be caused by excessive release of catabolic hormones including
catecholamines, glucagon, and cortisol. There is a shift from anabolic–catabolic homeostasis to
hypercatabolic state requiring increased substrates for energy. The resting metabolic rate is directly
related to the severity of burn injury and a persistent hypermetabolic state is unsustainable. This
hypermetabolism can be reduced by promptly treating sepsis as well as performing early excision and
grafting of burn wounds. Recent studies have shown efficacy of a nonselective beta-blocker such as
propranolol which inhibits the effect of catecholamines and slows muscle catabolism. Herndon et al67
demonstrated that propranolol in acute burns in the pediatric population improved net muscle synthesis
and increased lean body mass. Additionally, current standard of care includes providing pharmacologic
agents such as oxandrolone (testosterone analog given 0.1 mg/kg q12h). Oxandrolone improves muscle
synthetic activity, increases expression of muscle anabolic genes, and increases net muscle protein
synthesis improving lean body mass composition and has been shown to reduce weight loss, improve
donor site wound healing, and decrease hospital stay. Patients with burn injuries greater than 30%
should receive oxandrolone for 6 months as the hypermetabolic state has been shown to persist
following major burn injury. Despite being well tolerated, patients on oxandrolone should have liver
function tests monitored weekly. Human growth hormone and insulin-like growth factor have also been
investigated but results have been indeterminate.
Glucose Control
383
Burn injury results in an increase in hepatic gluconeogenesis and impaired insulin-mediated glucose
transport into skeletal and cardiac muscles and adipose tissue. Hypermetabolism seen in burn injury also
leads to hyperglycemia and insulin resistance and thus glucose should be monitored in large burn injury
patients. Currently, data do not support strict glucose control (<110 mg/dL) but moderate blood
glucose control is recommended (<180 mg/dL) and may decrease infectious complications.68
WOUND MANAGEMENT
There are a variety of burn wound dressing materials. Patient factors such as burn wound depth,
condition, location of the burn, and comfort during dressing changes dictate the choice utilized.47
Although the indications for systemic antibiotic therapy have not been clearly defined, use of
antimicrobial dressings is recommended. Silvadene (silver sulfadiazine) is a silver-containing cream that
has broad-spectrum coverage against both gram-negative and positive bacteria. Silvadene is commonly
used on the skin of both partial- and full-thickness burn injuries. Its use is contraindicated in patients
with sulfa allergies and over wounds near the eyes.69 A self-limited leukopenia is commonly seen during
the initial days of Silvadene treatment, but its use can be continued as leukocyte counts recover quickly
without intervention. Sulfamylon (mafenide acetate) is an analogous agent that is used over
cartilaginous areas such as the nose or ear due to increased tissue penetration compared to other
dressing materials. Since topical Sulfamylon cream can be used without secondary dressing, it can be
used for open burn wound therapy and regular examination of the burn wound surface. Both the cream
and a 5% solution of Sulfamylon are equally effective.70 Sulfamylon cream is useful for ear burns when
there is risk of cartilage exposure. Sulfamylon may cause increased pain in the burn wound. In addition
to the cream, Sulfamylon soaks can also be used for burn and postoperative dressings. Patients receiving
large surface area Sulfamylon dressings should be monitored for complications such as hyperchloremic
metabolic acidosis that can occur due to its mechanism of action as a carbonic anhydrase inhibitor.
Silver nitrate can also be used by soaking dressings in a 0.5% to 1.0% concentration solution and
applied 3 to 4 times a day. These dressings offer several advantages over Sulfamylon soaks as they
cover fungus in addition to bacteria and are more cost effective. If not careful, however, silver nitrate
does cause significant staining of anything it contacts. If grafts are placed in an area with surrounding
cellulitis, silver soaks can be used during the first few days when the compressive dressing is still
needed.
Bacitracin and Xeroform are additional examples of antimicrobial-type dressing regimens and can be
used after the first dressing takedown. While both can be used anywhere on the body, bacitracin is
commonly used for facial burns.
For patients who are at lower risk of infection based on the appearance of burn wounds, dressings
may be changed with less frequency to achieve a balance between pain control and the need for wound
coverage. Acticoat is one such option that is mainly used in partial-thickness burn injuries. This dressing
consists of silver-impregnated sheets that have antimicrobial properties and can be changed less
frequently, reducing pain and cost.71 The nanocrystalline particles in Acticoat are able to reduce wound
infection and promote wound healing compared to older silver products, including silver nitrate.72
When using Acticoat, it is important to remember to moisten it with water and not normal saline as
sodium can inactivate the silver. There are other commercial products in addition to Acticoat that utilize
the principle of nanocrystalline dressings. These dressings can be attached with mild adhesive
(Mepilex), wrapped or placed on like a glove (Silveron).
While dressing changes are sometimes used to optimize a wound before and after operative
interventions, dressings also have the potential to completely heal a wound without the need for
surgical intervention depending on the overall appearance of the burn and patient as a whole. Thus, a
proper wound care team must not only include a critical care physician and surgeon, but it must also
include a specialized wound care nurse to appropriately address this central modality of care for any
burn patient.
Donor sites can be the most painful area for the patient and thus consistent donor site care should be
provided. Like other wounds, these wounds heal in a moist environment and though dry Xeroform can
be used, this can be extremely painful for the patient. We prefer a non-adherent dressing like mepilex
that maintains wound moisture in addition to having an antimicrobial silver.
OPERATIVE INTERVENTIONS
384
Excision and Grafting
After initial stabilization of the patient, which generally takes 24 to 48 hours, surgical intervention
should occur as soon as possible since there are no benefits to delaying surgery when it is clear that a
burn wound is of sufficient depth that it will not heal on its own.73,74 Early excision of devitalized tissue
appears to reduce the local and system effects of mediators released from burned tissue, thus reducing
the progressive pathophysiologic derangements. Excision also removes dead skin which can serve as a
nidus for wound infection. Tangential excision with a sharp blade on a guarded device removes necrotic
tissue while preserving as much of the underlying viable tissue as possible. For large burn wounds,
debridement should occur within 2 to 4 days of the initial injury. If there are insufficient donor sites to
autograft all of the burn wounds, the debrided wound should be covered temporarily with allograft.75
Alternatively, the burn can be completely excised within the first several days after injury, and a
temporary skin substitute can be used to close the wound remaining after available autologous skin has
been harvested and grafted (Fig. 12-3). Sequential debridement and grafting is the backbone of burn
care in those suffering from large TBSA burns. The use of allograft also allows the surgeon to assess the
depth of the injury and the adequacy of excision. If the homograft has good take, then it is likely an
autograft will also take.
Figure 12-3. Full-thickness friction burn staged with integra to allow for full declaration of the wound prior to grafting. Top row
shows initial injury. Middle row shows integra placement and bottom row shows after final debridement and graft.
During tangential excision, tissue is debrided until healthy, bleeding tissue is reached. Hemodynamic
stability and correction of hematologic and metabolic derangements are helpful for such operative cases
given the large amount of blood that may be lost during debridement. A discussion in the preoperative
time out should take place between the surgeon and anesthetist about the amount of blood loss
expected, the blood products available, and the transfusion triggers for the case. Arterial lines as well as
large bore IVs and often a central line should be in place prior to beginning the operation. In general,
hemoglobin fluids are not an accurate during acute blood loss anemia caused by intraoperative bleeding
after a large debridement. In any burn over 20%, a preoperative blood type and crossmatch should be
performed and packed red blood cells should be placed in the operating room to avoid intraoperative
acute blood loss anemia. Several measures can be used to decrease intraoperative blood loss, but the
385
need to debride to bleeding tissue makes bloodless surgery impossible. Techniques to decrease blood
loss include the use of tourniquets on the extremities as well as the use of topical spray thrombin and
epinephrine-soaked Telfa pads placed immediately after excision followed by wrapping this area with
epinephrine-soaked Kerlix gauze. We use 1:1,000,000 epinephrine in a saline solution as a hemostatic
dressing after excision. In regions where circumferential wrapping cannot be performed, epinephrine
solution can be used as an injectable solution to perform dermatoclysis. An 18G spinal needle on the end
of a 60-cc syringe or tumescent device can be used to deliver this solution under the skin in areas of
bleeding. Similarly, we use epinephrine injection solution as a preharvest tumescent solution for donor
sites. This helps create a flat surface on which to run the dermatome and decreases postharvest blood
loss. If working on an extremity, a good strategy is to start proximally and perform the excision
followed by inflation of the tourniquet. Subsequently, the distal excision can be performed under
tourniquet control.
In addition to achieving a healthy and well-vascularized wound bed after debridement, it is also
essential to classify and examine the wounds further during this process. At this time, the distinction
between superficial and deep partial-thickness burns must be made. While superficial partial-thickness
injuries can heal on their own with dressing changes and without grafting, deeper burns must be treated
with skin grafting. Given the association between early debridement and grafting with improved
functional- and scar-related outcomes, the earlier this distinction is made the faster a treatment plan can
be formulated.
Figure 12-4. Grafting back of donor site with 4:1 split-thickness skin graft. (Top) Intraop placement of graft back. (Bottom) 4
weeks postop from graft back.
Grafting exists in many forms and decisions on coverage material and thickness of graft must be made
in a strategic fashion to optimize functional and aesthetic outcomes. The gold standard is to use the
patient’s own tissue or autograft for reconstruction. These grafts can be excised in thicknesses ranging
from 0.008 to 0.018 in, with 0.012 in as a standard. Thinner grafts are helpful if the surgeon is planning
to reharvest donor sites or if the patient has thin skin due to increased age or chronic
immunosuppression, as thin grafts lead to faster donor site healing. Thinner grafts increase the
likelihood of skin graft take and decrease the risk of superficial epidermolysis of the graft, however,
thin grafts also lead to greater secondary contracture. In patients where delayed donor site wound
healing is expected such as elderly patients and patients on chronic immunosuppressives, grafting back
the donor site with 4:1 meshed grafts can accelerate healing (Fig. 12-4).
After a decision regarding the use of allograft versus autograft has been made, attention is turned to
the size and thickness of the skin graft. Commonly, split-thickness skin grafts (STFG) composed of the
epidermis and a thin layer of dermis are utilized to minimize donor site morbidity and optimize graft
take. Thin grafts are more likely to succeed than thick grafts as it is easier to adhere and for
neovascularization to occur. There are certain areas, however, where split-thickness grafts should not be
used since they cause greater secondary contracture and less color match over time as compared to full-
thickness grafts. Areas of function, such as the hands and feet, lose a remarkable amount of utility if
afflicted by scar contracture and may benefit from full-thickness grafts.76 If split-thickness skin is used
on the feet and hands, the grafts should be harvested on the thick side and meshing should be avoided if
possible (Fig. 12-5). Similarly, aesthetically important areas, such as the face, are also more amenable
386
to full-thickness skin grafting (FTSG) to optimize color match and minimize contracture.77 If the cheeks
or periorbital regions are involved, (FTSG) should be placed prior to the development of ectropion
which can be extremely difficult to treat. The abdomen can offer a site for large full-thickness harvest
using an abdominoplasty incision (Fig. 12-6). Full-thickness grafts, nonetheless, are limited by increased
donor site morbidity due to the need to obtain both the epidermis and dermis and also require closing
the tissues primarily to avoid additional wounds. There is also more difficulty with successful and
complete healing of the graft given that a more robust blood supply within the wound bed is necessary
to optimize take of this thicker piece of tissue. Both full- and split-thickness grafts can be meshed to
increase the surface area that may be covered. Commonly performed in a 1:1 or 1:1.5 ratio, meshing
also allows for fluid egress, which minimizes the risk of fluid accumulation beneath the graft, a common
cause of skin graft failure. Meshing should not be performed over cosmetically sensitive areas given
that the meshed pattern will be quite apparent even after complete healing has been achieved. Both
types of skin grafts should be bolstered once placed to minimize shear, improve contact, and allow for
imbibition and inosculation.
Figure 12-5. Sheet grafting of full-thickness hand burns. In general meshed grafts should be avoided on the hands and across
important joints to avoid scar contracture. (Left) Preop photo. (Middle) Intraop photo. (Right) 1-month postop photo.
387
Figure 12-6. Use of full-thickness skin graft to prevent facial ectropion. Full-thickness graft harvested from the abdomen. (Left
column) Intraop photos. (Middle figures) Intraop donor site photos. (Right column) Postop 2-week photo.
When burn injuries lead to large regions of exposed tendons, especially in the distal 1/3 of the lower
extremity, free tissue transfer is often required (Fig. 12-7). It is necessary to ensure all dead tissue is
debrided prior to coverage with a free flap to mitigate infection and flap failure. Additionally, if the
patient is elderly or has vascular insufficiency, a preoperative computed tomography angiogram should
be obtained.
In larger burn wounds, patients may not have an adequate surface area available for donor sites. In
such cases, allograft can be used for initial coverage. This homograft will serve as a temporary coverage
and its take will ensure that the initial excision was performed at the correct depth. Allografts will
eventually be rejected as the body recognizes the newly engrafted skin as foreign material after 10 to
13 days. The process is initiated by the placement of the allografts, which is associated with an
inflammatory process, leading to the activation of the innate immune response. Donor dendritic cells
migrate from the graft to the recipient’s secondary lymphoid organs where they present donor antigens
and elicit an adaptive immune response. This response results in activated effector T cells from the
donor leaving the secondary lymphoid organs and infiltrating the graft where they mediate the rejection
of the allograft.78
If insufficient autograft exists even after temporary allograft, the surgeon should consider use of
cultured epidermal autografts. Cultured epidermal autografts utilize the ability to grow keratinocytes in
vitro to generate cohesive sheets of stratified epithelium, which maintain the characteristics of authentic
epidermis. This technique was developed by Rheinwald and Green in 1975.79 A 3- to 4-cm2 sample is
taken usually from the axilla or pubic area at the time of initial debridement, and epidermal cells are
isolated from the small skin biopsy and plated onto a layer of feeder cells that act as a supporting
“feeder layer.”80 The feeder layer supports optimal clonal expansion of proliferative epithelial cells and
promotes keratinocyte growth. Under optimal growth conditions, keratinocytes initiate growing
colonies and after 3 to 4 weeks, the cultured epidermal autograft sheets are 8 to 10 cells thick.81,82
These constructs require advanced planning as it takes at least 3 to 4 weeks to develop. Additionally,
risks and benefits should be discussed with the family and patient as there is a high percentage of graft
loss due to fragility. Furthermore, case reports of squamous cell cancer developing from cultured
epidermal autograft sites exist.
Order of Coverage
6 The first operations performed in large burn patients set the stage for how quickly a patient will
recover. The first priority should be to excise all eschar and achieve coverage, with autograft if
available or with allograft if not available. In patients with large TBSA burns, it is crucial to get the
back excised and covered first as delay of this step will make it difficult to have a patient stable enough
to tolerate a prone position. Additional strategies to improve coverage of the back include the use of
autograft meshed 3:1 covered with allograft meshed 2:1 and a secure bolster placed over top. This
minimizes sheer and loss of the autograft. Early coverage of the back and avoidance of prone
positioning may also mitigate the need to perform an early tracheostomy. Once the posterior areas of
the patient are excised and covered, then attention can be turned to the anterior regions and the
extremities.
388
Figure 12-7. Use of free anterolateral thigh flap for reconstruction of lateral full-thickness ankle burn with exposed tendon. Top
left shows initial injury. Middle left shows ALT flap inset. Bottom left shows final ALT placement. Top right shows ALT donor site
intra op. Middle left shows donor site 1 week postop. Bottom right shows ALT 1 week postop.
Extremity Treatment
Burns of the hands and feet often require a multidisciplinary approach with involvement of therapists,
hand and plastic surgeons. Early evaluation must verify adequate perfusion. Extremity elevation
benefits hand burns by limiting edema and active range of motion is necessary to maintain function.
Splinting should put the axilla at 90 degrees, elbow in extension and hand in intrinsic plus with the
metacarpophalangeal joints at 70 to 90 degrees and the interphalangeal joint and the wrist in 20- to 30-
degree extension.
Palmar hand or plantar foot burns occur on specialized skin and are composed of a thicker dermal
layer and thus should be managed conservatively. If after 3 to 4 weeks no healing has occurred, full
thickness burns should be considered. Small palmar digit burns can be treated with a full thickness
hyperthenar graft.
Though the hands and feet are important to excise and cover early, these areas require the use of
sheet or 1:1 meshed grafts. These areas should not delay the coverage of large areas such as the back
which can use widely meshed grafts. More important, for the digits, is the use of early K-wire fixation
in the intrinsic plus position in deep burns to the fingers. K-wires should be placed in the fingers to keep
them in the intrinsic plus position: MC flexed at 70 to 90 degrees, wrist 20 to 30 degrees, IP joints in
full extension, and thumb kept abducted and slightly opposed. This will help prevent severe joint flexion
contractures which can lead to the loss of digits if straightened in a delayed fashion.
Genital Burns
Genital burns should be investigated for abuse in children. Burned foreskin must be reduced to a normal
position to avoid paraphimosis. Penile and scrotal burns will often heal without excision and grafting.
Bladder catheterization and urethral stenting is not required for genital burns and increase the risk of
infection.
Skin Alternatives
Integra is a newer alternative for temporary coverage and creation of a neodermis in a wound after
debridement. Composed of bovine collagen and silicone film, this construct is designed to mimic the
epidermis and dermis of the missing tissue.75,83 Its structure allows for the growth of healthy
granulation tissue into a wound bed to optimize the wound niche to promote greater and healthier take
389
of the skin graft that will eventually be placed over the site of injury. This is especially important over
areas of function, such as the hand, which has the potential for significant debility if scar or graft
contracture occurs over the traumatized site. Integra is also important for areas that do not have enough
viable or vascularized tissue to support a skin graft (Fig. 12-3). Integra, however, often fails in burn
patients due to infection and requires constant soaks with Sulfamylon. Additionally, clinicians should
examine the Integra frequently and remove any areas of silicone under which there is concern for
infection.
Figure 12-8. Xenograft treatment of superficial partial-thickness burn to avoid use of STSG and to improve pain. (Top, left)
Intraop photos of superficial partial-thickness burn. (Top, right and bottom, left) Placement of xenograft over burn using
interrupted absorbably sutures. (Bottom, right) 1-month postop from xenograft placement.
Porcine xenografts are an alternative to dressing changes alone in superficial partial-thickness burn
wounds. In wounds that are likely to heal by themselves taking the patient to the operating room,
performing a good debridement under anesthetic, and placement of xenograft to the burn wound can be
beneficial (Fig. 12-8). The xenograft can minimize pain, improve wound healing, and de-escalate the
complexity of dressing changes. This benefit is greatest in children or patients with tolerance to narcotic
pain medications due to excessive pharmacologic supplementation prior to becoming injured.
PAIN CONTROL
Acute Pain
Burn injuries are among the most painful traumatic injuries sustained given their extensive nature.
Thermal injury to the overlying epidermis leads to exposed nerve endings which are sensitive to
stimulation. Thus, superficial partial-thickness burn injuries often cause the most pain to the patient.
Deeper partial-thickness and full-thickness injuries may not cause as much pain to palpation; however,
these regions are still painful due to the inflammatory response. Given the multifactorial nature of burn
pain, elimination of pain in burn patients is not possible. Outcomes are often improved if a dedicated
physician with expertise in pain management is part of the burn team. When establishing a pain
regimen, the physician should focus on treating acute as well as chronic pain. A successful regimen often
includes the use of short- to intermediate-acting narcotics to treat acute pain as well as a long-acting
narcotic such as methadone for chronic pain. Procedural pain during dressing changes can be treated
with short-acting narcotics. Some patients will also benefit from Neurontin to alleviate neurologic pain.
Additional studies are underway to investigate the use of Seroquel for patients with a large anxiety
component associated with their pain. Balancing of narcotic dosing over time is essential to preserve
390
their acute pain relief effect and to avoid situations in which tolerance renders all available agents and
doses ineffective.
Chronic Pain and Substance Abuse

The burn patient population that is admitted with underlying substance abuse and alcohol dependency is
a particular challenge for the burn team to successfully treat with regard to pain relief. In such
circumstances, the team should have high vigilance for symptoms of drug or alcohol withdrawal. New
studies are investigating prophylactic treatment with barbiturates to prevent alcohol withdrawal rather
than currently used strategies which are largely reactionary and treat withdrawal after symptoms occur.
Involvement of psychiatrist or pain specialist in the prescription of these drugs is beneficial. Methadone
can also serve as a helpful adjunct for patients with chronic pain given its decreased addictive potential
relative to other narcotics.
INFECTIONS
Wound Infections
Burn wound sepsis is a severe sequelae of burn injuries caused by colonization of the damaged skin and
soft tissues with infectious bacteria or fungi. The most common organisms are Staphylococcus aureus,
Streptococcus pneumoniae, and Pseudomonas aeruginosa. Despite the morbidity of this complication, its
incidence has decreased dramatically with the use of early excision and grafting and appropriate topical
antibiotics therapy. If burn wound infection is suspected, wound dressings should be taken down and a
quantitative culture should be obtained. A bacterial count of greater than or equal to 105 colony-
forming units bacteria/gram of tissue is considered significant infection, though the data from which
this number was derived date back to the 1960s. General critical care infection protocols should be
followed with burn wound debridement if the patient does not yet have skin grafts placed. If adequate
excision has been performed and the patient already has skin grafts placed, then antibiotic soaks or
cream dressing changes and IV antibiotics will often help combat infection. Quantitative cultures should
be obtained every 3 to 4 days when treating burn wound infection to gauge progress and allow for
escalation or de-escalation of treatment.
Vascular Catheter–Related Infections

Central venous access should be obtained using sterile technique and antibiotic-impregnated catheters as
these have proven efficacious in the general critical care population84 (ref is Pronovost/Keystone).
Additionally, central venous catheters should be placed in nonburned areas if possible. Routine changing
of catheter after a specific time period has not been shown to improve outcomes. However, close
attention should be paid to catheters in place for over 7 days, especially in burn areas if the patient is
febrile and has signs of systemic infection. If a catheter-related infection is suspected, two peripheral
blood cultures should be drawn. A culture specifically from the catheter does not improve diagnosis or
outcomes. Despite the increased use of PICC lines, these catheters have equal if not increased risk of
infection relative to central venous catheters.
Pneumonia
Along with increased survival of burn patients comes increased time burn patients are on the mechanical
ventilator. Increased incidence of pneumonia is seen with inhalation injuries and prolonged intubation
and mechanical ventilation. As in other critical care populations, an emphasis should be placed on daily
awakening and extubation/spontaneous breathing trials. Additionally, all patients on the ventilator
should have their head of bed elevated greater than 30 degrees and daily chlorhexidine mouthwashes
may be beneficial. If a pulmonary infection is suspected, a CXR should be performed and a quantitative
culture specimen should be obtained from the bronchial tree. A quantitative result greater than 103 is
considered positive and should be treated.
Deep Vein Thrombosis

The dangers and need for prophylaxis in general surgical and burn patients have been highlighted in
recent studies. Burn patients have increased risk with increased number of operations, pneumonia, and
central venous access. All inpatients should receive prophylaxis with heparin 5,000 U three times a day
391
or weight-based enoxaparin daily (PMID: 21979849).
BURN RECONSTRUCTION
Optimizing Acute Treatment to Minimize the Need for Reconstruction
As in any plastic and reconstructive surgery case, meticulous planning and foresight is imperative.
During the acute burn injury stages, emphasis should be placed on general coverage of burn wounds and
large flaps and local tissue rearrangements should be delayed. If there is a high likelihood that the
patient might need a flap or local tissue rearrangement in the future, the region of graft harvest should
be carefully planned. For example, if a patient has a large neck burn or exposed lower extremity
tendons or bone and if an anterolateral thigh flap would help, then the thigh should be avoided as a
donor site. Surgeons should consider the fact that a meshed skin graft will have an abnormal appearance
once it heals as well as causing increased hypertrophic scarring. Donor sites should be harvested from
inconspicuous locations in case a hypertrophic scar results. Other examples requiring acute
reconstructive surgery include eyelid contracture with exposure keratitis and cervical contractures
causing airway issues. Once acute grafts and donor sites have healed patients and physicians should
focus on maximizing normal scar healing. Normal wound healing requires a balance in the hydration of
the wound and water-based moisturizers should be encouraged. Silicone sheeting or other occlusive
dressings can help in early hydration of the wound.85–87 Additionally, attempts should be made to
minimize tension off of the scar with potential applications of new devices. Compression garments are
also commonly used to decrease formation of hypertrophic scarring, though their efficacy is still
debated.88,89
Hypertrophic Scarring
Thermal burn injuries can cause tremendous morbidity, leaving the patient with not only cosmetic but
also functional impairments. Hypertrophic scarring is a major complication after burn injury with a
prevalence of 32% to 72%. Several risk factors have been identified that contribute to its development
including the localization of the burn injury, burn depth, time to heal, and skin color.90,91 While the
precise mechanism by which hypertrophic scarring occurs by remain unclear, strong and persistent
expression of transforming growth factor beta (TGF-β), focal adhesion kinase-1 (FAK1) and its receptors
have been associated with postburn hypertrophic scarring. Furthermore, a critical step in the healing
process that is altered is the transition from granulation tissue into normal scarring. During this
remodeling process, wound epithelization and scar collagen are formed but accompanied by a gradual
decrease in cellularity due to apoptosis. However, early immature hypertrophic scars caused by burns
are hypercellular and during the process of remodeling and maturing, fibroblast density does not
resemble that of normal healing.92 Apoptosis of myofibroblasts occurs 12 days after injury in normal
wound healing, but in hypertrophic scar tissue, the maximum apoptosis occurs much later at 19 to 30
months.93 These events result in a significantly higher percentage of myofibroblast and hypertrophy of
the scar tissue following severe burn injuries.
One of the key pathologic factors that must be addressed in any hypertrophic scar is tension. A new
concept of “scar rehabilitation” has emerged with the key idea being to improve the environment of the
scar without actually excising the scar. The most important step in rehabilitating the scar is release of
tension. Rather than excising the scar, this involves just releasing the area of greatest tension. Despite
not removing any tissue, a large defect is often created once the tension is released. This defect can then
be treated by adding new tissue such as a FTSG or a thick STFG. Additional ways to relieve tension
involve the use of tissue rearrangements such as a Z-plasty. A Z-plasty lengthens the scar at the expense
of width alleviating tension along the central axis of the hypertrophic scar. In general Z-plasty
rearrangements are made with 60-degree angles to maximize tissue gain without causing excess tension
on the donor site closure. Alternative V-Y advancements are useful if there is healthy tissue surrounds
the scar and can be advanced into the area of the contracture release. Both Z-plasties and V-Y
advancements relieve tension on the scar that help create the hypertrophic environment. By relieving
this tension, the scars can heal in a more normal environment and often will do so without the raised
erythematous characteristics initially present. The physiology of the Z-plasty is thought to result from
improved collagen remodeling after relief of tension.94,95 Z-plasties can be used to flatten a
hypertrophic scar or elevate a depressed scar as long as the lateral limbs extend into normal tissue. The
classic design of a Z-plasty has a central segment with limbs oriented at 60 degrees (although can be 30
392
to 90 degrees) with all 3 lines of equal length (Fig. 12-9). Widening the angle of the limbs increases
percent gain in length along the central limb. Multiple Z-plasties can be designed in series to improve
contracture release in large hypertrophic scars.
Although less well studied, postburn pruritus is another significant problem affecting almost 100% of
pediatric and 87% adult patients and may persist for many years, resulting in a scratching/inflammation
cycle leading to hypertrophic scarring. Treatment options are limited for postburn pruritus, commonly
involving antihistamines and moisturization of the skin with only incomplete resolution of symptoms
and thus significant deterioration in quality of life.96
Current treatment strategies for hypertrophic scars include surgical manipulation, intralesional
corticosteroid injection, cryotherapy, and laser therapy. Surgical manipulation to remove the excess skin
remains the traditional treatment for hypertrophic scar. Recent studies investigating the role of fat
grafting into scars have shown promise to further improve function and appearance.97 Patients who
have undergone fat transfer reported satisfactory results 6 months after the procedure, indicating
considerable improvement in the features of the skin, skin texture, and thickness. Histologic
examination demonstrates new collagen deposition, neovascularization, and dermal hyperplasia in
regions treated with fat grafting, which mimics surrounding undamaged skin. Intralesional
corticosteroid suppresses the inflammatory process in wounds, diminishes collagen synthesis, and
enhances collagen degradation.98 Conversely, cryotherapy induces vascular damage that leads to anoxia
and ultimately tissue necrosis and has yielded marked improvement of hypertrophic scars.99 Efficacy is
limited to the management of small scars.
Figure 12-9. Z-plasty diagrams demonstrated tissue rearrangement used for hypertrophic burn scars.
LASER SCAR REHABILITATION

7 Since the introduction of laser treatment in the mid-1980s, additional lasers with different
wavelengths have been employed. Encouraging results have been obtained with the 585-nm wavelength
pulsed dye laser (PDL), which has been recognized as an excellent therapeutic option for the treatment
of younger hypertrophic scars.100 PDL induces the dissociation of disulfide bonds in collagen fibers and
leads to collagen fiber realignment, decreased fibroblast proliferation, and neocollagenesis. Repeated
treatments, generally between 2 and 6 are required for the optimal resolution. Shorter-pulse durations
are generally more effective for scar improvement.101 Unlike vascular malformations and hemangiomas,
scars also tend to respond better to low or medium PDL fluences, about 4 to 7 J/cm2, than to higher
fluences.102 Low-, short-pulse duration PDL fluences induce local damage to the vascular endothelium
followed by mural platelet thrombi, while high PDL fluences at longer-pulse durations tend to cause
immediate intravascular coagulation with cessation of blood flow.103 Side effects include
erythema/purpura for 7 to 14 days, hyperpigmentation, and hypopigmentation. Though these lasers are
393
effective in improving scar erythema, they do not have a substantial effect on the thickness or contour
of hypertrophic scars. Controversy still exists about how much of this redness would subside if given
adequate time compared to laser treatments (Fig. 12-10).
Recently, research studies have demonstrated the benefit of fractional photothermolysis in the
treatment of hypertrophic scarring. Though the exact mechanism is unknown, this concept uses a CO2
laser (10,600 nm), which is an ablative laser that targets water in underlying tissues. The laser creates
columns of tissue destruction, which stimulates collagen production in adjacent uninjured columns of
tissue. Only a portion of the epidermis and dermis is treated with columns of energy in order to create
targeted areas of thermal damage (microthermal treatment zones). The untreated areas are a reservoir
of collagen and promote tissue regrowth. Fractional lasers, as opposed to nonfractional lasers allow for
greater penetration with decreased risk of scarring. This healing will take place outside of the acute
inflammation period and thus allow for a more normal wound healing cascade than existed at the time
of the initial excision and graft. The adjacent uninjured tissue allows for more rapid tissue regeneration
from follicles and sweat glands. Ablative lasers have a greater potential depth of treatment compared to
nonablative lasers (4 mm compared to 1.8 mm). Ablative lasers appear to be more effective for thicker
scars and those associated with restriction. Overall, this creates a more smooth appearance and allows
meshed grafts to appear less obvious. Patients have described less tightness as well as decreased
pruritus and improved overall appearance (Fig. 12-11).104
Recent studies also have demonstrated the benefit of fractional CO2 laser for pruritis. Often multi-
modality treatment with PDL for erythematous scars, fractional CO2 laser for thick and pruritic scars
and local tissue rearrangement to relieve tension lead to improved outcomes (Fig. 12-12).
Figure 12-10. Pulsed dye laser scar rehabilitation.
394
Tissue Expansion
A tissue expander (TE) is an artificial filling device that is used to grow and expand local tissue to
reconstruct an adjacent soft tissue defect. A silicone elastomer reservoir is placed beneath the donor
tissue and slowly filled over time with saline, causing the overlying soft tissue envelope to stretch with
a net increase in surface area per unit volume. Advantages to TE are that it allows the surgeon to
reconstruct “like with like” using donor and recipient tissues that share similarities in color, thickness,
texture, and hair-bearing patterns. Larger soft tissue defects that would usually require a local flap for
reconstruction can be closed primarily using expanded local tissue, limiting donor site morbidity. A
robust angiogenic response is achieved histologically within the expanded local tissue resembling an
incisional delay phenomenon. Predictable amounts of donor tissue can be gained through the expansion
process. As a reconstructive technique, it is versatile, reliable, and repeatable, and can be applied to
many regions of the body.
On should use the largest expander possible with a base diameter approximately two to three times
that of the diameter of the soft tissue defect to be reconstructed. If the expander contains a base plate or
rigid backing, this side should be placed along the floor of the pocket to guide the direction of
expansion outward. Multiple expanders are sometimes needed to reconstruct a single defect, depending
on the availability of donor tissue. Rectangular expanders are useful on the trunk and extremities, and
result in the greatest amount of actual tissue gain, however, these should be avoided on the scalp
(approximately 40% of theoretical tissue gain). Round expanders are most commonly used in breast
reconstruction, and result in the least amount of actual tissue gain (approximately 25% of theoretical
tissue gain). Crescent expanders are useful in scalp reconstruction, and gain more tissue centrally than
peripherally. Custom expanders are helpful for irregular defects, but may be more expensive.
Figure 12-11. Ablative laser rehabilitation.
Remote filling ports are connected to the TE via silastic tubing, and can either be placed
subcutaneously (most common) for percutaneous access or externalized for direct access. It is crucial not
to make the tunnel too wide or the filling port will fall and be difficult to fill. Integrated filling ports
are located within the expander, although this design may increase the risk of inadvertent puncture of
the outer shell. The expander is usually placed adjacent and parallel to the long axis of the soft tissue
defect. If placed in the extremities, the expander should not cross any joints or impinge on joint motion.
Donor tissue must be well vascularized, free of unstable scar. Expanders should be used cautiously in
irradiated tissue or patients with poorly controlled diabetes mellitus, vascular disease, or connective
tissue disorders. The expander pocket can be developed in the subcutaneous, submuscular, or subgaleal
planes depending on the location of the soft tissue defect. The size of the expander pocket should be
individually tailored to allow the expander to lie completely flat with minimal wrinkling.
Excessive dissection should be limited to prevent expander migration postoperatively, and meticulous
hemostasis is important to minimize hematoma formation. Incisions are placed radial to the expander
pocket to minimize tension on the incision during the expansion process. Undue tension placed on the
incision during expansion can cause dehiscence and exposure of the expander. One should consider
future reconstructive options when planning incision placement such that the incisions can easily be
incorporated into planned flaps or the tissue to be resected. Endoscopic-assisted expander placement
utilizes smaller incisions and allows more direct visualization of the expander pocket, but at the expense
of a steep learning curve and altered depth perception.
395
Figure 12-12. Multi-modality treatment can result in improved outcomes.
The tissue expansion process usually begins 2 weeks postoperatively and continues on a weekly basis
thereafter. The expander is filled until the patient expresses discomfort or the overlying skin blanches.
The expansion process is complete based on surgeon preference when he/she deems there is enough
donor tissue available to reconstruct the soft tissue defect. Additional “over” expansion is often
recommended to ensure adequate soft tissue coverage.
Disadvantages of tissue expansion include the need for multiple operations (at least two for placement
and removal of the expander) and outpatient visits. Definitive reconstruction is delayed secondary to
the expansion process. Specific complications related to the presence of foreign material can be as high
as 30% (e.g., infection, exposure, or extrusion). This complication risk is higher in the extremities and
scalp.
Specific Anatomic Concerns

Neck contractures are the most common wound healing complication of burn injury. Functionally this
can limit range of motion and oral competence. Surgical release of the scar contracture down to
platysma or subplatysmal layer followed by coverage with large FTSG or thick STSG followed by
aggressive range of motion 5 days after having patient in neck brace is an option for correction. If the
contraction is severe, a free tissue transfer may be required after neck release. Postoperatively it is
crucial to use compression garments for 6 to 18 months and neck bracing to keep the neck extended to
prevent contracture recurrence.
Ectropion is a common complication after periorbital burns. This deformity is caused by inadequate
tissue. If the ectropion is caused by an extrinsic contracture, scar release and provision of additional
tissue are needed to prevent recurrence.
Early ectropion requires early opthalmologic and surgical attention as it can lead to corneal abrasions.
Surgically, the contracted lid should be released and a large full thickness graft should be placed (Fig.
12-11). If excess tension, a midface lift and lateral canthoplasty can provide additional support.
Additionally, temporary or permanent tarsorrhaphies should be placed to protect the globe.
The axilla also represents a common area of contracture because it is difficult to maintain adequate
positioning in the acute phase of burn wound healing. Anatomically the axilla can be divided into the
anterior axillary fold, midaxillary line, and posterior axillary line. The Shoulder should be kept 90 to
120 degrees abduction, 15 to 20 degrees flexion (60 to 80 degrees arm elevation). There are three
grades of axillary contractures:
1A: involves anterior axillary fold
1B: involves posterior axillary fold
2: involves both axillary folds
3: involves both folds and axillary dome
Type 1 and 2 contractures can be treated with sequential release and thick STSGs or FTSGs. Type 3
contractures require local and distant flaps including parascapular and latissimus flaps. It is important to
pay attention to where hair-bearing regions are transposed. Postoperative occupational therapy and
396
splinting are necessary to prevent recurrence.
Nailbed Reconstruction
Eponychial fold and decreasing range of motion of the distal interphalangeal joint (DIP). To improve
the DIP range of motion and proximal to the DIPJ releasing the skin proximally and distally taking care
not to injure the underlying extensor tendon. A full thickness graft is then placed (Fig. 12-12).
ASSOCIATED COMPLICATIONS OF BURN INJURIES

Muscle Catabolism and Wasting
Burn injury involving large areas of the body is associated with significant pathophysiologic sequelae,
which can persist up to several years after the acute injury. There are significant changes in essential
metabolic processes, which shift physiologic homeostasis to a catabolic state, resulting in loss of lean
body mass. The TBSA affected by the burn injury plays an important role, since reestablishing a
functional skin barrier initially takes priority and requires a protein substrate, which is often provided
by skeletal muscle.105
Muscle catabolism after burn injury is mediated by several factors including increased energy
requirement106 and heightened inflammatory state involving the systemic release of stress hormones,
catecholamines, and glucocorticoids, which mediate the underlying metabolic derangements. Other
factors include prolonged immobilization and the loss of a functional skin barrier, which lead to
disturbed thermoregulation requiring increased energy expenditure to maintain body temperature. The
consequences can have devastating effects on the convalescence of pediatric burn patients, where an
increased catabolic state can lead to delayed linear growth for up to 2 years after the injury.107 The
physiologic response of skeletal muscle to anabolic stimuli is altered in pediatric patients with amino
acid infusion therapy failing to stimulate a net protein deposition in skeletal muscle even 6 to 12
months post injury.108,109
Studies investigating the effect of burn injury on physiologic changes in skeletal muscle have
uncovered a critical role for mitochondrial function showing that processes involving carbohydrate
metabolism, lipid metabolism, and oxidative phosphorylation are significantly altered.110 Righi et al.111
demonstrated that treatment with a mitochondria-targeted antioxidant in a mouse burn model
significantly increases mitochondrial ATP secretion and ameliorates oxidative stress, suggesting that
reactive oxygen species play a significant role in burn pathogenesis. Improvements in skeletal muscle
mitochondrial function have also been attributed to the effect of fenofibrate, a peroxisome proliferator-
activated receptor-α agonist used to treat impaired glucose metabolism commonly observed after burn
injury. In pediatric burn patients, fenofibrate treatment improved glucose levels and insulin
sensitivity.112 Other therapeutic approaches, which have shown significant benefit in clinical trials
include the blockage of beta-adrenergic receptors, resulting in attenuated catecholamine effect and
improved net muscle protein balance.67 Anabolic steroids such as oxandrolone, and physical exercise
have been shown to increase lean body mass in children who suffered from >40% TBSA burn injury.113
When the body is in a prolonged catabolic state due to the increase in caloric requirements, patients
must consume at least 2.5 to 3 g/kg/day of protein.75 Nutritional shakes and high-calorie foods are a
necessity to optimize the conditions for wound healing. It is important to start nutrition as soon as
possible, preferentially using the enteric route. Nasogastric or nasoduodenal/jejunal feeding tubes
should be inserted early in the care of this patient population. Dieticians are crucial members of the
burn care team in creating individualized feeding plans and ensuring that nutrition is at the forefront of
daily care. Albumin and prealbumin levels can be trended over time to ensure that adequate
nourishment is achieved.
Patients should also be referred to physical and occupational therapy. A therapeutic exercise program
should be implemented to maintain normal range of motion, strength, and endurance. In order to
counteract the catabolic effects of burn injuries, a program of active and active-assisted exercise is
necessary. Depending on the severity of the burn and the patient’s willingness to tolerate the associated
pain with exercise, passive range of motion exercises should be prescribed. In the event that full range
of motion is not achievable, a program of stretching can be prescribed in its place. Anesthesia can be
used to assist these exercises when patients cannot tolerate pain.
Range of motion exercises can also minimize skin contractures, as skin is a tissue that requires
sustained mechanical stretch to facilitate lengthening of the underlying collagen and extracellular matrix
397
compartments. Initial skin exercises should attempt to elongate the skin with repetitive low loads with
differences in length. Following this initial precondition, a prolonged stretch is applied to maximize skin
laxity. Blanching is a clinical sign that capillary blood flow is impeded and is a good sign that the tissue
has reached its maximum yield point. Strength exercise should follow as soon as the patient can tolerate
it. Strength programs best suited for burn patients should include progressive resistive exercises. Fatigue
and loss of endurance are major issues as a patient recovers. It is important to include endurance
training and monitor cardiopulmonary response. Concurrently, patients should be encouraged to walk as
ambulating patients have fewer lower extremity contractures, endurance problems, and venous
thrombosis.
Heterotopic Ossification
Heterotopic ossification (HO) is the pathologic formation of bone in extraskeletal regions of soft tissue
including muscle, joint spaces, and often encasing major nerves (Fig. 12-13). This complication of burn
injury causes significant pain, joint restriction, and contractures.113 The incidence of HO is proportional
to the severity of the injury with an increased incidence in severely burned patients. HO may affect all
areas of the body but is most frequently encountered in the elbow joint (Fig. 12-13).114,115 While the
etiology of HO remains elusive, common risk factors that have been identified include upper extremity
burns, large TBSA burns, young age, prolonged immobilization116 and a delay in time to wound
closure.117
Early detection and diagnosis of heterotopic bone formation is critical in the clinical management of
this complication, which oftentimes involves surgical resection. The success rates of surgical
intervention are not well established and are associated with a high recurrence rate. Perioperative
radiotherapy has been suggested as an adjunct to surgical resection and has been shown to reduce the
recurrence rate to some extent.118 While the pathophysiologic processes underlying the development of
heterotopic bone formation are poorly understood, several studies have implicated increased
inflammatory signaling and the involvement of progenitor cells as crucial contributing elements.
Pharmacologic interventions have been shown to have some efficacy in limiting the severity of HO.
Bisphosphonates and non-steroidal anti inflammatory have been used for prophylaxis and treatment of
HO with some success.119,120 However, there is no consensus on which drug should be prescribed and
when treatment should begin. It has been proposed that bisphosphonates should be prescribed as soon
as elevated alkaline phosphatase is noted or imaging studies establish the presence of HO. NSAIDs limit
the severity of HO when delivered as a preventative therapy. The primary pathway thought to play a
role is the bone morphogenetic protein (BMP) receptor 1 pathway; specifically the ALK2 kinase domain
which stimulates canonical smad signaling. Though diagnosis is often not made until after 3 to 4 weeks
after the burn injury, pathologic changes occur much sooner and thus treatments should target this early
osteogenic signaling if prophylaxis is to be achieved. The effect of early active and passive range of
motion on HO is unknown. Though the elbow is the most common site, the reason for this high
incidence is unknown.
398
Figure 12-13. Heterotopic ossification.
Marjolin’s Ulcer
Similar to chronic wounds from other etiologies, chronic untreated burn scars can lead to malignant
degeneration. Squamous cell carcinoma is the most common type of malignancy observed. Malignancies
are rare in an era of early excision and grafting. Malignancy requires wide excision with at least a 2 cm
margin as well as sentinel lymph node biopsy. If the sentinel node is positive, a compete lymph node
excision should be performed.
Clinical Research
Clinical research determines the safety and efficacy of medications, devices, diagnostic tools, and
treatment regimens and has provided new insights to effectively care for burn patients. Within the last
decade, critical care, wound care treatment, and burn reconstruction research have advanced in both
diagnosis and identification of efficacious therapies to improve the overall recovery process for burn
victims.
Critical care research has focused on the delivery of adequate care during the initial phase following
the traumatic burn injury. Immediately following the trauma, burn patients experience severe shock due
to concomitant inflammation leading to severe edema. While rigorous fluid resuscitation has been
shown to increase overall survival for patients with high TBSA involvement, novel resuscitation
methods have recently been investigated. In a prospective randomized study, clinicians investigated the
use of colloids within the first 24 hours of resuscitation.121 Patients with a TBSA burn injury greater
than 15% were either provided with crystalloid resuscitation or a mixture of crystalloid and
hydroxyethyl starch. Patients given colloids required less fluid, experienced less edema, and had a lower
C-reactive protein indicative of less inflammation. Additional studies have investigated the use of
therapeutic plasma exchange for refractory burn resuscitation and discovered that patients had reduced
lactate levels, increased mean arterial pressure, and improved urine output after treatment.122 Our
recommendation and common practice use crystalloid rather than colloid as outcomes in burn patients
have not been conclusively shown to be improved. These studies highlight the complexity of burn shock
resuscitation and the need for ongoing research in the field.
Studies have investigated the role of regulating glucose levels in burn patients during the critical
phase. Stress hyperglycemia after severe burn injury has long been established as a physiologic response
to trauma. Recent studies have demonstrated the need for early glycemic control, as burn patients who
did not have optimal glucose levels experienced increased mortality. Intensive insulin therapy in
critically ill burn patients limited the number of infections and sepsis and improved overall organ
function.123 In general moderate glycemic control as demonstrated by the NICE-SUGAR trial appears
399
efficacious.124 Delivery of insulin also decreased inflammatory responses, as noted by decrease levels of
systemic IL-6 and C-reactive protein, and also improved body density, body fat, and lean body mass.
Insulin therapy also reduced resting energy expenditure in the first week following the burn injury,
improved mitochondrial function, and hepatic glucose metabolism.125 Furthermore, the glucose
variability experienced by a burn patient during the critical period is also associated with increased
mortality rates, suggesting that consistent and tight glucose control may provide a significant survival
benefit.126 Taken together, these studies build an argument that in burn patients, glucose control with
insulin therapy may reduce inflammation, improve energy utilization, and improve overall prognosis.
Another important area of research is the development of new technology to aid in wound assessment
and treatment. Punch biopsy, laser Doppler imaging, and near-infrared spectroscopy have been
employed to diagnosis the burn depth and severity of the primary wound site. Additional studies
advocate for the use of confocal laser scanning microscopy (CLSM) due to its greater contrast and
sensitivity. This technology images wounds in vivo without any physical dissection using a laser source.
CLSM was able to determine wound depth by assessing the number of perfused dermal papillae and was
able to accurately classify burns based on the amount of perfusion.127 Recent development of
extracorporeal shock wave treatment (ESWT) has shown promise as it promotes angiogenesis, increases
perfusion, and accelerates wound healing. In a pilot study, patients treated with ESWT demonstrated
increase blood flow to the burn wound within 3 weeks.128 This therapy shows great promise, as it is a
noninvasive measure to improve wound healing.
Advances in burn reconstruction have also been noted in the last decade. While TEs have been a
mainstay of burn reconstruction, several studies have surveyed the use of endoscopic-assisted placement
of expanders and the use of osmotic TEs.129,130 Both endoscope-assisted placement of expanders and
osmotic TEs offer advantages over the traditional methods, as they are more cosmetically acceptable
and require fewer injections, respectively. As TE technology continues to improve with new expansion
techniques and devices, discovering the best technique and devices will be an important component of
burn reconstruction. Cultured epithelial autografts, as discussed in previous sections, have gained
interest as an alternative for cutaneous coverage for patients with large burn wounds and small
potential donor sites. With final engraftment percentages as high as 73% and 90% patient survival rate,
it is an attractive alterative for patients with severe and extensive burns.
BASIC SCIENCE AND TRANSLATIONAL SCIENCE RESEARCH

Basic science and translational science research in burn injuries have significantly advanced in the last
50 years and have focused on both understanding and treating the primary wound site as well as
complications that arise from these traumatic burn injuries.
Wound healing can be described in three different stages: inflammation, proliferation, and remodeling
phase. Hypertrophic scarring is an aberrant form of the normal wound healing process that does not
extend beyond the original wound margins. Hypertrophic scar formation involves the constitutively
active proliferative phase of wound healing, resulting in high vascularity and dense extracellular matrix
deposition.131 Histologic studies suggest that a robust inflammatory response, involving mast cells,
macrophages, fibrocytes, and lymphocytes, may underlie the excessive fibrosis seen in hypertrophic scar
formation.132 The secretion of TGF-beta1, platelet-derived growth factors (PDGFs), and epidermal
growth factor contributes to the inflammatory response and results in excessive inflammatory cell
stimulation, fibroblast proliferation, adhesion, neovascularization, matrix production, and ultimately
contraction.133 As such, translational science research from the bench to the bedside focuses on new
therapies targeted at quenching the inflammatory response, limiting fibrosis, and inhibiting
angiogenesis by targeting the mediators of this scaring process.134,135 Additional basic science research
aimed at understanding the wound healing process and translational science research investigating new
treatment options will continue to advance our understanding and treatment of burn-related injuries.
Additional studies into the precise cause of secondary complications such has HO has gained
significant interest due to the increase in presence of HO in veterans who have sustained combat
injuries. While the precise pathophysiology behind HO is still unclear, it is thought to be related to local
and systemic factors, causing osteoblastic differentiation of local cells. Previous studies have attempted
to elucidate the local and systemic wound inflammatory response leading to HO, through the
identification of cytokine and chemokines secreted from the wound.136 Serum analysis demonstrated a
profound systemic inflammatory response in burn patients, as burn patients maintained increased levels
of IL-6 and macrophage chemoattractant protein (MCP)-1 over time. Both IL-6 and MCP-1 are
400
inflammatory agents that function in recruiting monocytes and macrophages to the site of injury,
indicating sustained inflammation throughout the wound healing process. Furthermore, MCP-1 has also
been implicated in bone remodeling and may be an earlier indicator of HO development. Locally,
proinflammatory cytokine MIP-1 alpha has been shown to be upregulated, indicating robust
inflammation locally. This inflammatory response is believed to enhance bone regeneration; however,
the precise cells and cytokines involved for this enhanced osteogenesis remain unknown. Studies have
shed some light into what might contribute to this enhanced osteogenesis. RUNX2 has been shown to
increase in the presence of macrophages and inflammatory cytokines and this increased expression
results in an increase in bone mineralization.137 Other studies have demonstrated an increase in the
tumor necrosis factor family and ILs, including IL-1, IL6, IL-8, IL-10, IL12, and IL-18.139
The most recent work in this field has focused on BMP signaling as a central mechanism that leads to
ectopic bone formation. Early studies demonstrated that inhibition of transcriptional activity of BMP
type I receptors with antagonists such as noggin and chordin has been shown to disrupt the osteoblast
differentiation signaling pathways.139,140 Mice lacking noggin showed overactivity of BMP and
displayed HO. The role of BMP signaling as an important regulator of ectopic bone formation, along
with other mediators such as PDGF, insulin-like growth factor 1 (IGF-1), and TGF-beta1, continues to be
the focus of research. Identifying pharmacologic therapies that inhibit the overactive inflammatory
response may inhibit the development of HO.141
Additional studies have focused on the identification of progenitor cells responsible for HO. Nesti et
al.140 identified and isolated a population of multilineage mesenchymal stem cells with osteogenic
potential that were localized primarily in traumatized tissue. Mesenchymal stem cells are multipotent,
adult progenitor cells of great interest because of their unique immunologic properties and regenerative
potential.142 These progenitor cells have been shown to promote wound healing and regeneration of
surround tissues by migrating to the site of injury, promoting repair and regeneration of damaged
tissue, modulate the immune and inflammatory response, and secrete trophic factors that are important
in wound healing and tissue remodeling.142–146 Tissue resident progenitor cells are known to be highly
sensitive to the surrounding inflammatory milieu.147,148 Interestingly, a study by Wu et al.149 indicates
that exposure of skeletal muscle satellite cells to the serum of burned rats is sufficient to promote their
osteogenic differentiation, suggesting that both systemic and local inflammations may play a role in
driving stem cell differentiation. In addition, studies have recently shown that burn injury promotes HO
of adipose-derived stem cells in a murine model of scald injury. Microcomputed tomography and
histologic analysis demonstrated increased endochondral ossification in the burn group compared to the
sham control, a process which was most likely mediated through increased vascularization.150 While
resident mesenchymal stem cells seem to be implicated in the pathogenesis of HO, there is reason to
believe that the immunomodulatory properties of these cells may be activated to suppress the
proinflammatory microenvironment when applied externally.151 Further studies are necessary to fully
elucidate the therapeutic utility of these cells.
Other groups have shown that these mesenchymal progenitor cells can be isolated from both health
and traumatized muscles. Both health and traumatized muscles have osteoprogenitor cells that have the
potential to form ectopic bone after injury.140 Laboratories have suggested that cells responsible for HO
are from the endothelium of the local vasculature.152 These studies suggest that in a setting of
chronically stimulated BMP activity, muscle injury and associated inflammation sufficiently trigger
heterotopic bone formation and that cells of vascular origin are essential to the development of ectopic
bone. This cell lineage, along with stimulating factors such as BMP that create the correct environment
for bone formation, could be target for the development of therapeutic interventions to treat HO.153
Further understanding the signaling pathways and the involvement of MSC differentiation is essential
for the development of early diagnostic and prognostic tests and the development of novel prophylactic
therapies.
REHABILITATION
In addition to an increased need for reconstructive surgery secondary to increased survival, there is also
an increased need to focus on functional, social, and psychological rehabilitation. The National Institute
of Disability and Rehabilitation Research (NIDRR) has continued to fund multi-institutional research to
better understand long-term rehabilitative outcomes and needs. Therapists must play an integral role of
inpatient and follow-up care. Inpatient care should include aggressive splinting and range of motion. As
patients transition to discharge, therapists should work on strengthening, performing activities of daily
401
living, and occupational guidance.
NONBURN CONDITIONS COMMONLY CARED FOR IN BURN

CENTERS
Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis syndrome (TENS) have widespread
necrosis of the superficial portion of the epidermis (Fig. 12-14). SJS/TEN is commonly associated with
sulfonamides, trimethoprim-sulfamethoxazole, oxican NSAIDs, chlormezanone, and carbamazepine.
However, a single offending drug is identified in less than 50% of cases. Antibiotic-associated SJS/TEN
presents ~7 days after drug is first taken whereas anticonvulsant-associated SJS/TES can present up to 2
months after drug is first taken. TEN can also be caused by staphylococcal infections in
immunocompromised patients. In general SJS total involvement is defined as less than 10% TBSA with
widespread erythematous or purpuric macules or flat atypical targets are present. TEN has total
cutaneous involvement of greater than 30% TBSA and SJS-TENS overlap involves 10% to 30%. Given
the difficulty distinguishing these from drug eruptions we recommend a biopsy be sent. This biopsy is
also crucial for treatment as steroids are often recommended for drug eruptions but they have not been
shown to improve outcomes in patients with SJS and TENS. It is crucial in these patients to assess the
oral, opthalmologic, and urogenital mucosa. Oral mucosal involvement can create a difficult airway as
the difficult airway team should be present if intubation is necessary. We recommend aggressive
lubrication of the periorbita and an ophthalmology consult if the eyes are involved and OB/Gyn should
be consulted for vaginal mucosal involvement. Treatment of the skin sloughing should include a
nonstick silver impregnated gauze. If large skin involvement we typically use acticoat. Some centers,
however, have demonstrated success with xenograft treatment of large open areas. Currently the data
do not support steroid or intravenous immunoglobulin (IVIG) treatment.
Figure 12-14. Stevens–Johnson syndrome and toxic epidermal necrolysis syndrome.
402
Figure 12-15. Ischemia of the extremities leading to amputation.
Staph scalded skin syndrome has a similar skin appearance to TENS except that it also has positive
blood cultures. These wounds are usually more superficial than TEN and the mucosa and conjunctiva are
typically not involved. Patients should receive empiric and subsequently culture-based
antistaphylococcal antibiotics.
Purpura fulminans often presents after streptococcal or meningococcal sepsis. These patients often
have multisystem organ failure secondary to septic shock and vasopressive treatments for
cardiovascular support. Patients often suffer from ischemia of the extremities. Treatment of the wounds
should be supportive until the patient is stable enough for a definitive operation. Given that tissue death
occurs from ischemia, these patients often require amputations (Fig. 12-15).
CONCLUSION
Burns are responsible for significant morbidity and mortality and are among the most complex and
devastating of all traumatic injuries. Early proper diagnosis of burn depth and extent allows for the
delivery of appropriate treatment ensures the best prognosis for burn patients. Early tangential excision
and autografting remain the foundation of burn treatment. New technologies have advanced the method
of diagnosis from punch biopsies to less invasive imaging studies. Diagnosis of secondary burn
complications, such as joint contracture and HO, has also advanced with new imaging tools, such as the
Raman spectroscopy, that may allow for earlier detection and treatment of ectopic bone formation. The
management of burn patients requires a team of physicians, nurses, critical care specialists, physical
therapists, and counselor to provide optimal care to patients and lessen the burden of the initial burn
injury. Novel clinical, basic science, and translational science researches continue to improve our
understanding of the pathophysiology of burn injuries. By elucidating the pathophysiology of both the
primary wound and secondary complications will assist in the treatment during the critical period and
following the initial trauma and prevent secondary burn complications.
APPENDIX
Burn Resuscitation Flowsheet
403
References
1. American Burn Association National Burn Repository. In. 2013.
2. Association AB. National Burn Repository. In. 2009.
3. Repository NB. Report of data from 1999–2008. In. 2009.
4. Shields B, Comstock R, Fernandez S, et al. Healthcare resource utilization and epidemiology of
pediatric burn-associated hospitalizations, United States, 2000. J Burn Care Res 2007;28:811–826.
5. Conner K, Williams L, McKenzie L, et al. Pediatric pedestrian injuries associated hospital resource
utilization in the United States, 2003. J Trauma 2010;68:1406–1412.
6. CDC. Web-based injury and statistics query and reporting sytem (WISQARS). In: Control CfD, ed.
Center for Disease Control; 2009.
7. Pressel D. Evaluation of physical abuse in children. Am Fam Physician 2000;61:3057–3064.
8. Birky M, Halpin B, Caplan Y, et al. Fire fatality study. Fire Mater 2004;3:211–217.
9. Davidge K, Fish J. Older Adults and Burns. Geriatr Aging 2008;11:270–275.
10. Ryan C, Thorpe W, Mullin P, et al. A persistent fire hazard for older adults: cooking-related
clothing ignition. J Am Geriatr Soc 1997;45:1283–1285.
11. Ryan C, Schoenfeld D, Thorpe W, et al. Objective estimates for the probability of death from burn
injuries. N Engl J Med 1998;338:362–366.
12. Muller M, Pegg S, Rule M. Determinants of death following burn injury. Br J Surg 2001;88:583–
587.
13. Webbenmeyer L, Amelon M, Morgan L, et al. Predicting survival in an elderly burn patient
population. Burns 2001;27:583–590.
14. Bernard S, Paulozzi L, Wallace D; Centers for Disease Control and Prevention (CDC). Fatal injuries
among children by race and ethnicity – United States, 1999–2002. MMWR Surveill Summ 2007;56:1–
20.
15. Fagenholz P, Sheridan R, Harris N, et al. National study of emergency department visits for burn
injuries. J Burn Care Res 2007;28:681–690.
16. Gulaid J, Sacks J, Sattin R. Deaths from residential fires among older people, United States, 1984. J
Am Geriatr Soc 1989;37:331–334.
17. Hunt J, Purdue G. The elderly burn patient. Am J Surg 1992;164:472–476.
18. McGill V, Kowal-Vern A, Gamelli R. Outcome for older burn patients. Arch Surg 2000;135:320–325.
19. Barillo D, Goode R. Fire fatality study: demographics of fire victims. Burns 1996;22:85–88.
20. Mallonee S, Istre G, Rosenberg M, et al. Surveillance and prevention of residential-fire injuries. N
Engl J Med 1996;335:27–31.
21. Istre G, McCoy M, Carlin D, et al. Residential fire related deaths and injuries among children:
fireplay, smoke alarms, and prevention. Inj Prev 2002;8:128–132.
22. Repository ABA-NB. 2012 Report. In. 2013.
23. DiVincenti F, Moncrief J, Pruitt BJ. Electrical injuries: a review of 65 cases. J Trauma 1969;9:497–
404
507.
24. Purdue GF, Hunt JL. Electrocardiographic monitoring after electrical injury: necessity or luxury. J
Trauma 1986;26:166–167.
25. Bruen KJ, Ballard JR, Morris SE, et al. Reduction of the incidence of amputation in frostbite injury
with thrombolytic therapy. Arch Surg 2007;142:546–551; discussion 551–553.
26. Gibran NS, Heimbach DM. Mediators in thermal injury. Semin Nephrol 1993;13:344–358.
27. Santos FX, Arroyo C, Garcia I, et al. Role of mast cells in the pathogenesis of postburn
inflammatory response: reactive oxygen species as mast cell stimulators. Burns 2000;26:145–147.
28. Zhang XJ, Irtun O, Zheng Y, et al. Methysergide reduces nonnutritive blood flow in normal and
scalded skin. Am J Physiol Endocrinol Metab 2000;278:E452–E461.
29. Garcia-Avello A, Lorente JA, Cesar-Perez J, et al. Degree of hypercoagulability and
hyperfibrinolysis is related to organ failure and prognosis after burn trauma. Thromb Res
1998;89:59–64.
30. Maass DL, White J, Horton JW. IL-1beta and IL-6 act synergistically with TNF-alpha to alter cardiac
contractile function after burn trauma. Shock 2002;18:360–366.
31. Carlson DL, Lightfoot E Jr, Bryant DD, et al. Burn plasma mediates cardiac myocyte apoptosis via
endotoxin. Am J Physiol Heart Circ Physiol 2002;282:H1907–H1914.
32. Maass DL, Hybki DP, White J, et al. The time course of cardiac NF-kappaB activation and TNF-
alpha secretion by cardiac myocytes after burn injury: contribution to burn-related cardiac
contractile dysfunction. Shock 2002;17:293–299.
33. White DJ, Maass DL, Sanders B, et al. Cardiomyocyte intracellular calcium and cardiac dysfunction
after burn trauma. Crit Care Med 2002;30:14–22.
34. Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet
2004;363:1895–1902.
35. Fagan SP, Bilodeau ML, Goverman J. Burn intensive care. Surg Clin North Am 2014;94:765–779.
36. Morio B, Irtun O, Herndon DN, et al. Propranolol decreases splanchnic triacylglycerol storage in
burn patients receiving a high-carbohydrate diet. Ann Surg 2002;236:218–225.
37. Jeschke MG, Finnerty CC, Kulp GA, et al. Combination of recombinant human growth hormone and
propranolol decreases hypermetabolism and inflammation in severely burned children. Pediatr Crit
Care Med 2008;9:209–216.
38. Wilkins JP, Suman OE, Benjamin DA, et al. Comparison of self-reported and monitored compliance
of daily injection of human growth hormone in burned children. Burns 2003;29:697–701.
39. Ramirez RJ, Wolf SE, Herndon DN. Is there a role for growth hormone in the clinical management
of burn injuries? Growth Horm IGF Res 1998;8(suppl B):99–105.
40. Jeschke MG, Wolf SE, DebRoy MA, et al. The combination of growth hormone with hepatocyte
growth factor alters the acute phase response. Shock 1999;12:181–187.
41. Klein GL, Wolf SE, Langman CB, et al. Effects of therapy with recombinant human growth hormone
on insulin-like growth factor system components and serum levels of biochemical markers of bone
formation in children after severe burn injury. J Clin Endocrinol Metab 1998;83:21–24.
42. Herndon DN, Pierre EJ, Stokes KN, et al. Growth hormone treatment for burned children. Horm Res
1996;45(suppl 1):29–31.
43. Herndon DN, Hawkins HK, Nguyen TT, et al. Characterization of growth hormone enhanced donor
site healing in patients with large cutaneous burns. Ann Surg 1995;221:649–656; discussion 656–
659.
44. Herndon DN, Barrow RE, Kunkel KR, et al. Effects of recombinant human growth hormone on
donor-site healing in severely burned children. Ann Surg 1990;212:424–429; discussion 430–431.
45. Committee on Trauma. Excerpted from Guidelines for the Operation of Burn Centers (pp. 79–86),
Resources for Optimal Care of the Injured Patient 2006, American College of Surgeons.
http://www.ameriburn.org/BurnCenterReferralCriteria.pdf
46. Bezuhly M, Fish JS. Acute burn care. Plast Reconstr Surg 2012;130:349e–358e.
47. Branski LK, Herndon DN, Byrd JF, et al. Transpulmonary thermodilution for hemodynamic
measurements in severely burned children. Crit Care. 2011;15(2): R118. doi:10.1186/cc10147.
48. Thorne C. Grabb and Smith’s Plastic Surgery. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
405
49. Cartotto R, Callum J. A review of the use of human albumin in burn patients. J Burn Care Res
2012;33:702–717.
50. Melinyshyn A, Callum J, Jeschke MC, et al. Albumin supplementation for hypoalbuminemia
following burns: unnecessary and costly! J Burn Care Res 2013;34:8–17.
51. Park SH, Hemmila MR, Wahl WL. Early albumin use improves mortality in difficult to resuscitate
burn patients. J Trauma Acute Care Surg 2012;73:1294–1297.
52. Graves TA, Cioffi WG, McManus WF, et al. Fluid resuscitation of infants and children with massive
thermal injury. J Trauma 1988;28:1656–1659.
53. Stawicki SP, Hoff WS, Cipolla J, et al. Use of non-invasive esophageal echo-Doppler system in the
ICU: a practical experience. J Trauma 2005;59:506–507.
54. Wang GY, Ma B, Tang HT, et al. Esophageal echo-Doppler monitoring in burn shock resuscitation:
are hemodynamic variables the critical standard guiding fluid therapy? J Trauma 2008;65:1396–
1401.
55. Dai NT, Chen TM, Cheng TY, et al. The comparison of early fluid therapy in extensive flame burns
between inhalation and noninhalation injuries. Burns 1998;24:671–675.
56. Schiller WR, Bay RC. Hemodynamic and oxygen transport monitoring in management of burns.
New Horiz 1996;4:475–482.
57. Lorente JA, Ezpeleta A, Esteban A, et al. Systemic hemodynamics, gastric intramucosal PCO2
changes, and outcome in critically ill burn patients. Crit Care Med 2000;28:1728–1735.
58. Holm C, Melcer B, Horbrand F, et al. Haemodynamic and oxygen transport responses in survivors
and non-survivors following thermal injury. Burns 2000;26:25–33.
59. Kashefi NS, Nathan JI, Dissanaike S. Does a nebulized heparin/N-acetylcysteine protocol improve
outcomes in adult smoke inhalation? Plast Reconstr Surg Glob Open 2014;2:e165.
60. Miller AC, Rivero A, Ziad S, et al. Influence of nebulized unfractionated heparin and N-
acetylcysteine in acute lung injury after smoke inhalation injury. J Burn Care Res 2009;30:249–256.
61. Palmieri TL, Enkhbaatar P, Bayliss R, et al. Continuous nebulized albuterol attenuates acute lung
injury in an ovine model of combined burn and smoke inhalation. Crit Care Med 2006;34:1719–
1724.
62. Salman D, Finney SJ, Griffiths MJ. Strategies to reduce ventilator-associated lung injury (VALI).
Burns 2013;39:200–211.
63. Peck MD, Koppelman T. Low-tidal-volume ventilation as a strategy to reduce ventilator-associated
injury in ALI and ARDS. J Burn Care Res 2009;30:172–175.
64. Chung KK, Wolf SE, Renz EM, et al. High-frequency percussive ventilation and low tidal volume
ventilation in burns: a randomized controlled trial. Crit Care Med 2010;38:1970–1977.
65. Mosier MJ, Pham TN. American Burn Association Practice guidelines for prevention, diagnosis, and
treatment of ventilator-associated pneumonia (VAP) in burn patients. J Burn Care Res 2009;30:910–
928.
66. Herndon DN, Barrow RE, Stein M, et al. Increased mortality with intravenous supplemental feeding
in severely burned patients. J Burn Care Rehabil 1989;10:309–313.
67. Herndon DN, Hart DW, Wolf SE, et al. Reversal of catabolism by beta-blockade after severe burns.
N Engl J Med 2001;345:1223–1229.
68. Hemmila MR, Taddonio MA, Arbabi S, et al. Intensive insulin therapy is associated with reduced
infectious complications in burn patients. Surgery 2008;144(4):629–635.
69. Atiyeh BS, Costagliola M, Hayek SN, et al. Review effect of silver on burn wound infection control
and healing: review of the literature. Burns 2007;33:139–148.
70. Falcone PA, Harrison HN, Sowemimo GO, et al. Mafenide acetate concentrations and bacteriostasis
in experimental burn wounds treated with a three-layered laminated mafenide-saline dressing. Ann
Plast Surg 1980;5:226–229.
71. Fong J, Wood F. Nanocrystalline silver dressings in wound management: a review. Nanomedicine
2006;1:441–449.
72. Gravante G, Caruso R, Sorge R, et al. Nanocrystalline silver: a systematic review of randomized
trials conducted on burned patients and an evidence-based assessment of potential advantages over
older silver formulations. Ann Plast Surg 2009;63:201–205.
406
73. Engav L, Hiembach D, Reus J, et al. Early excision and grafting vs. nonoperative treatment of burns
of indeterminant depth: a randomized prospective study. J Trauma 1983;23:510–517.
74. Gray D, Pine R, Harnar T, et al. Early surgical excision versus conventional therapy in patients with
20 to 40 percent burns. A comparative study. Am J Surg 1982;144:76–80.
75. Mulholland MW. Greenfield’s Surgery. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
76. Sterling J, Gibran NS, Klein MB. Acute management of hand burns. Hand Clin 2009;25:453–459.
77. Klein MB, Moore ML, Costa B, et al. Primer on the management of face burns at the University of
Washington. J Burn Care Res 2005;26:2–6.
78. Benichou G, Yamada Y, Yun SH, et al. Immune recognition and rejection of allogeneic skin grafts.
Immunotherapy 2011;3:757–770.
79. Ronfard V, Rives JM, Neveux Y, et al. Long-term regeneration of human epidermis on third degree
burns transplanted with autologous cultured epithelium grown on a fibrin matrix. Transplantation
2000;70:1588–1598.
80. Atiyeh BS. Cultured epithelial autograft (CEA) in burn treatment: three decades later. Burns
2007;33:405–413.
81. Elliott M, Vandervord J. Initial experience with cultured epithelial autografts in massively burnt
patients. ANZ J Surg 2002;72:893–895.
82. Paddle-Ledinek JE, Cruickshank DG, Masterton JP. Skin replacement by cultured keratinocyte
grafts: an Australia experience. Burns 1997;23:204–211.
83. Brown D, Borschel GH. Michigan Manual of Plastic Surgery. Philadelphia, PA: Lippincott Williams &
Wilkins; 2004.
84. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-
related infections. Healthcare Infection Control Practices Advisory Committee. Am J Infect Control
2011;39(4 suppl 1):S1–34. doi:10.1016/j.ajic.2011.01.003
85. Tandara AA, Mustoe TA. The role of the epidermis in the control of scarring: evidence for
mechanism of action for silicone gel. J Plast Reconstr Aesthet Surg 2008;61:1219–1225.
86. Mustoe TA. Evolution of silicone therapy and mechanism of action in scar management. Aesthetic
Plast Surg 2008;32:82–92.
87. Saulis AS, Chao JD, Telser A, et al. Silicone occlusive treatment of hypertrophic scar in the rabbit
model. Aesthet Surg J 2002;22:147–153.
88. Steinstraesser L, Flak E, Witte B, et al. Pressure garment therapy alone and in combination with
silicone for the prevention of hypertrophic scarring: randomized controlled trial with
intraindividual comparison. Plast Reconstr Surg 2011;128:306e–313e.
89. Van den Kerckhove E, Stappaerts K, Fieuws S, et al. The assessment of erythema and thickness on
burn related scars during pressure garment therapy as a preventive measure for hypertrophic
scarring. Burns 2005;31:696–702.
90. Lawrence JW, Mason ST, Schomer K, et al. Epidemiology and impact of scarring after burn injury:
a systematic review of the literature. J Burn Care Res 2012;33:136–146.
91. Gangemi EN, Gregori D, Berchialla P, et al. Epidemiology and risk factors for pathologic scarring
after burn wounds. Arch Facial Plast Surg 2008;10:93–102.
92. Nedelec B, Shankowsky H, Scott PG, et al. Myofibroblasts and apoptosis in human hypertrophic
scars: the effect of interferon-alpha2b. Surgery 2001; 130:798–808.
93. Armour A, Scott PG, Tredget EE. Cellular and molecular pathology of HTS: basis for treatment.
Wound Repair Regen 2007;15:S6–S17.
94. Longacre JJ, Berry HK, Basom CR, et al. The effects of Z plasty on hypertrophic scars. Scand J Plast
Reconstr Surg 1976;10:113–128.
95. Davis JS. The relaxation of scar contractures by means of the Z-, or reversed Z-type incision:
stressing the use of scar infiltrated tissues. Ann Surg 1931;94:871–884.
96. Parnell LK, Nedelec B, Rachelska G, et al. Assessment of pruritus characteristics and impact on burn
survivors. J Burn Care Res 2012;33:407–418.
97. Klinger M, Marazzi M, Vigo D. Fat injection for cases of severe burn outcomes: a new perspective
of scar remodeling and reduction. Aesthetic Plast Surg 2008;32:465–469.
98. Reish RG, Eriksson E. Scar treatments: preclinical and clinical studies. J Am Coll Surg 2008;206:719–
407
730.
99. Zouboulis CC, Blume U, Buttner P, et al. Outcomes of cryosurgery in keloids and hypertrophic
scars. A prospective consecutive trial of case series. Arch Dermatol 1993;129:1146–1151.
100. Alster TS, Handrick C. Laser treatment of hypertrophic scars, keloids, and striae. Semin Cutan Med
Surg 2000;19:287–292.
101. Manuskiatti W, Wanitphakdeedecha R, Fitzpatrick RE. Effect of pulse width of a 595-nm flashlamp-
pumped pulsed dye laser on the treatment response of keloidal and hypertrophic sternotomy scars.
Dermatol Surg 2007;33:152–161.
102. Manuskiatti W, Fitzpatrick RE, Goldman MP. Energy density and numbers of treatment affect
response of keloidal and hypertrophic sternotomy scars to the 585-nm flashlamp-pumped pulsed-
dye laser. J Am Acad Dermatol 2001;45:557–565.
103. Garden JM, Tan OT, Kerschmann R, et al. Effect of dye laser pulse duration on selective cutaneous
vascular injury. J Invest Dermatol 1986;87:653–657.
104. Manstein D, Herron GS, Sink RK, et al. Fractional photothermolysis: a new concept for cutaneous
remodeling using microscopic patterns of thermal injury. Laser Surg Med 2004;34:426–438.
105. Gore DC, Chinkes DL, Wolf SE, et al. Quantification of protein metabolism in vivo for skin, wound,
and muscle in severe burn patients. JPEN J Parenter Enteral Nutr 2006;30:331–338.
106. Jeschke MG, Gauglitz GG, Kulp GA, et al. Long-term persistance of the pathophysiologic response
to severe burn injury. PLoS One 2011;6:e21245.
107. Rutan RL, Herndon DN. Growth delay in postburn pediatric patients. Arch Surg 1990;125:392–395.
108. Tuvdendorj D, Chinkes DL, Zhang XJ, et al. Skeletal muscle is anabolically unresponsive to an
amino acid infusion in pediatric burn patients 6 months postinjury. Ann Surg 2011;253:592–597.
109. Porter C, Cotter M, Diaz EC, et al. Amino acid infusion fails to stimulate skeletal muscle protein
synthesis up to 1 year after injury in children with severe burns. J Trauma Acute Care Surg
2013;74:1480–1485.
110. Padfield KE, Astrakas LG, Zhang Q, et al. Burn injury causes mitochondrial dysfunction in skeletal
muscle. Proc Natl Acad Sci U S A 2005;102:5368–5373.
111. Righi V, Constantinou C, Mintzopoulos D, et al. Mitochondria-targeted antioxidant promotes
recovery of skeletal muscle mitochondrial function after burn trauma assessed by in vivo 31P
nuclear magnetic resonance and electron paramagnetic resonance spectroscopy. FASEB J
2013;27:2521–2530.
112. Cree MG, Zwetsloot JJ, Herndon DN, et al. Insulin sensitivity and mitochondrial function are
improved in children with burn injury during a randomized controlled trial of fenofibrate. Ann Surg
2007;245:214–221.
113. Przkora R, Herndon DN, Suman OE. The effects of oxandrolone and exercise on muscle mass and
function in children with severe burns. Pediatrics 2007;119:e109–e116.
114. Elledge ES, Smith AA, McManus WF, et al. Heterotopic bone formation in burned patients. J
Trauma 1988;28:684–687.
115. Esselman PC, Thombs BD, Magyar-Russell G, et al. Burn rehabilitation: state of the science. Am J
Phys Med Rehabil 2006;85:383–413.
116. Evans EB. Orthopaedic measures in the treatment of severe burns. J Bone Joint Surg Am
1966;48:643–669.
117. Klein MB, Logsetty S, Costa B, et al. Extended time to wound closure is associated with increased
risk of heterotopic ossification of the elbow. J Burn Care Res 2007;28:447–450.
118. Maender C, Sahajpal D, Wright TW. Treatment of heterotopic ossification of the elbow following
burn injury: recommendations for surgical excision and perioperative prophylaxis using radiation
therapy. J Shoulder Elbow Surg 2010;19:1269–1275.
119. Orzel J, Rudd T. Heterotopic bone formation: clinical, laboratory, and imaging correlation. J Nucl
Med 1985;26:125–132.
120. Neal B, Rogers A, Clark T, et al. A systematic survey of 13 randomized trials of non-steroidal anti-
inflammatory drugs for the prevention of heterotopic bone formation after major hip surgery. Acta
Orthop Scand 2000;71:122–128.
121. Fearonce G, Faraklas I, Saffle J, et al. Peripherally inserted central venous catheters and central
venous catheters in burn patients: a comparative review. J Burn Care Res 2010;31:31–35.
408
122. Neff L, Allman J, Holmes H. The use of therapeutic plasma exchange (TPE) in the setting of
refractory burn shock. Burns 2010;36:372–378.
123. Cartotto R, Zhou A. Fluid creep: the pendulum hasn’t swung back yet! J Burn Care Res
2010;31:551–558.
124. Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill
patients. N Engl J Med 2009;360:1283–1297.
125. Webbenmeyer L, Sevier A, Liao J, et al. The impact of opioid administration on resuscitation
volumes in thermally injured patients. J Burn Care Res 2010;31:40–47.
126. Pidcoke H, Wanek S, Rohleder L, et al. Glucose variability is associated with high mortality after
severe burn. J Trauma 2009;67:990–995.
127. Altintas MA, Altintas AA, Knobloch K, et al. Differentiation of superficial-partial vs. deep-partial
thickness burn injuries in vivo by confocal-laser-scanning microscopy. Burns 2009;35:80–86.
128. Arno A, Garcia O, Hernan I, et al. Extracorporeal shock waves, a new non-surgical method to treat
severe burns. Burns 2010;36:477–482.
129. Sood R, Roggy D, Zieger M, et al. Cultured epithelial autografts for coverage of large burn wounds
in eighty-eight patients: the Indiana University experience. J Burn Care Res 2010;31:559–568.
130. Sood R, Balledux J, Koumanis D, et al. Coverage of large pediatric wounds with cultured epithelial
autografts in congenital nevi and burns: results and technique. J Burn Care Res 2009;30:576–586.
131. Ehrlich H, Desmoulière A, Diegelmann R, et al. Morphological and immunochemical differences
between keloid and hypertrophic scar. Am J Pathol 1994;145:105–113.
132. Wulff B, Parent A, Meleski M, et al. Mast cells contribute to scar formation during fetal wound
healing. J Invest Dermatol 2012;132:458–465.
133. Wilgus T, Bergdall V, Tober K, et al. The impact of cyclooxygenase-2 mediated inflammation on
scarless fetal wound healing. Am J Pathol 2004;165:753–761.
134. Peranteau W, Zhang L, Muvarak N, et al. IL-10 overexpression decreases inflammatory mediators
and promotes regenerative healing in an adult model of scar formation. J Invest Dermatol
2008;128:1852–1860.
135. Gordon A, Kozin E, Keswani S, et al. Permissive environment in postnatal wounds induced by
adenoviral-mediated overexpression of the anti-inflammatory cytokine interleukin-10 prevents scar
formation. Wound Repair Regen 2008;16:70–79.
136. Potter B, Fosberg J, Davis T, et al. Heterotopic ossification following combat-related trauma. J
Bone Joint Surg Am 2010;92:74–89.
137. Guihard P, Danger Y, Brounais B, et al. Induction of osteogenesis in mesenchymal stem cells by
activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells 2012;30:762–772.
138. Pignolo R, Xu M, Russell E, et al. Heterozygous inactivation of Gnas in adipose-derived
mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic
ossification. J Bone Miner Res 2011;26:2647–2655.
139. Hannallah D, Peng H, Young B, et al. Retroviral delivery of Noggin inhibits the formation of
heterotopic ossification induced by BMP-4, demineralized bone matrix, and trauma in an animal
model. J Bone Joint Surg Am 2004;86-A:80–91.
140. Nesti L, Jackson W, Shanti R, et al. Differentiation potential of multipotent progenitor cells derived
from war-traumatized muscle tissue. J Bone Joint Surg Am 2008;90:2390–2398.
141. Zhang K, Wang L, Zhang S, et al. Celecoxib inhibits the heterotopic ossification in the rat model
with Achilles tenotomy. Eur J Orthop Surg Traumatol 2013;23:145–148.
142. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol
2008;8:726–736.
143. Caplan A. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell
Physiol 2007;213:341–347.
144. Chamberlain G, Fox J, Ashton B, et al. Concise review: mesenchymal stem cells: their phenotype,
differentiation capacity, immunological features, and potential for homing. Stem Cells
2007;25:2739–2749.
145. Phinney D, Prockop D. Concise review: mesenchymal stem/multipotent stromal cells: the state of
transdifferentiation and modes of tissue repair–current views. Stem Cells 2007;25:2896–2902.
409
146. Gimble J, Katz A, Bunnell B. Adipose-derived stem cells for regenerative medicine. Circ Res
2007;100:1249–1260.
147. Mountziaris PM, Spicer PP, Kasper FK, et al. Harnessing and modulating inflammation in strategies
for bone regeneration. Tissue Eng Part B Rev 2011;17:393–402.
148. Nelson ER, Wong VW, Krebsbach PH, et al. Heterotopic ossification following burn injury: the role
of stem cells. J Burn Care Res 2012;33:463–470.
149. Wu X, Rathbone CR. Satellite cell functional alterations following cutaneous burn in rats include an
increase in their osteogenic potential. J Surg Res 2013;184(2):e9–16.
150. Peterson JR, De La Rosa S, Sun H, et al. Burn injury enhances bone formation in heterotopic
ossification model. Ann Surg 2014;259(5):993–998.
151. Djouad F, Bouffi C, Ghannam S, et al. Mesenchymal stem cells: innovative therapeutic tools for
rheumatic diseases. Nature reviews. Rheumatology 2009;5:392–399.
152. Lounev V, Ramachandran R, Wosczyna M, et al. Identification of progenitor cells that contribute to
heterotopic skeletogenesis. J Bone Joint Surg Am 2009;91:652–663.
153. Hsu J, Keenan M. Current review of heterotopic ossification. J Orthopaedics 2010;20:126–130.
410
Chapter 13
Anesthesiology and Pain Management

Sachin Kheterpal and Michael R. Mathis
Key Points
1 Anesthetics are generalized depressants of consciousness, pain, cardiopulmonary function, motor

function, and recall.
2 To prevent movement and to facilitate the surgical exposure, neuromuscular blocking agents are
generally used. These drugs are competitive or noncompetitive inhibitors of the neurotransmitter
acetylcholine at the neuromuscular junction.
3 Residual neuromuscular blockade is a common and underappreciated phenomenon that impacts
postoperative adverse events such as hypoxemia, pneumonia, reintubation, and prolonged recovery
room stay. Suggamadex, a novel medication capable of reversing deep neuromuscular blockade, may
revolutionize perioperative care for high-risk patients.
4 Opioids produce profound analgesia and respiratory depression. They have no amnesic properties,
minimal direct myocardial depressive effects, and no muscle-relaxant properties.
5 Propofol is unique because it is rapidly cleared through hepatic metabolism to inactive metabolites
in a way that the patient becomes alert soon after cessation of the infusion. However, as the
duration and dose of the maintenance infusion is increased, the time to return of consciousness is
also significantly increased.
6 Although neuraxial techniques may decrease pulmonary complications, they are associated with
hemodynamic instability and are contraindicated in patients with severe flow-dependent
cardiovascular diseases.
7 Peripheral nerve blockade can be used in lieu of general anesthesia as a primary anesthetic for
surgery, or in conjunction with general anesthesia to serve as a postoperative pain management
technique. Use of long-acting local anesthetics or placement of an indwelling continuous catheter
provides long-term (16 hours to several days) pain relief.
8 The concept of airway management should be focused on not just endotracheal intubation, but also
mask ventilation. Until the airway can be secured via intubation, the patient must be supported
through mask ventilation. The key elements of an airway examination are an assessment of obesity,
mouth opening, neck flexion and extension, Mallampati oropharyngeal classification, presence of
beard, and mandibular protrusion ability.
9 Laryngeal mask airways offer an alternative to endotracheal intubation for general anesthesia
airway management in selected patients and procedures.
10 More than 8% of patients undergoing major noncardiac surgery will experience postoperative
myocardial ischemia, elevating their risk of 30-day mortality. Benefits must be weighed against risk
of initiating preoperative beta-blockers, alpha-blockers, and aspirin.
11 The appropriate duration to defer elective surgery after coronary stenting remains controversial, but
recent guidelines from the American College of Cardiology/American Heart Association recommend
365 days for drug-eluting stents and 30 days for bare-metal stents. The role for antiplatelet therapy
remains a major question, but data suggest that cessation of recommended antiplatelet therapy in
the perioperative period may have significant coronary thrombotic risks without major
improvement in bleeding adverse events.
12 The three goals of the preoperative evaluation are (a) to develop an anesthetic plan that considers
the patient’s medical condition, the requirements of the surgical procedure, and the patient’s
preferences; (b) to ensure that the patient’s chronic disease is under appropriate medical therapy
before an elective procedure; and (c) to gain rapport with and the confidence of the patient, answer
any questions, and allay fears.
13 Patients receiving chronic pain or opioid addiction therapy with buprenorphine (Subutex, Suboxone)
can be particularly challenging to manage in the postoperative period and should be immediately
411
referred to their primary care physician and an anesthesiologist to create a pain management plan
prior to the day of surgery. Buprenorphine is mixed opioid agonist/antagonist that tightly binds at
the μ-receptor and has a long and varied half-life (24 to 60 hours). It can inhibit the analgesic
benefits of traditional opioids in the postoperative period, resulting in uncontrolled pain, decreased
patient satisfaction, and the potential for adverse events due to the need for very high doses of
opioids.
14 As positive-pressure ventilation impedes venous return within a closed thorax, decreases in systolic
pressure associated with a respiratory pattern can be detected. In patients with sinus rhythm with
stable cardiac contractility, the degree of systolic pressure variation (SPV) is inversely related to the
intravascular volume status of the patient. The normal range of SPV is 5 to 10 mm Hg. Other
measures such as pulse pressure variation (PPV) use similar physiologic assumptions to assess
volume status.
15 Enhanced recovery programs incorporating preoperative optimization, standardized surgical and
anesthesia protocols, and goal directed therapy may improve patient outcomes and reduce costs.
16 Postoperative acute pain management may require a multimodal approach that incorporates opioids,
peripheral nerve blockade, and nonopioid analgesics. Chronic pain patients can be particularly
difficult to manage and may require preoperative optimization by an anesthesiologist.
The goal of intraoperative anesthesiology interventions is to enable the safe conduct of otherwise
painful interventional procedures with maintenance of patient cardiopulmonary, renal, and neurologic
homeostasis while optimizing procedural conditions. The state of general anesthesia is a combination of
hypnosis, amnesia, analgesia, and muscle relaxation. This state can be achieved by administration of
single or multiple anesthetic agents via inhalational or intravenous routes. Historically, anesthesia was
achieved by inhaling volatile anesthetic vapors that produced each of these conditions in proportion to
the concentration achieved in the central nervous system. Anesthesia can also be achieved by using a
balance of multiple pharmacologic agents, each targeted to produce a specific effect. These are the
hypnotic/sedatives, analgesics, and neuromuscular blocking agents. As the concentration of
hypnotic/sedative and analgesic agents increases, cardiovascular and respiratory functions may be
progressively blunted. For this reason, modern anesthetics usually require titration of these agents to
optimize conditions for the surgery while maintaining cardiovascular stability.
Surgical anesthesia is administered with a high degree of safety 30 to 40 million times a year in the
United States, despite the serious potential complications of technical or judgment errors. The high
degree of success of both surgical and anesthetic outcomes is due to the efforts of thousands of surgeons
and anesthesiologists who have advanced the art and science of their field.1 Although modern surgical
techniques, regional or neuraxial blockade procedures, and systemic analgesics have made it possible to
ameliorate perioperative pain, significant challenges in postoperative pain management remain. Pain
not only is unpleasant, but also can provoke a stress response within the body, leading to significant
adverse physiologic effects.
ANESTHETIC AGENTS AND THEIR PHYSIOLOGIC EFFECTS

Inhalation Agents
1 Anesthetics are generalized depressants of consciousness, pain, cardiopulmonary function, motor
function, and recall. The potent inhalation agents (e.g., isoflurane, sevoflurane, desflurane) produce
these effects in a dose-dependent fashion. The measurement used to compare the potency of inhalation
agents is the minimum alveolar concentration (MAC), an empirically derived number defined as the
expired percent concentration required to prevent movement on painful stimulation (incision) in half of
experimental subjects. There is significant patient-to-patient variability independent of underlying
comorbidities. Compounding this variability are the effects of age, weight, pre-existing heart disease,
liver disease, and medications other than the inhalational anesthetic. Table 13-1 lists the modern
commonly used inhalation agents and their MACs and side effects. In general, all agents depress blood
pressure by myocardial depression and vasodilation, resulting in systemic hypotension. There is a
generalized depression of cerebral function and cerebral metabolic rate of oxygen consumption,
although cerebral blood flow may increase because of cerebrovascular dilatation and a loss of flow-
metabolism coupling. Renal blood flow and glomerular filtration rate are reduced by 20% to 50%. The
412
body’s normally tight regulation of core body temperature is lost, resulting in a redistribution of heat
from the core to the periphery. The combination of these effects, the cold environment of the operating
room, and open body cavities make the patient extremely vulnerable to hypothermia (core body
temperature <36°C).
Intravenous Sedatives/Hypnotics
Several commonly used intravenous sedative/hypnotic medications can also be used in lieu of an
inhalational anesthetic to achieve the hypnotic component of the state of anesthesia. A constant
intravenous infusion of these medications is used to achieve and maintain a blood concentration that
results in the loss of consciousness and prevents recall. Unlike the inhalational agents, currently, there is
no ability to measure the patient’s expired or blood concentration of these intravenous agents. As a
result, the infusion rate is titrated to effect by observing patient movement (if muscle relaxants are not
used concurrently) and hemodynamic responses to procedural stimuli. Of note, the sedative/hypnotic
intravenous agents do not possess clinically useful muscle relaxant or analgesic properties and must be
combined with other agents to deliver a “balanced” anesthetic. The most commonly used intravenous
agent for maintenance of anesthesia is propofol, a lipid-soluble substituted isopropyl phenol, that
produces hypnosis and sedation through interactions with Γ-aminobutyric acid (GABA), the primary
inhibitory neurotransmitter of the central nervous system. When administered as a continuous infusion,
propofol can achieve minimal levels of sedation, deep sedation, or general anesthesia. Additional details
regarding the use and side effects of propofol are discussed later. Other classic agents such as
benzodiazepines can also be used as maintenance infusions, but do not enable the rapid return to
consciousness that propofol offers. A novel, highly specific α2-receptor agonist, dexmedetomidine, has
recently demonstrated an exciting role as an intravenous sedative/hypnotic that also has analgesic
effects and a lack of respiratory depression. In the perioperative setting, it is currently limited to use as
an adjunct to propofol and inhalational anesthetics for general anesthesia or as a sole agent during
procedural sedation.
Table 13-1 Common Inhalation Agents: Minimum Alveolar Concentrations and

Effects
Muscle Relaxants
2 To prevent movement and to facilitate the surgical exposure, neuromuscular blocking agents are
generally used. These drugs are competitive or noncompetitive inhibitors of the neurotransmitter
acetylcholine at the neuromuscular junction. The only noncompetitive inhibitor used clinically is
succinylcholine. This drug rapidly binds to the nicotinic receptors and produces depolarization at the
neuromuscular junction, clinically manifesting as fine-muscle fasciculations occurring about 30 to 60
seconds after injection. Succinylcholine cannot be reversed, but has a short duration of action (<10
minutes) because it is quickly hydrolyzed in the plasma by cholinesterase. Because of rapid onset and
short duration of action, succinylcholine is frequently used to facilitate endotracheal intubation when it
must be accomplished quickly, or when quickly regaining neuromuscular function is beneficial.
All other clinically useful muscle relaxants are termed competitive inhibitors and do not cause
depolarization when they attach at the neuromuscular junction (nondepolarizing). Because these agents
413
compete with endogenous acetylcholine, the block produced is in direct proportion to the concentration
of the agent relative to the concentration of acetylcholine. If the concentration ratio is low enough,
competitive relaxants can be reversed if the concentration of acetylcholine is artificially elevated.
Acetylcholine concentration can be increased by giving a drug that blocks its metabolism, an
anticholinesterase (e.g., neostigmine). The neuromuscular blocking agent is still present, but motor
function returns if the acetylcholine concentration is high enough to overwhelm the blocking agent.
There is a ceiling to which anticholinesterase drugs can safely elevate circulating acetylcholine; above
this threshold, a novel selective relaxant binding agent, suggamadex, may be used to reverse the effects
of specific nondepolarizing neuromuscular blocking drugs (rocuronium and vecuronium). Using
anticholinesterases to reverse neuromuscular relaxants is not analogous to using naloxone to reverse the
effects of opioids. The reversal agent neostigmine does not compete or combine with the relaxant.
Unfortunately, there are systemic consequences to increasing the plasma concentration of
acetylcholine. Acetylcholine is the predominant neurotransmitter in the preganglionic sympathetic and
parasympathetic nervous systems and in the postganglionic parasympathetic nervous system. For this
reason, an anticholinergic drug (atropine or glycopyrrolate) must be given with the anticholinesterase
to prevent the undesirable effects of a generalized acetylcholine overdose. Given these side effect
profiles of anticholinesterase drugs, the selective relaxant binding agent suggamadex – recently
approved for use in the US – offers new promise for reversing high levels neuromuscular blockade. The
common neuromuscular blocking drugs and their doses, durations, and side effects are listed in Table
13-2; common regimens of reversal agents are shown in Table 13-3.
3 Postoperative residual neuromuscular blockade is now recognized as a common problem after
routine administration of nondepolarizing muscle relaxants. The evaluation of depth of muscle
relaxation is a subjective process based upon empirical pharmacokinetics or visual inspection of a
patient’s peripheral nerve response to an artificial electrical stimulation. During peripheral nerve
stimulator monitoring, two electrode patches are placed on the patient’s skin along the course of a
peripheral nerve which innervates a distinct and observable muscle group. Commonly used monitoring
locations include the ulnar nerve, ophthalmic branch of the facial nerve, or the posterior tibial nerve.
Next, the electrodes are connected to a hand-held device which delivers four short transcutaneous bursts
of electricity, ranging from 10 to 100 mA every 0.5 seconds, hence the term “train-of-four monitoring.”
A clinician visually inspects the response to each electrical stimulation. In a patient without any
pharmacologic neuromuscular blockade, the strength of the fourth muscle response (or “twitch”)
matches that of the first. In the face of complete pharmacologic competitive inhibition of neuromuscular
transmission, no muscular twitches are observed at all. At varying levels of neuromuscular blockade in
between, the fourth, third, or second twitch may be absent. Due to competitive blocking of the
neuromuscular junction nicotinic receptor, each incremental stimulation results in a weaker response
because of increasingly limited receptors available for stimulation. The ratio between the strength of
the fourth twitch and the first twitch is known as the train-of-four ratio. During normal neuromuscular
transmission, the ratio is 1. Historically, a ratio of 0.7 was considered adequate muscular strength for
extubation. However, more recent literature suggests that a ratio between 0.7 and 0.9 still exposes the
patient to significant risks of atelectasis, hypoxemia, aspiration, pneumonia, and possibly reintubation.
In routine practice, a clinician is incapable of assessing a concept as precise or nuanced as train-of-four
ratio. As a result, the number of twitches observed is typically reported, that is, 0/4, 1/4, 2/4, 3/4, 4/4.
A patient with 3/4 or 4/4 twitches is capable of responding to cholinesterase inhibitors and return to
normal function. A patient with 0/4, 1/4, or 2/4 is unlikely to respond to cholinesterase inhibitors with
full return of muscular strength. Data from multiple centers have demonstrated that a significant
proportion of patients demonstrated residual neuromuscular blockade of <0.9 in the recovery room
despite reversal.
Table 13-2 Common Neuromuscular Blocking Drugs and Reversal Agents
414
Table 13-3 Drugs for Antagonizing Nondepolarizing Neuromuscular Blockadea
The use of subjective train-of-four monitor is inferior to objective acceleromyography, a calibrated

device used to accurately establish the train-of-four ratio. It requires careful calibration and setup, and
access to the patient’s arm and hand. Although clinically effective at eliminating the limitations of
subjective train-of-four monitoring, its use remains limited because of the time spent in set up, and an
underappreciation of the frequency of residual neuromuscular blockade. It has been promoted by
patient safety experts, and is beginning to demonstrate increased penetration in Europe.
In addition to the limitations intrinsic to nerve monitoring devices themselves, nerve monitoring must
be performed with caution, as muscles in the body are not equally sensitive to muscle relaxants. The
diaphragm is most resistant to neuromuscular blockade, whereas the neck and pharyngeal muscles that
support the airway are most sensitive. It is possible for an intubated patient to spontaneously ventilate
and even to produce a large negative inspiratory effort and yet develop complete airway obstruction
when extubated because of the effects of residual muscle relaxant on the upper airway muscles.
As described earlier, a novel class of compounds known as selective relaxant binding agents, – currently
comprised of only one FDA-approved drug, suggamadex – may serve to revolutionize the practice of
neuromuscular blockade and its reversal. Such compounds are able to rapidly reverse the effects of
profound levels of muscle relaxation (0/4 twitches) created by steroidal nondepolarizing muscle
relaxant agents such as rocuronium, vecuronium, or pancuronium. Rather than attempting to increase
the concentration of acetylcholine, these agents physically bind free muscle relaxant molecules within a
cyclodextrin ring structure. This decreases the concentration of free muscle relaxant and allows
acetylcholine to function normally at the neuromuscular junction. The cyclodextrin–muscle relaxant
combination is then eliminated via the kidney. This offers the ability to rapidly (<3 minutes) reverse
profound muscle relaxation as surgical conditions warrant.2 This will enable profound relaxation during
wound closure, and then immediate reversal of blockade just prior to extubation. Its significant expense,
approximately $US 200 for a single dose of reversal of deep blockade, has limited its use.
Opioids (Narcotics) and Other Intravenous Analgesics

4 Narcotics and synthetic analogues belong to the class of drugs called opioids. The most commonly used
drugs in this family are morphine, fentanyl, and hydromorphone. Since the mid-1980s, a series of
synthetic opioids have been developed with fentanyl as the prototype. More recently developed
415
synthetics (sufentanil, alfentanil, and remifentanil) are more potent and of varying duration (Table 13-
4). Opioids produce profound analgesia and respiratory depression. They have no amnesic properties,
minimal direct myocardial depressive effects, and no muscle-relaxant properties. Opioids can produce
significant hemodynamic effects indirectly by releasing histamine or blunting the patient’s sympathetic
vascular tone because of analgesic properties. The latter effect depends on the degree of sympathetic
tone that is present at baseline. Acutely injured patients may be hypovolemic and in pain, with high
sympathetic tone and peripheral vascular resistance. Patients in this condition can experience dramatic
drops in systemic blood pressure with minimal doses of opioids. For this reason, it is important to titrate
narcotics in small incremental doses. Because of the lack of direct myocardial depression and the
absence of histamine release with the synthetic opioids, they are frequently used as the primary
anesthetic in combination with an amnesic agent and a muscle relaxant in patients with significant
myocardial dysfunction.
When opioids are titrated intravenously, patients first become apneic because of the respiratory
depressive effect (shifting the CO2 response curve), but they still breathe on command. As the dose
increases, patients become apneic and unresponsive.
Opioids are primarily analgesic and not amnesic. Patients can be totally aware and have substantial
recall of conversations despite appearing completely anesthetized. All opioids can be reversed with
naloxone. The duration of action of naloxone can be shorter than that of the opioid, and patients must
be observed carefully for renarcotization after they have been treated with naloxone. Naloxone reversal
of opioids can be dangerous because the agent acutely reverses not only the analgesic effects of the
opioid but also the analgesic effects of native endorphins. Naloxone treatment has been associated with
acute pulmonary edema and myocardial ischemia and should not be used electively to reverse the
effects of a narcotic. It is appropriately used in an emergency situation when the airway is poorly
controlled and the patient is not ventilating because of an opioid overdose.
Table 13-4 Analgesics
Propofol
5 Propofol is a lipid-soluble substituted isopropyl phenol that produces a rapid induction of anesthesia in
30 seconds followed by awakening in 4 to 8 minutes after a single bolus. Intravenous propofol can
effectively produce total anesthesia (for less stimulating procedures), including amnesia, some
analgesia, and some degree of muscle relaxation. Propofol is unique because it is rapidly cleared
through hepatic metabolism to inactive metabolites in a way that the patient becomes alert soon after
cessation of the infusion. However, as the duration and dose of the maintenance infusion is increased,
the time to return to consciousness is also significantly increased. This context-sensitive half-life of
propofol must be incorporated into expectations of a “quick wake-up.” Propofol has direct antiemetic
properties and is a valid alternative to inhalational anesthetics in patients who have demonstrated a
history of prolonged, refractory postoperative nausea and vomiting. It has an important role in
intensive care units when used as a continuous infusion sedative at dosages of 25 to 50 μg/kg/min.
However, prolonged infusions have been associated with a lethal metabolic derangement known as
propofol infusion syndrome, characterized by a profound metabolic acidosis and cardiovascular
compromise.3 Due to dose-dependent direct myocardial depression and peripheral vasodilation, propofol
can produce significant hypotension when IV induction doses are administered. It also produces
416
significant pain on injection in peripheral veins. Pain can be diminished or eliminated by pretreatment
with IV lidocaine via the vein to be used for propofol administration. Propofol is insoluble in aqueous
solution and therefore comes dissolved in a lipid emulsion that has the associated risk of bacterial
contamination. Once a vial of propofol is opened, it is not recommended that it be used after 12 hours.
Ketamine
Ketamine is a phencyclidine derivative that produces anesthesia characterized by dissociation between
the thalamus and limbic systems. Induction of anesthesia is achieved within 60 seconds after IV injection
of 1 to 2 mg/kg or within 2 to 4 minutes of intramuscular (IM) injection of 5 to 10 mg/kg. Patients
appear to be in a cataleptic state in which their eyes remain open with a slow nystagmic gaze. The drug
produces intense amnesia and analgesia but has been associated with unpleasant visual and auditory
hallucinations that can progress to delirium. The incidence of these problems can be significantly
reduced if benzodiazepines are also administered with the drug. At low doses (0.1 to 0.2 mg/kg IV or 2
mg/kg IM), patients continue to spontaneously ventilate, but cannot be expected to protect the airway
should vomiting occur. At higher doses, ketamine acts as a respiratory depressant and produces
complete apnea. Ketamine also has direct and indirect sympathetic nervous system stimulatory effects,
which can be useful in hypovolemic patients. These effects are diminished or absent in patients who are
catecholamine depleted. The sympathetic stimulatory effect increases myocardial oxygen consumption
and intracranial pressure, and ketamine is relatively contraindicated in patients with ischemic heart
disease or space-occupying intracerebral lesions. Owing to its analgesic properties and relatively
preserved respiration, ketamine is frequently used as an IV analgesic during debridement procedures, at
doses listed in Table 13-4. IM ketamine (1 to 2 mg/kg) is also very useful for sedating patients who are
difficult to manage (e.g., combative or cognitively disabled patient), so IV access can be obtained.
Ketamine’s most frequent use is in subanesthetic doses as part of multimodal analgesic regimens hoping
to minimize the use of opioids. For procedures requiring general anesthesia that may have significant
postoperative opioid requirements, a preincision ketamine bolus dose with a low-dose intraoperative
infusion may be associated with improved acute and chronic pain outcomes.4
Amnesics and Anxiolytics

Benzodiazepines are the primary class of agents used as amnesics and anxiolytics. The prototype drug,
diazepam, has been more recently replaced by its water-soluble analog of shorter duration, midazolam.
Lorazepam also belongs in this family of agents, but because it has a very long duration of action, it is
not routinely used intraoperatively. Lorazepam has intensive care unit applications (Table 13-5).
Benzodiazepines produce anxiolysis and some degree of amnesia, but have no analgesic properties.
Intraoperatively, midazolam is always used in conjunction with an opioid or inhalation agent.
Midazolam can be used in combination with the short-acting opioid fentanyl to produce conscious
sedation for minor procedures. Benzodiazepines can produce apnea and have synergistic adverse effects
with narcotics. Very small doses of midazolam and fentanyl can quickly produce an unconscious apneic
patient. As with all anesthetics, benzodiazepines used as IV agents for sedation should be given in small
incremental doses to achieve the desired effect. A reversal agent is also available for benzodiazepines
(flumazenil). The recommended dosages of these drugs and the reversal agents appear in Table 13-5.
Table 13-5 Anxiolytics and Amnesics (Benzodiazepines)
417
Local Anesthetics
Local anesthetics constitute a class of drugs that temporarily block nerve conduction by binding to
neuronal sodium channels. As the concentration of the local anesthetic increases around the nerve,
autonomic transmission will be blocked first, followed by sensory transmission, and then motor nerve
transmission. These drugs can be injected locally into tissue to produce a field block, around peripheral
nerves to produce a specific dermatomal block, around nerve plexuses to produce a major conductive
block, or into the subarachnoid or epidural space to produce extensive neuraxial blockade. All the
methods have been used to assist in the provision of an alternative form of balanced anesthesia by
supplementing analgesia and muscle relaxation.
Adverse consequences associated with the use of local anesthetics fall into three categories: acute
central nervous system toxicity due to excessive plasma concentration, hemodynamic and respiratory
consequences due to excessive conduction block of the sympathetic or motor nerves, and allergic
reactions. Whenever a local anesthetic is injected, there can be inadvertent intravascular injection or an
overdose of the drug because of rapid uptake from the tissues. Overdose can produce seizures, as well
as cardiovascular collapse from ensuing arrhythmias. Complications can be minimized by withdrawing
before injection to avoid an intravascular injection and limiting dosages to the safe range (Table 13-6).
Table 13-6 Local Anesthetics
6 When local anesthetics are administered for a spinal or epidural block, they produce a progressive
blockade of the sympathetic nervous system, which produces systemic vasodilation. Sympathetic nerves
travel along the thoracolumbar region with the first four thoracic branches, including the cardiac
sympathetic accelerators. A sympathetic blockade of this entire region produces a characteristic
profound systemic vasodilatation and bradycardia. This condition is referred to as total sympathectomy,
and the hypotension that ensues is usually below the minimal cerebral perfusion pressure required to
maintain consciousness. Affected patients are bradycardic, hypotensive, unconscious, and usually apneic.
This disastrous situation is easily remedied if treated quickly with a vasopressor (phenylephrine or
ephedrine) and atropine or small doses of epinephrine (increments of 10 μg for an adult). If not treated
promptly, the situation proceeds to cardiac arrest. In this emergency situation, the treatment of high
doses of epinephrine is 10 to 40 μg/kg, or 1 to 4 mg for an adult. The doses of epinephrine are higher
than in a usual cardiac arrest because of the total sympathectomy.5 Because the level of sympathetic
block is two to six dermatomal levels higher than the sensory block, it is often difficult to obtain a high
spinal sensory level without approaching a total sympathectomy. For this reason, spinal or epidural
techniques can present a prohibitively high risk in patients with severe flow-dependent cardiovascular
disease.
Local anesthetics are chemically divided into two groups: esters and amides. The esters (2-
chloroprocaine and tetracaine) produce metabolites that are related to p-aminobenzoic acid and have
been associated with allergic reactions. Amides (lidocaine and bupivacaine) are rarely associated with
allergic reactions. If an allergic reaction does occur, it is most likely due to the preservative
(methylparaben) used in multidose vials of lidocaine.
418
NEURAXIAL BLOCKADE
Although general anesthesia is employed for millions of surgical procedures each year in the United
States, many operations can be performed safely using neuraxial blockade. The two primary neuraxial
techniques, a “single-shot” spinal and continuous epidural catheter, can be used for lower extremity and
lower abdominal procedures. In both techniques, a small dose of local anesthetic is administered near
spinal nerve roots in order to temporarily ablate sensory input from the peripheral somatic and visceral
structures. In the case of a spinal anesthetic – also known as a subarachnoid block – the intrathecal sac
surrounding the cauda equina at vertebral interspace L2-L3 or below is located using a sterile, small-
caliber needle (25 gauge typically). Once cerebrospinal fluid is observed in the hub of a needle, 1 to 2
mL of preservative-free local anesthetic (typically bupivacaine or lidocaine) is injected into the
intrathecal space. The needle is then completely withdrawn. This local anesthetic serves to directly
inactivate efferent and afferent transmission at the nerve roots it comes in contact with. Because local
anesthetics are not specific to specific nerve fiber types, blockade of sensory, motor, and sympathetic
nerves occurs. The spread of local anesthetic within the subarachnoid space is primarily determined by
three factors: (a) the vertebral interspace accessed, (b) the density of the local anesthetic in relation to
the density of cerebrospinal fluid (a concept known as baricity), and (c) the position of the patient
during injection and immediately thereafter. In order to eliminate the risk of needle puncture of the
spinal cord, subarachnoid blocks are only performed below L2-L3 in adults and L3-L4 in children. The
local anesthetic solution may be combined with vasoconstrictors such as epinephrine or opioids such as
fentanyl or morphine in order to increase the density or duration of the sensory blockade. Surgical
anesthesia ranging from 1 to 2 hours can be achieved using a subarachnoid block. Because of concerns
regarding permanent nerve damage, intrathecal catheters are typically not used.6,7 As a result, most
subarachnoid blocks are “single-shot” techniques that cannot be redosed.
In the case of epidural techniques, the nerve roots are blocked outside the thecal sac in potential
space between the ligamentum flavum and dura mater. This space is accessed sterilely using a 19-gauge
introducer needle and a loss of resistance technique. Once the space is identified, a 21-gauge catheter is
inserted into the space via the introducer needle and the needle is removed. After testing to reduce the
likelihood of inadvertent intravascular or intrathecal placement of the catheter, the epidural catheter
can be taped in place. Because the epidural catheter can be left in place for several days, redosing is
possible. Dilute local anesthetics combined with vasoconstrictors or opioids are the mainstay of epidural
therapy. Epidural neuraxial techniques can be used for surgical anesthesia, as an adjunct to general
anesthesia, or for postoperative pain relief. Epidural catheters can be placed in the thoracic or lumbar
regions because the intrathecal sac is not being accessed; associated dermatomal spread and analgesia is
observed. Epidural techniques often fail to result in a dense sacral nerve root blockade, so this may be a
poor choice for surgical anesthesia at or below the knee.
PERIPHERAL NERVE BLOCKADE

7 Peripheral nerve blockade (PNB) has been used for surgical anesthesia of the extremities since the
days of intravenous regional anesthesia described by Bier in 1908. PNB differs from neuraxial
techniques in that it targets peripheral nerves after they have formed from the combinations of nerve
roots. Upper extremity, lower extremity, and visceral peripheral nerves are targets of these peripheral
nerve blocks. Much like neuraxial blockade, PNB can be used to achieve intraoperative surgical
anesthesia, intraoperative analgesia as an adjunct to general anesthesia, or for postoperative analgesia.
Use of long-acting local anesthetics or placement of an indwelling continuous catheter provides long-
term (16 hours to several days) pain relief. The effective use of PNB requires excellent communication
between the anesthesiologist and surgeon to ensure that the planned surgical procedure site(s) and any
other sources of procedural stimulation (e.g., tourniquet) are adequately addressed by the block. A
specific preoperative planning discussion to match the planned surgical procedure to a feasible
dermatomal distribution of blockade is essential. Even when blockade of a dermatomal distribution
specific to a surgical procedure is feasible, a PNB may be contraindicated if a neurologic examination
performed at or near the surgical site in the early postoperative period is necessary.
Because of the limited distribution of sympathetic blockade, PNB has a much smaller hemodynamic
effect than general or neuraxial anesthesia. In addition, if general or neuraxial anesthesia can be
supplanted by a PNB, the residual unwanted side effects of these anesthetics can be avoided, resulting in
improved patient satisfaction, improved quality and speed of recovery, and expedited
419
hospital/procedural center discharge. However, PNB is not without side effects; the impact of phrenic
nerve motor blockade associated with specific upper extremity blocks (common with interscalene and
rare with supraclavicular) may have significant consequences for patients with underlying pulmonary
disease.
Historically, anatomic landmark-based identification of peripheral nerves was complemented by use
of electrical stimulator needles with the hope of eliciting specific motor responses confirming correct
needle placement. The technical challenges of establishing precise anatomic location percutaneously by
assessing patient symptoms in response to electric stimulation of specific muscle groups are significant.
Concerns regarding possible intraneural injection or vascular injury persisted for many years. However,
modern anesthesia techniques now employ real-time ultrasound guidance of a PNB needle under direct
visualization. Vascular structures and nerves are visualized in relation to a PNB needle in order to
decrease the likelihood of intravascular or intraneural injection, increase the likelihood of an efficacious
block, and minimize the dose of local anesthetic required to achieve an efficacious block. Despite direct
visualization using ultrasound, PNB in adults are typically performed in the awake state to minimize the
risk of intraneural injection, which may be detected via patient complaint of significant pain upon
injection. PNB can be extremely difficult or contraindicated in patients with challenging body habitus,
local superficial infection at the site of needle entry, significant coagulopathy, or implants near the area
to be visualized or injected.
While PNB targets named major peripheral nerves resulting in both motor and sensory blockade
sufficient for surgical anesthesia, field blocks target small cutaneous sensory nerve fibers, used more
commonly to achieve moderate sensory blockade for postoperative analgesia. These blocks typically do
not achieve sensory blockade sufficient for surgical anesthesia and must be augmented by general
anesthesia or deep sedation. Procedures such as transversus abdominis plane (TAP), adductor canal,
intercostal nerve, and local infiltration enable postoperative analgesia.
SEDATION ANALGESIA FOR MINOR SURGICAL PROCEDURES

There are a variety of minor surgical procedures that can be accomplished safely and comfortably with
anesthesia provided by infiltration of local anesthetics (most commonly 1% lidocaine or 0.25%
bupivacaine) and mild sedation/anxiolysis provided by IV agents. All IV benzodiazepines, narcotics, and
other IV anesthetics produce apnea if given in a high enough dose. Because there is a substantial patient-
to-patient variability in response to a given dose, IV anxiolytics must be given in small incremental
doses slowly to achieve a safe sedated state. When attempting to provide appropriate sedation analgesia
for a procedure, it is worth noting that inadequate infiltration of local anesthetic cannot be compensated
by increased doses of IV sedatives. Such doses of sedatives as well as narcotics cannot overcome the
pain associated with a surgical incision; furthermore, if large doses of narcotics are given for this
purpose, a patient may quickly become apneic once the surgical stimulus ends. This is due to the fact
that duration of the respiratory depression for even short-acting narcotics is much longer than the
painful stimulus of the incision. Because of the potentially serious consequences of an apneic episode,
the Joint Commission has required that all patients receiving sedation for minor surgical or medical
procedures undergo the following8:
Figure 13-1. Classification of the patient’s upper airway based on the size of the tongue and the pharyngeal structures visible on
420
mouth opening. Class I, soft palate and anterior/posterior tonsillar pillars, and uvula visible; Class II, tonsillar pillars and part of
uvula hidden by base of tongue; Class III, soft and hard palate visible; Class IV, soft palate not visible, only hard palate visible.
(Redrawn from Stoelting RK, Miller RD. Basics of Anesthesia, 5th ed. New York: Churchill Livingston; 2007:146.)
Table 13-7 Sedation Scale
1. A preprocedure evaluation including an airway examination (Fig. 13-1)

2. Appropriate monitoring: pulse oximetry as a minimum
3. Documentation of the patient’s vital signs and arterial saturation as well as the dose and timing of
sedatives provided during the procedure
4. Documentation of a recovery period and a return to a safe recovered state
The preprocedure evaluation should include current medications, coexisting disease, and a brief
physical examination including an evaluation of the airway. The most common drug used to provide
sedation is midazolam. This is a fast-onset, relatively short-acting benzodiazepine that can be easily
titrated to produce a sedated yet cooperative arousable state. It is usually given to adults in incremental
doses of 1 mg (0.01 mg/kg in children). Narcotics such as fentanyl even in small doses act
synergistically with benzodiazepines to cause a more sedated state with a much higher incidence of
apnea. To assess the effect of the drug, a validated sedation scale can be of value. The scale used at the
University of Michigan is presented in Table 13-7.9
AIRWAY EVALUATION FOR THE NONANESTHESIOLOGIST

8 9 An essential skill for all clinicians is the assessment of a patient’s airway. It is important to
determine how difficult it may be to obtain control of the airway if a patient requires ventilatory
support. The concept of airway management should be focused on not just endotracheal intubation, but
also mask ventilation. Until the airway can be secured via intubation, the patient must be supported
through mask ventilation.10 Supraglottic airway devices (laryngeal mask airways) are of additional
consideration, used for both definitive airway management as well as a rescue technique for failed mask
ventilation or failed intubation. Limitations to supraglottic airway devices, however, include a relative
lack of protection from aspiration, as well as a limited ability to provide adequate positive pressure
ventilation in patients prone to airway obstruction (e.g. morbidly obese, sleep apnea). The key elements
of an airway examination are an assessment of obesity, mouth opening, neck flexion and extension,
Mallampati oropharyngeal classification, presence of beard, and mandibular protrusion ability (Table
13-8).11 Despite decades of research, there is no perfect combination of clinical tests to predict difficult
intubation. However, the presence of abnormalities in three or more of the aforementioned elements
increases the likelihood of a difficult mask ventilation and/or difficult intubation by more than eight-
fold.11 In patients with multiple (three or more) airway abnormalities, the presence of a beard is an
easily corrected characteristic: the patient should be asked to shave the beard in order to improve the
ability to manage the airway. Assessment of oropharyngeal classification is performed by having
patients open their mouth and maximally protrude the tongue without phonation. This Mallampati
oropharyngeal assessment can be classified depending on whether the uvula can be completely seen
(class 1), only partly seen (class 2), or not seen, with the hard and soft palate visible (class 3), or only
the hard palate visible (class 4) (Fig. 13-1).12
Table 13-8 Standard Airway Examination for Nonanesthesiologists
421
RISKS ASSOCIATED WITH ANESTHESIA
Because the entire purpose of surgical anesthesia is to obtund or completely block physiologic
protective mechanisms, there is an underlying baseline anesthetic risk even without a surgical
procedure. Fortunately, with the advent of newer agents and monitoring techniques, it is estimated that
the mortality rate directly attributable to anesthesia alone has decreased from about 1 in 10,000
patients in the 1950s to as low as 1 in 200,000 or less for healthy patients today.13 Although a 1 in
200,000 risk of death or serious neurologic impairment may appear small, when dire consequences
occur in a young patient undergoing a purely elective procedure, the consequences are devastating for
everyone involved. When patients are placed in a condition in which they cannot breathe, there is
always the possibility of a technical or judgmental error resulting in hypoxia and brain damage or
death. It has been estimated that between 50% and 75% of anesthetic-caused deaths are due to human
error and are preventable. Because the consequences of an anesthetic mishap are usually severe, the
emotional and financial costs are high.
Historically, the most common problems associated with adverse outcomes were related to the airway
and included inadequate ventilation, unrecognized esophageal intubation, unrecognized extubation, and
unrecognized disconnection from the ventilator. The incidence of these problems has been significantly
reduced by including capnometry and pulse oximetry in addition to other noninvasive monitors,
although a cause-and-effect relation has been difficult to prove. Efforts to improve outcome can be
approached at three levels: (a) reduction of the incidence of rare but catastrophic anesthetic-related
problems, (b) improvement of the care and experience of every patient undergoing anesthesia and
surgery, and (c) improvement of the preparation and management of patients with pre-existing medical
conditions who have higher morbidity and mortality rates. The first goal has been addressed in part
with improved monitoring techniques, standardized anesthesia machine checklists, and anesthesiology
training. Others have been advanced by the addition of comprehensive pain management, as discussed
later in this chapter. Issues of pre-existing medical disease and how they affect the anesthetic plan are
also briefly discussed later in this chapter.
Cardiovascular Diseases
Hypertension
Hypertension is the most common pre-existing medical disease in patients presenting for surgery and is
a major risk factor for renal, cerebrovascular, peripheral vascular, and coronary artery diseases, as well
as congestive heart failure (CHF). It is particularly associated with lipid disorders, diabetes, and obesity.
It is these associated comorbidities that are most likely to lead to morbidity and mortality in the
perioperative period, and therefore, the presence of hypertension should prompt the surgeon to review
the history and physical examination for them. Hypertensive patients should be treated medically to
render them normotensive before elective surgery. For elective surgical procedures, a sufficient period
of time preoperatively should be allocated for antihypertensive management, as rapid correction of
hypertension immediately prior to surgery is not without risk of comorbidities, including stroke and
other end-organ malperfusion. In general, antihypertension medications should be continued throughout
the perioperative period. However, patients treated with angiotensin receptor blockers (ARBs), such as
valsartan, candesartan, losartan, or angiotensin-converting enzyme inhibitors (ACE-Is), such as
lisinopril, captopril, or ramipril, who are exposed to general anesthesia, are at risk for developing
profound, refractory intraoperative hypotension. This ACE-I/ARB hypotension has been treated
422
successfully with terlipressin, vasopressin, and methylene blue.14–16 As a result, most medical centers
now recommend withholding ACE-Is/ARBs the morning of surgery.17,18 Patients on concomitant diuretic
therapy are at greatest risk for intraoperative hypotension requiring treatment.19,20
The incidence of hypotension and myocardial ischemia intraoperatively is higher in untreated
hypertensive patients than in adequately treated hypertensive patients if the preoperative diastolic
pressure is 110 mm Hg or higher.21 Inadequately treated hypertensive patients undergoing carotid
endarterectomies have an increased incidence of neurologic deficits, and those with a history of prior
myocardial infarctions have an increased incidence of reinfarction. Patients commonly have an elevated
blood pressure on admission to the hospital. Hypertensive patients can have exaggerated responses to
painful stimuli and have a higher incidence of perioperative ischemia.
Coronary Artery Disease

Much of the anesthetic preoperative evaluation has historically been focused on the detection and
treatment of coronary artery disease. Coronary artery disease or its risk factors are present in about
30% of patients who undergo major surgery each year.22 It is the leading cause of death in the United
States and continues to be a major cause of postoperative morbidity and mortality.23 The goal of the
preoperative cardiac evaluation is to identify patients who are at increased risk of perioperative cardiac
morbidity and ensure that their chronic conditions are optimized. Although perioperative cardiac events
are the leading cause of death following anesthesia and surgery, it has been difficult to define patient
characteristics that accurately predict a high risk of adverse outcome.24 It has been even more difficult
to modify that risk effectively.25 Preoperative CHF is clearly a significant risk factor, as is recent
myocardial infarction or unstable angina (Table 13-9). Diabetes mellitus (DM), atherosclerotic vascular
disease, and hypertension also appear to confer risk, although less than with CHF or unstable angina.
Perioperative risk in patients with valvular heart disease varies with the severity of the disease as
represented by CHF, pulmonary hypertension, and dysrhythmias. Dysrhythmias are also a concern in
the presence of coronary artery disease. Age and stable angina remain controversial as predictors of
perioperative risk, with equal numbers of supporting and refuting studies. The value of
revascularization remains controversial as well. In patients without significant pulmonary disease, the
ability to climb two flights of stairs without stopping or experiencing symptoms of angina or shortness
of breath is considered a good practical test of cardiac reserve. Unfortunately, many patients with
ischemic heart disease have concomitant pulmonary disease or other medical problems that limit their
activity. A history of myocardial infarction is important information. Large retrospective studies have
found that the incidence of reinfarction is related to the time elapsed since the previous myocardial
infarction.26–28 The incidence of reinfarction appears to stabilize at about 6% (50-fold higher than
patient without myocardial infarction) after 6 months. The highest rate of reinfarction occurs in the 0-
to 3-month period. Mortality from reinfarction, for patients undergoing noncardiac surgery (Table 13-
10), has been reported to be between 20% and 50% and usually occurs within the first 48 hours after
surgery.
Table 13-9 Clinical Predictors of Increased Perioperative Cardiovascular Risk

(Myocardial Infarction, Heart Failure, Death)
423
Table 13-10 Cardiac Risk Stratification for Noncardiac Surgical Procedures
10 Perioperative cardiac adverse event risk reduction has undergone significant changes over the past
decade. Despite these efforts, a large, international prospective study across 15,000 patients
demonstrated that more than 8% of patients undergoing major inpatient surgery still experience
postoperative myocardial ischemia.29 These patients have significantly increased 30-day mortality, even
though only 15% of perioperative ischemic episodes included typical cardiac symptoms. Previous
retrospective studies demonstrating value to coronary revascularization spurred aggressive preoperative
coronary artery disease identification and management. However, recent data have questioned the
value of coronary revascularization among asymptomatic patients in not only the perioperative period,
but also in the general medical population.30,31 The most recent American College of Cardiology
(ACC)/American Heart Association (AHA) guidelines reserve preoperative coronary revascularization
for patients demonstrating asymptomatic left main coronary artery disease, three-vessel disease,
reduced ejection fraction, unstable angina, or acute myocardial infarction.32 Furthermore, large
retrospective and prospective studies have demonstrated that the institution of perioperative beta-
blockade also bears significant risks that must be weighed against possible benefits.33,34 As a result, the
424
most recent ACC/AHA guidelines reserve the institution of beta-blocker therapy for only high-risk
patients that would warrant blockade independent of the surgical procedure.32 Patients already on beta-
blocker therapy should be continued on the therapy throughout the perioperative period.32 The
widespread use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, commonly
known as statins, for cardiovascular disease and hyperlipidemia has introduced another medication into
the surgical preoperative evaluation. Although prospective data establishing the value of instituting
preoperative statin therapy are limited, there is general consensus that these medications should not be
withdrawn during the perioperative period.35 A large randomized controlled trial evaluating the benefit
of other promising agents – clonidine and aspirin – as perioperative optimization standards failed to
demonstrate benefit.36,37
All patients in high-risk groups or with a history of ischemic heart disease must be evaluated and
properly treated before elective surgery. All elective surgery should be delayed for 6 months after
myocardial infarction. If this is not feasible, invasive monitoring should be considered in the
perioperative period and intensive postoperative observation should continue for at least 48 hours. The
intrusiveness of the surgical procedure also plays a part in the overall risk and need for preoperative
workup of heart disease. The AHA has produced and updated an algorithm for the recommended
preoperative workup (Algorithm 13-1).32
Percutaneous Coronary Intervention With Stenting

11 The widespread use of percutaneous intervention for coronary artery disease via stenting (with or
without drug-eluting coating) has introduced a new level of clinical complexity. In-stent thrombosis is a
feared complication with profound morbidity and mortality. Given the known proinflammatory and
prothrombotic physiologic state induced by acute illness, surgery, and anesthesia, coronary stents may
be at elevated risk for thrombosis during the perioperative period. Large retrospective studies have
demonstrated that the risk of perioperative in-stent thrombosis is increased if noncardiac surgery is
performed soon after percutaneous coronary intervention.38,39 The appropriate duration to defer
elective surgery after coronary stenting remains controversial, but recent ACC/AHA guidelines
recommend 365 days for drug-eluting stents and 30 days for bare-metal stents.32 The role for
antiplatelet therapy remains a major question, but data suggest that cessation of recommended
antiplatelet therapy in the perioperative period may have significant coronary thrombotic risks without
major improvement in bleeding adverse events.38,39 The decision to stop antiplatelet therapy prior to
recommended guidelines should be limited to specific procedures that demand a nearly bloodless
surgical field or in procedures involving closed spaces incapable of tolerating minor theoretical
increases in bleeding (intracranial, minimally invasive spine surgery). Recent data and
recommendations in the surgical literature demonstrate that continuation of aspirin therapy throughout
the perioperative period in patients with coronary artery stents should be the standard of care.32
Congestive Heart Failure

CHF has been described as the single most important factor predicting postoperative cardiac
morbidity.40 All elective surgical procedures should be deferred until heart failure is medically
optimized. If surgery cannot be deferred, aggressive perioperative management is warranted with a
goal of optimizing cardiac output. In contrast to isolated ischemic heart disease, CHF is more easily
diagnosed by history, physical examination, and basic preoperative laboratory workup, including
electrocardiography (ECG) and chest radiography. Because patients with left, right, or both left and
right ventricular dysfunction are less tolerant of the fluid shifts associated with surgery and the
myocardial depression associated with the anesthetic, they constitute the highest-risk group for
postoperative complications. Recent data demonstrate that although cardiac complications have
historically been the focus of surveillance and prevention, pulmonary and infectious complications may
warrant similar attention.41
425
Algorithm 13-1. Decision aid for preoperative cardiac evaluation prior to noncardiac surgery. This decision tree for preoperative
evaluation takes into account not only the patient’s physical status but also the severity of the surgical procedure. ACC, American
College of Cardiology; AHA, American Heart Association; LOE, level of evidence.
Pulmonary Disease
Pulmonary disease is classically divided into acute and chronic restrictive and obstructive disease.
Restrictive disease is defined by processes that reduce lung volumes, and obstructive disease is
characterized by reduced flow rates on pulmonary function tests.
Obstructive diseases are present in patients with forced expiratory volume in 1 second (FEV1)/forced
vital capacity (FVC) ratios of less than 50%. Obstructive pulmonary disease can be either chronic or
acute (asthma). In either case, the reversible component of obstruction should be reversed before
elective surgery. Patients are maintained on bronchodilator medications, and those with chronic
secretions are appropriately hydrated and receive therapy to mobilize secretions. In patients with
reactive airway disease, the endotracheal tube can induce severe bronchospasm. Even in patients who
are treated well preoperatively, reactive bronchospasm can complicate anesthetic induction and the
emergence from anesthesia. Severe bronchospasm is a life-threatening emergency that can be
challenging to diagnose and treat. Administration of potent local (albuterol) and systemic (epinephrine)
bronchodilators in a timely fashion is essential.
Regional or neuraxial anesthetics can be useful in these patients for peripheral surgery or for
procedures that require an anesthetic sensory level below T6. As the sensory and motor levels rise to T6
and above, patients lose significant accessory motor function that can decrease expiratory reserve
volume and the ability to cough and clear secretions. Because of tenuous pulmonary status and the high
incidence of postoperative pulmonary complications, these high-risk patients should be extubated with
caution only when they meet adequate extubation criteria relative to preoperative test data. Changes in
pulmonary mechanics and frequency of postoperative pulmonary complications are greatest after upper
abdominal surgery. Both vital capacity and functional residual capacity are reduced, reaching lowest
levels in the first 24 hours postoperatively. In the high-risk groups, therapy should be directed toward
restoring functional residual capacity to preoperative levels. Such therapy improves compliance and gas
exchange. Because of the potential adverse effects of systemic narcotics on respiratory drive, the use of
epidural narcotics and local anesthetics for postoperative pain control is very popular. These techniques
allow the patients to be extubated earlier and, in patients with intrathoracic and upper abdominal
426
surgery, help restore pulmonary function toward preoperative values.42
Obesity
Obesity causes a host of problems on both sides of the surgical drapes. Obesity is defined as a body
mass index (BMI) greater than or equal to 30 kg/m2. BMI can be easily calculated by dividing the
patient’s weight in kilograms by the square of his or her height in meters. The pathophysiologic changes
associated with morbid obesity (BMI ≥40 kg/m2) affect the respiratory, cardiovascular, and
gastrointestinal systems. Patients have an external restrictive lung disease that reduces functional
residual capacity and worsens with the supine position. Breathing effort increases and ventilation
becomes diaphragmatic and position dependent. Increased airway pressures required to maintain
adequate ventilation in obese patients predispose this patient group to barotrauma, furthering their risk
of pulmonary complications. Obese patients frequently desaturate at night and have a high incidence of
sleep apnea. Because of increased blood volume and frequent desaturations, obese patients can develop
pulmonary hypertension and right-sided heart failure. Obese individuals have a high incidence of
coronary artery disease. Because of size alone, they have increased cardiovascular demands with limited
cardiac reserve and exercise tolerance. Obese patients have a high incidence of hiatal hernia and
gastroesophageal reflux, increasing the risk for aspiration on induction and emergence from anesthesia.
Issues as mundane as venous access can cause significant problems in this patient group.
A significant concern of the anesthesiologist is gaining adequate control of the airway. The combined
problems of aspiration risk, rapid desaturation caused by reduced functional residual capacity and
increased oxygen demand, and technical difficulties associated with intubation due to anatomic fat
deposits make intubation a high-risk procedure. If problems occur, there can be significant technical
difficulties in obtaining a rapid cricothyrotomy. For these reasons, a nasal or oral awake intubation can
be useful or even imperative. Patients should receive prophylactic administration of H2-receptor
antagonists and a nonparticulate antacid to improve the pH of gastric contents. If intubations are to be
done after induction of anesthesia, they should be performed in a rapid sequence using cricoid pressure.
To prevent aspiration on emergence, obese patients should be extubated when fully awake, preferably
in the sitting position. Regional anesthetics can be very useful when peripheral procedures are planned.
Unfortunately, morbidly obese patients can develop pulmonary failure just by lying flat, making it
difficult to use epidural or spinal anesthetics for abdominal procedures. Epidural analgesics for
postoperative pain management allow earlier extubation and ambulation of these patients.43
Diabetes Mellitus
The incidence of DM is rising, particularly, type 2 DM in the elderly. This is a systemic disorder that has
particular relevance for the anesthesiologist and surgeon because of its effect on the vascular, renal,
nervous, and immune systems. Patients with DM should be investigated for the presence of concomitant
coronary artery disease, peripheral vascular occlusive disease, renal failure, and autonomic and
peripheral neuropathy. Problems with cardiovascular instability, fluid balance, and aspiration due to
gastroparesis should be expected. In addition, these patients are more prone to infection and have
problems with temperature control. The management of the diabetic state in these patients is important
and complicated. Hypoglycemia during the anesthetic state is a feared complication because of
challenges in prompt diagnosis. Oral hypoglycemic agents such as glipizide should be stopped prior to
surgery and hyperglycemic situations treated with short-acting intravenous or subcutaneous insulin
during the perioperative period. Insulin-dependent diabetics for same-day admission or outpatient
surgery should take one-half of their usual morning dose of long-acting insulin. After the establishment
of an IV line, laboratory blood samples are drawn and treatment of hyper- or hypoglycemia is started.
Additional insulin is then given according to the results of frequent (every 1 to 2 hours) blood sugar
monitoring. Although there are compelling data associating perioperative hyperglycemia with adverse
postoperative events, there are no randomized controlled trials demonstrating improved outcomes with
aggressive intraoperative hyperglycemia management.44 Furthermore, complications from
hypoglycemia are arguably greater than those from hyperglycemia, and are more likely as insulin
therapy becomes more aggressive during the perioperative period.
Renal Insufficiency and Failure

Because the kidneys play a vital role in metabolic, synthetic, and fluid management homeostasis, renal
failure is associated with many effects on the cardiovascular, pulmonary, hematologic, gastrointestinal,
and immune system. Pre-existing renal insufficiency is a known risk factor for postoperative myocardial
427
infarction and renal failure.45,46 Optimizing the fluid and metabolic status of a patient in end-stage renal
disease is of vital importance. Elective surgery should be delayed until such optimization is performed.
In emergent situations, the urgent need for hemodialysis should be considered intraoperatively or
postoperatively to avoid life-threatening electrolyte and fluid derangements. Although postoperative
renal failure has historically been the focus of cardiac surgery researchers, national data suggest that
nearly 15% of patients undergoing general surgery procedures will also experience postoperative acute
kidney injury, as defined by a 0.3 mg/dL increase in serum creatinine within seven postoperative
days.47 Risk factors for postoperative acute kidney injury in patients undergoing general surgery are
listed in Table 13-11. These data should be considered during the patient consent process.
Table 13-11 Predictors of Postoperative Acute Kidney Injury After General

Surgery Procedures
Obstructive Sleep Apnea

With the rise in obesity prevalence, obstructive sleep apnea (OSA) is emerging as a major comorbidity
that has an impact on postoperative outcomes and costs.48 The physiologic changes on the upper airway,
lungs, pulmonary circulation, heart, and brain are extensive and challenge not only the immediate
perioperative period, but also postoperative management.49 These patients are prone to airway collapse
at induction and emergence, hypoxemia, delayed emergence, respiratory depression, and cardiovascular
collapse.50 Preliminary data demonstrate increased sensitivity to the effects of opiates as well.51
Observational data demonstrate a relationship between OSA treatment and a reduction in postoperative
complications, but prospective interventional trials have yet to be conducted.52,53 Nevertheless, the
standard protocol for all preoperative evaluations should be the use of a locally accepted OSA screening
tool (STOP-BANG questionnaire, Perioperative Sleep Apnea Prediction score, etc.) and ensuring
postoperative access to continuous positive airway pressure therapy for patients currently prescribed
such therapy as outpatients. Some undiagnosed or noncompliant patients may require initiation of
therapy in the immediate postoperative period and the perioperative resources to fulfill clinical urgency
are essential.
RISKS ASSOCIATED WITH REGIONAL TECHNIQUES IN PATIENTS

BEING TREATED WITH ANTICOAGULANTS
As the indications for anticoagulant therapy have increased, ranging from drug-eluting stents to atrial
fibrillation and venous thromboembolism prophylaxis, the number of patients and types of
anticoagulant therapy has continued to increase. In particular, low–molecular-weight heparin (LMWH)
and oral direct factor Xa inhibitors are often part of a patient’s pre- or postoperative therapy plan. The
use of neuraxial or PNB anesthesia in patients with preoperative anticoagulation requires careful
planning and assessment of the risks and benefits of specific anesthetic techniques and withdrawal of
anticoagulant therapy. LMWH raises specific concerns of crippling epidural hematoma formation when
neuraxial techniques are used. For that reason, the American Society of Regional Anesthesia has
published specific guidelines for central conduction block (spinal and epidural anesthesia) to try to
minimize the incidence of this devastating complication54: In general, LMWH therapy requires
coordination of neuraxial administration at least 12 hours after the last dose. Coumadin, clopidogrel,
and ticlopidine should be held for at least 5, 7, and 14 days prior to neuraxial techniques, respectively.
The absence of any reversal agents or reliable diagnostic testing for oral direct Xa inhibitors requires a
428
conservative approach of withdrawal of therapy and no data currently exist to establish a specific
threshold. Data regarding risks for PNB are even more scarce and local protocols should be established
and followed. Unlike neuraxial techniques, the PNB techniques involve more compliant fascial planes
that may allow for increased bleeding without compressive injury to nerve structures.
PREOPERATIVE EVALUATION
12 The three goals of the preoperative evaluation are (a) to develop an anesthetic plan that considers
the patient’s medical condition, the requirements of the surgical procedure, and the patient’s
preferences; (b) to ensure that the patient’s chronic disease is under appropriate medical therapy before
an elective procedure; and (c) to gain rapport with and the confidence of the patient, answer any
questions, and allay fears.
Optimally, to complete this task, an anesthesiologist would meet every patient before the planned
surgical procedure to review the medical history, complete a physical examination, discuss the options
and associated anesthetic risks, and develop an anesthetic plan. In the past, this was accomplished when
the anesthesiologist visited the patient in the hospital the night before surgery. Currently, it is rare to
have patients admitted the night before surgery even before the most comprehensive and complex
surgical procedures. The evaluation must still be accomplished, but it must be done on an ambulatory
basis, which creates associated logistical problems.
A patient’s medical conditions should be optimized before an elective surgical procedure. This
optimization is best performed by the primary care physician, with medical specialty consultation, if
necessary. The following questions must be answered when evaluating a patient undergoing an elective
surgical procedure (Table 13-12). What must be included in the preoperative evaluation? Second, who is
involved in this process? When and where are all the steps in this process to be conducted? How should
all the information be coordinated so that it is available to the appropriate personnel at the appropriate
time? If the procedure is deemed a surgical emergency, the anesthesiologist is responsible for assessing
the patient quickly, developing the appropriate anesthetic plan, and proceeding to the operating room
as soon as possible. In an emergency situation, the anesthesiologist is not obligated to seek medical
consultation to evaluate chronic medical problems because time is essential.
The following steps must be completed before moving the patient into the operating room:
1. A comorbidity-focused history and physical examination
2. Appropriate laboratory studies and medical consultations
3. An anesthesiologist’s preoperative evaluation with assignment of an American Society of
Anesthesiologists (ASA) physical status
4. Discussion with the patient the options and risks
5. Development and communication of the anesthetic plan to the patient and surgeon
6. Acute optimization of any pertinent medical conditions
Table 13-12 Results Hospital Mortality Rates in Relation to Age, Preoperative

Disease, and Surgery
The history and physical examination have repeatedly been shown to be the most valuable parts of
the preoperative assessment. To enable ideal operative planning and postoperative care, it is the
surgeon’s responsibility to obtain a basic history that includes current medical conditions, current
medication, and previous surgical history. In addition, the anesthesiologist must review previous
429
anesthetic problems experienced by the patient or blood relatives, the patient’s exercise tolerance, and
additional details regarding general medical conditions. This evaluation not only determines the
laboratory tests that may be required but also allows for the assignment of ASA physical status (PS)
(Table 13-13). The classification serves as a general measure of the patient’s state of well-being, taking
into account all problems the patient brings to the operating room, including systemic disturbances
caused by the surgical illness. Although studies of anesthetic mortality show a correlation with the PS
classification, this categorization does not describe the risk directly. The risk of any operation is
determined not only by patient-related factors but also by procedure-specific ones. For patients with
complex medical problems, it is frequently helpful to supplement the surgical history and physical
examination with a recent assessment by the patient’s primary physician in order to assess the patient’s
long-term health trajectory. There are no data demonstrating the value of routine preoperative medical
consultation.55
The value of preoperative laboratory studies has undergone substantial reevaluation since the mid-
1980s. In the past, a surgical procedure was an opportunity to obtain a battery of baseline laboratory
tests, even for ASA PS-1 patients. The current thinking is that a laboratory test should not be ordered
unless a change in the surgical or anesthetic plan is anticipated. The only preoperative screening test
required at the University of Michigan, for instance, is an ECG within a year of the planned surgical
procedure for men older than 50 years and women older than 60 years of age. For procedures with
significant anticipated blood loss, a type and cross match is ordered, and a preoperative hematocrit is
also required. All other tests should have an indication based on history and physical examination. A
current strategy for selecting tests indicated by patient history is presented in Table 13-14. Electronic
patient questionnaires have also been developed, allowing the appropriate laboratories to be selected
based on the patient’s response to questions.56
Table 13-13 Physical Status Classification of the American Society of

Anesthesiologists
Table 13-14 Simplified Strategy for Preoperative Testing
Discussions of the options of anesthetic techniques and anesthetic risks are best performed by the
anesthesiologist who will provide the anesthetic. If the surgeon prefers a specific anesthetic technique,
this is best communicated directly to the anesthesiologist rather than recommended to the patient. The
430
development of the anesthetic plan must be determined by the anesthesiologist.
The history, physical examination, and laboratory studies should be performed by the surgeon as soon
as the surgical procedure is scheduled. The results of the laboratory studies must be evaluated well in
advance of the day of surgery so that positive findings can be attended to in a timely manner. For
healthy patients (ASA PS-1 and PS-2), the preoperative anesthetic assessment can be conducted by the
anesthesiologist on the day of the procedure. If the patients have complex medical problems (ASA PS-3
or greater) or have significant concerns they want to discuss with an anesthesiologist, they should be
evaluated before the day of surgery. Because of the logistical problems of scheduling, most institutions
have developed preoperative anesthesia clinics where this process can take place.
13 In addition, the patient’s medication regimen should be reviewed to ensure that appropriate
medications are continued or discontinued in the days and hours leading up to an elective procedure. In
general, diuretics and ACE-I/ARB medications should not be taken the day of surgery. Several important
classes of medications should be continued as per the patient’s normal regimen: chronic pain therapy
(including opioids), beta-blockers, statins, and proton pump inhibitors. The decision regarding
anticoagulant therapy is a complex one that must take into account the indication for therapy, the
likelihood and impact of surgical bleeding, and the risk of perioperative thrombosis. Insulin and oral
hypoglycemic agents should be continued at a reduced dose given the fasting state of the surgical
patient. Patients receiving chronic pain or opioid addiction therapy with buprenorphine (Subutex,
Suboxone) can be particularly challenging to manage in the postoperative period and should be
immediately referred to their primary care physician and an anesthesiologist to create a pain
management plan prior to the day of surgery. Buprenorphine is mixed opioid agonist/antagonist that
tightly binds at the μ receptor and has a long and varied half-life (24 to 60 hours). It can inhibit the
analgesic benefits of traditional opioids in the postoperative period, resulting in uncontrolled pain,
decreased patient satisfaction, and the potential for adverse events due to the need for very high doses
of opioids.57 A management protocol used at the University of Michigan is demonstrated in Algorithm
13-2.
An obvious problem that concerns anesthesiologists is the potential of a difficult intubation. This can
be assessed as discussed earlier (Fig. 13-1 and Table 13-18). Even if a patient has no medical problem,
the possibility of a difficult airway warrants that the patient be seen preoperatively and evaluated.
These patients can always be approached by an awake fiberoptic technique, but this takes planning and
can cause a significant delay if there is no prior warning.
MONITORING THE SURGICAL PATIENT

One of the more obvious changes in anesthesia care has been the routine use of an array of electronic
monitoring devices to provide continuous surveillance of physiologic status. Because the art and science
of anesthesiology involves titrating pharmacologic agents to produce desired physiologic effects, there
must be a measured parameter to which drug dosages are titrated. Depending on the severity of pre-
existing disease and the extent and duration of the surgical procedure, invasive techniques can be used
to provide comprehensive continuous data to guide the titration of fluid therapy and cardiovascular
agents.
Monitors of Oxygenation
Pulse oximetry has been called the most significant advance in patient monitoring to date. This device
continuously, noninvasively, and inexpensively provides arterial hemoglobin saturation (SaO2) and
peripheral pulse by measuring light absorption in a manner similar to that of a laboratory co-oximeter.
A laboratory co-oximeter shines light through a cuvette filled with a blood sample. Each hemoglobin
species absorbs light in direct proportion to its concentration (Beer–Lambert law). A cooximeter
requires one wavelength of light for each hemoglobin species to be measured, that is, one wavelength
for oxyhemoglobin and one for reduced hemoglobin. To measure other hemoglobins, such as
carboxyhemoglobin or methemoglobin, the device requires four wavelengths of light.
The traditional pulse oximeter uses two wavelengths of light, one red and one infrared, that shine
through a tissue bed, usually a finger. Opposite the light sources is a photodiode that measures the
transmitted light intensity. A large proportion of the light absorbed as it passes through the tissues is
not associated with arterial blood but with other components of the tissue, such as skin, muscle, bone,
and venous blood. Therefore, the device analyzes only the pulsatile component of absorption and
431
assumes that anything that pulses within the tissue bed is arterial blood, hence the name pulse oximeter.
Actually, the pulse oximeter measures the ratio of the pulsatile component of red light absorbed to the
pulsatile component of the infrared light absorbed. This ratio changes with SaO2. The exact relation
between this ratio and SaO2 has been empirically determined from volunteer studies and is programmed
into the electronics of the oximeter. If any artifacts occur in a pulsatile nature, they may be erroneously
integrated into the equation, causing erroneous SaO2 estimates.
Several things should be remembered when interpreting a pulse oximeter’s output. First, the device
measures SaO2 and not arterial oxygen tension (PaO2). The PaO2 must drop below 80 mm Hg before
any significant change in SaO2 occurs. As the PaO2 drops below 60 mm Hg, the SaO2 rapidly falls as the
inflection point of the sigmoidal oxyhemoglobin dissociation curve is approached. As a rough rule of
thumb, as SaO2 drops below 90%, the PaO2 can be estimated by subtracting 30 points from the SaO2.
For example, a SaO2 of 85% corresponds to a PaO2 of 55 mm Hg. Second, the pulse oximeter measures
saturation (milliliters of oxygen per deciliters of blood) and not arterial content or oxygen delivery to
tissues.
Because a traditional pulse oximeter uses only two wavelengths of light, it cannot detect the presence
of carboxyhemoglobin (carbon monoxide poisoning) or methemoglobin. Recently introduced pulse
oximeters incorporate additional wavelengths of light and are capable of detecting carboxyhemoglobin
and methemoglobin ratios as well.58 In addition, continuous measurement of hemoglobin (mg/dL) via
certain pulse oximeters allows the trending of intraoperative hemoglobin during procedures involving
moderate to large blood loss, guiding transfusion therapy. Although the margin of measurement error is
as large as 1 mg/dL when compared to central laboratory complete blood counts, the data do offer a
trend and may reduce unnecessary transfusions in clinical settings without access to point of care blood
gas machines.
Ventilation Monitors
By definition, a patient is appropriately ventilated when arterial carbon dioxide tension (PaCO2) is 40
mm Hg. Measuring the respiratory rate can document only the presence of ventilation, not its adequacy.
Capnography, or end-tidal CO2 monitoring, is the visual display of the CO2 concentration at the airway.
To understand the utility of capnography, one must understand dead-space (DS) components and how
they affect CO2 removal from the body.59 DS is defined as the portion of the tidal volume (VT) that does
not participate in gas exchange.
VT = DS - VA
The alveolar volume (VA) is the volume of the inspired gas that reaches well-perfused alveoli. The
remainder of the VT, which equals the DS, can be divided into three subcomponents: apparatus dead
space (DSap), anatomic dead space (DSan), and alveolar dead space (DSal). At the end of inspiration, the
respiratory apparatus (e.g., endotracheal tube) is filled with inspired gas that should not contain CO2.
Similarly, all the anatomic airways (trachea, bronchi, and all conducting airways down to the alveoli)
should be filled with inspired gas and should therefore contain no CO2. In this model, there are two
types of alveoli: those that are well perfused and those that are not perfused. The alveolar gas should
completely equilibrate with the arterial blood and contain CO2 at the same tension as the arterial blood;
ideally, PaCO2 should equal 40 mm Hg. As the patient expires, the CO2 detected at the patient’s mouth
first reflects the DSap gas having no CO2; followed by the DSan gas, again with no CO2; and finally the
alveolar gases, containing both DS and well-perfused alveolar gas. When mixed alveolar gas reaches the
airway, it produces a rapid rise in the CO2 concentration to a level somewhere between the
concentration in the alveolar gas (40 mm Hg) and the DSal (0 mm Hg), depending on each component’s
proportion of volume. For example, if half of the alveoli are DSal and PaCO2 equals 40 mm Hg, then the
plateau value of the capnogram should be 20 mm Hg, implying that half of the alveoli are not being
perfused. With inspiration, the CO2 value again drops to 0 until another expiration, and a square wave
appears again as the alveolar gas is detected at the mouth. With each breath, there should be a square
wave, whose height approaches the PaCO2 value as the amount of the DSal gas approaches 0.
432
Algorithm 13-2a. Algorithm for managing a patient on chronic buprenorphine therapy. APS, acute pain service; ICU, intensive care
unit; PCA, patient-controlled anesthesia; NSAIDs, nonsteroidal anti-inflammatory drugs.
433
Algorithm 13-2b.
In a healthy young adult, there is no significant DSal gas, and the end-tidal CO2 value equals the
PaCO2. Therefore, the difference between these values indicates the proportion of DSal in the patient.
The presence of a capnogram itself implies that there is metabolism (the production of CO2), circulation
(blood flow to the lungs), and ventilation (respiratory rate and an intact ventilator circuit).
Providing this information on a breath-to-breath basis, the continuous capnogram is extremely useful
in many critical situations. It can be used as a surveillance monitor of both the respiratory circuit and
the cardiovascular system. Any acute decrease in cardiac output will decrease blood flow to the lungs
and increase the DSal, causing an acute drop in end-tidal CO2. For this reason, the device was originally
used during neurosurgical procedures in the sitting position to detect the presence of air emboli. This
principle also allows the detection of pulmonary emboli or any acute drop in cardiac output. In fact, the
only acute catastrophic cardiopulmonary problem that will not be detected by the capnometer is arterial
desaturation. Therefore, the combination of the capnometer and the pulse oximeter creates a dynamic
duo for beat-to-beat and breath-to-breath surveillance of metabolism, circulation, ventilation, and
oxygenation.
Circulation Monitors
14 Hemodynamic stability can be monitored by a variety of methods, the most basic of which is
systemic arterial blood pressure. Intermittent, noninvasive measurement of systemic blood pressure
with an oscillometric blood pressure cuff is the standard in the operating room, and its accuracy equals
that of clinical measurements by auscultation. Blood pressure cuffs can be cycled as quickly as once per
minute, but when used for an extended duration, they should be cycled no more than once every 3 to 5
minutes. When tighter control or observation is required in patients with significant comorbidities or
large swings in hemodynamics due to surgical circumstances, invasive arterial monitoring is used.
Although pressure measurements provided by invasive techniques are different from those of
noninvasive techniques, they usually coincide closely. A continuous invasive arterial tracing can also be
used to assess the adequacy of fluid resuscitation by following the systolic pressure variation (SPV) with
positive-pressure ventilation. As positive-pressure ventilation impedes venous return within a closed
thorax, decreases in systolic pressure associated with a respiratory pattern can be detected. In patients
with sinus rhythm with stable cardiac contractility, the degree of SPV is inversely related to the
intravascular volume status of the patient. The normal range of SPV is 5 to 10 mm Hg. A systolic
pressure decrease of greater than 10 mm Hg during positive-pressure ventilation implies inadequate
preload and the need for more aggressive fluid resuscitation.
In this context, central venous access may be reserved for patients and procedures with the potential
for large, rapid volume resuscitation requirements or expected need for potent vasoconstrictors,
inotropes, or vasodilators not amenable to peripheral administration. Transesophageal
echocardiography (TEE) is now commonly used to assess cardiac function. This technique is easily used
in the anesthetized, intubated patient and can quickly assess systolic and diastolic function as well as
valvular dysfunction. Increasing familiarity in the use of TEE by noncardiac anesthesiologists may result
in the pulmonary artery catheter being reserved for very specific patients demonstrating the need for
pulmonary artery pressure monitoring or continuous cardiac output trending.
Finally, a wave of noninvasive continuous cardiac output monitors has gained the attention of
surgeons and anesthesiologists alike. These monitors, promising the realization of goal-directed therapy,
use indirect means to assess the missing aspect of blood pressure-focused hemodynamic management –
stroke volume. Thoracic electrical bioimpedance, pulse wave transit time, peripheral pulse contour
analysis, volume clamp, and other methods of estimating stroke volume have been in existence for
decades, but have seen a recent rise in interest as variation in intraoperative fluid management may
impact surgical outcomes. However, conflicting studies in real-world critically ill patients have failed to
establish that these monitors are capable of replacing traditional invasive monitoring routes or are
worth establishing as standards of care for all patients undergoing major surgery.60 Despite the absence
of compelling clinical data, many enhanced recovery protocols have begun including some type of
noninvasive cardiac output monitoring to guide fluid therapy.61 It is unclear whether these monitoring
devices offer superior guidance to sound clinical judgment administered by a vigilant anesthesiologist.
“Awareness” and Level of Consciousness Monitors

When delivering a general anesthetic, one of the major imperatives is to achieve and maintain a loss of
434
consciousness. Normally, this is achieved through careful observation of vital signs (heart rate, blood
pressure), physical examination signs (movement in a patient without neuromuscular blockade), and
delivery of inhalational or intravenous agents at doses consistent with a loss of consciousness. However,
this “science” is inexact and must account for patient age, comorbidities, chronic medications, surgical
stimulus, and patient-to-patient variability. As a result, patients may rarely experience “awareness under
anesthesia” – a state characterized not only by consciousness but also by recall of intraoperative events.
The laypress and public have increased their scrutiny of this perioperative event.
First, appropriate expectations and effective communication of the anesthetic are required. Recent
literature has demonstrated that patients undergoing regional anesthesia are as likely to report
unpleasant “awareness” as patients undergoing a general anesthetic.62 This is despite the reality that
loss of consciousness is only a goal of general anesthesia. Clearly, anesthesiologists must communicate
the anesthetic plan and expectations more accurately.
Second, several level of consciousness monitors have been developed in hopes of providing the
anesthesiologist with additional objective data to guide their assessment and actions. The current
generation of monitors generally uses electroencephalographic (EEG) analysis to provide the clinician
with an assessment of the relative “depth” of anesthesia achieved. Several commercially available
monitors such as the bispectral index (BIS) from Aspect Medical Systems and Entropy from General
Electric Healthcare are in common clinical use. Data evaluating the value of these EEG-based monitors
in reducing awareness are conflicting, with several large trials producing varying results.63,64 As a
result, the ASA has not adopted awareness monitors as a standard of care and leaves the decision to use
such monitoring technology to each provider, patient, and situation.65 The largest, most recent trials
have failed to demonstrate a measurable reduction in awareness.66,67
COMMON PROBLEMS IN THE POSTOPERATIVE PERIOD

Postanesthesia care units are required in any setting where surgical procedures are conducted. The
increased scope of surgery and the invasive technology used to monitor sicker patients has increased the
service at and training required to operate these facilities. In 2014, the ASA revised the Standards for
Postanesthesia Care (Table 13-15).
The scoring systems used to assess the postoperative patient direct attention to the primary areas of
concern. The postanesthesia recovery score is an attempt to evaluate postanesthesia patient status
(Table 13-16).68 This basic information should be incorporated in a record that provides clear
documentation of postoperative events. Documentation should also include details of postoperative
outpatient care, with a note indicating postoperative telephone contact made to elucidate problems.
Problems should receive appropriate follow-up, and written postoperative discharge instructions should
be provided for the patient.
Investigators have reported that 24% of patients experience a postanesthesia care unit complication.
Nausea, vomiting, and the need for airway support constitute 70% of these complications (Fig. 13-2).69
The need to maintain airway support was by far the most common respiratory complication. The
duration of the procedure as well as ASA classification and type of procedure had a significant bearing
on the incidence of complications in this study. Hypothermia was also a common problem that
prolonged postoperative postanesthesia care unit stay (Fig. 13-3). Hypothermia has the deleterious
effects of altering drug metabolism and delaying recovery. Furthermore, it causes shivering, which
increases the metabolic demand for oxygen.
Among cardiovascular complications in the postoperative period, none is more important or more
difficult to diagnose than myocardial ischemia. The association of perioperative myocardial ischemia
with cardiac morbidity has been clearly documented.26 In a series of high-risk patients undergoing
noncardiac surgery, researchers noted that “early postoperative myocardial ischemia is an important
correlate of adverse cardiac outcomes.”26 Diagnosis is complicated by the fact that only 10% to 30% of
patients suffering documented myocardial infarction have pain and that postoperative ECG T-wave
changes are often nonspecific.70 Instead, one must seek secondary indications of ongoing ischemia or
“angina equivalents,” such as hypotension, arrhythmias, elevated filling pressures, or postoperative
oliguria. Arrhythmias are common and are significant primarily because of the association with
myocardial ischemia or hypoxemia.
Table 13-15 Standards for Postanesthesia Care
435
Nausea and vomiting are rarely unifactorial and cause considerable discomfort to patients. Opioids
are responsible for stimulating the emesis center in a significant cohort of patients. These patients may
provide a clear history of opioid sensitivity and anesthetic and analgesic regimens may be tailored to
limit the exposure of these patients to these drugs. In general, however, there is little evidence to favor
one anesthetic or anesthetic technique over another, although propofol appears to have an antiemetic
effect. Nitrous oxide, often considered causative, does not appear to increase the incidence of nausea
according to well-documented studies. It is not unusual for an antiemetic agent to be included
preoperatively or as part of the anesthetic technique, especially in patients with a positive history or
those deemed to be at risk, such as menstruating young women undergoing laparoscopy. Standard usage
includes phenothiazines, butyrophenones, 5HT3 antagonists, and steroids. A multimodal approach that
avoids redosing of a given medication class has been demonstrated to be most beneficial.71 Despite
decades of research, classic medications such as droperidol remain a mainstay of therapy. The FDA
recently added a black-box warning to droperidol due to concerns of QT prolongation, but such concerns
have not been validated when compared to other perioperative medications; as a result, many
institutions continue to use droperidol for postoperative nausea and vomiting prophylaxis.72,73
Table 13-16 Postanesthesia Recovery Score
436
Figure 13-2. Major postanesthesia care unit complications by percentage of occurrence and number of patients experiencing each
complication. Nausea and vomiting were the most frequently observed complications. ROMI, rule out myocardial infarction.
(Reproduced with permission from Hines R, Barash PG, Watrous G, et al. Complications occurring in the postanesthesia care unit: a
survey. Anesth Analg 1992;74:505.)
437
Figure 13-3. Surgical procedures in which peripheral nerve blockade can provide postoperative pain relief.
Table 13-17 Differential Diagnosis of Delayed Emergence
The most common cause of delayed emergence is the residual effects of anesthesia. The differential
diagnosis of delayed emergence is best approached by ruling out physiologic, pharmacologic, and
neurologic cases, in this order (Table 13-17). There should be little confusion about the implication of
muscle relaxants because physical indications of ventilatory distress, combined with the readings of the
blockade monitor, should clearly indicate the role of these drugs. Where appropriate, opioids can be
reversed using titrated doses of naloxone. Flumazenil can be used for reversal of benzodiazepines.
ENHANCED RECOVERY PROTOCOLS

15 With the increasing adoption of minimally invasive surgical techniques and a realization that
postoperative complications may impact intraoperative management, nearly every surgical subspecialty
has begun efforts to establish enhanced recovery protocols. These comprehensive care management
plans dictate the preoperative preparation, intraoperative management, surgical technique, and
postoperative management choices made by all clinicians involved in the patient’s care: nurses,
anesthesiologists, surgeons, physical therapists, and consultants. While a consistent decrease in length of
438
stay, complications, and costs has been observed across the many trials assessed in many surgical
specialties, there are very few consistent protocols.74,75 It appears that the process of collaboration and
standardization involved in creating a multidisciplinary and multispecialty protocol may be the most
causal attribute in the success of enhanced recovery protocols. While some recommend use of
controversial anesthesiology management techniques such as goal-directed colloid fluid therapy, others
do not make such recommendations. The evolution of enhanced recovery protocols and implementation
science is an active area in all perioperative specialties.
POSTOPERATIVE ACUTE PAIN MANAGEMENT

Postoperative pain is an inevitable consequence of surgery. Its severity is site dependent (Table 13-18),
but the magnitude of the pain experienced by individual patients after similar surgical procedures is
influenced by a multitude of factors. Variation in patient experience has been clearly demonstrated by
several authors and is reflected in deficiencies in postoperative pain control.76 The recognition of this
clinical problem has prompted interest in underlying pain mechanisms and in innovative ways to
alleviate postoperative suffering.
In 1965, the crucial role of nociceptive C fiber feedback behavior and its modulation by cells in the
substantia gelatinosa of the dorsal horn was recognized.77 Repetitive stimulation of these fibers by
cellular mediators, such as kinins and catecholamines, promotes neural excitation, prolongs repetitive
firing, and lowers the threshold to further excitation. As a result, C fibers do not show fatigue, and the
stage is set for continuous pain. Counterirritation of large afferent activity has been shown empirically
to have beneficial effects. The gate-control theory provides an explanation for the inhibition of C fiber–
mediated pain. Serotonergic and enkephalinergic descending inhibitory pathways modulate activity in
the dorsal horn before information is relayed to the somatosensory cortex through the spinothalamic
tract. The common observation that pain is worse at night, when less sensory information is processed,
and that it decreases with daytime activity is an example of how this complex neural system functions.
Superficial somatic pain is well localized and has a protective function. Superficial somatic pain is
readily treated by common analgesic techniques. Deep somatic pain may not be well localized; may
have some protective function, as in joint immobilization; and is fairly responsive to a variety of
analgesics. Visceral pain, served almost entirely by C fiber activity, is poorly localized, often referred,
and difficult to treat. In major operations, all modes can be activated, compounding the clinical
challenge of providing adequate pain management. These clinical observations direct the focus of
postoperative pain management to the treatment of somatic pain by attacking the nociceptor and the
subsequent transmission of the painful impulse by the nerve fiber. The use of nonsteroidal anti-
inflammatory drugs with or without the injection of local anesthetics into the wound is very effective. If
done pre-emptively at the time of surgery, this approach can significantly benefit the patient’s
postoperative experience.Examples of nerve blocks for various procedures are shown in Figure 13-4.
Table 13-18 Percentage of Patients Who Require Analgesic Injections
439
Figure 13-4. Theoretical relation among dosing interval, analgesic drug concentration, and clinical effects when comparing a
patient-controlled analgesia system (solid line) to conventional intramuscular therapy (dashed line). (Reproduced with permission
from White PF. Patient-controlled analgesia: A new approach to the management of postoperative pain. Semin Anesth 1985;4:261.)
Table 13-19 Problems That Can Occur During Patient-Controlled Analgesia (PCA)
Therapy
Including potent opioids in the treatment of deep pain, both somatic and visceral, has been routine.
However, the responses to standard regimens have been notoriously unreliable, from inadequate pain
relief to narcosis, with complications at both ends of the scale. It was not until the 1980s that variations
in response were linked to variable serum concentrations of analgesic drugs. Interpatient variation in
serum levels to any standard dose can be fivefold, and interpatient therapeutic concentrations can vary
on a similar scale. When factored together, there is the potential for a 25-fold variation in patient
response to a standard drug prescription. Each patient has an individual therapeutic window. The
clinical implications are enormous.
In 1968, investigators demonstrated the virtue of small IV doses given on demand. As a result, the
patient experienced greater pain relief, yet used the same or less total narcotic. Although there was
significant patient variation, the demand from any individual patient, though cyclic, was constant.
Patient-controlled analgesia (PCA) and the technologic and administrative systems to provide it have
developed to a point of some sophistication, requiring servicing and a support structure with its own set
of problems (Table 13-19). PCA administration requires a receptive environment, education of all
personnel, and adequate patient instruction. PCA has received widespread acceptance by patients,
nursing staff, and physicians because it provides more prompt and painless analgesia that more closely
matches the patient’s need over time. PCA is as safe as conventional IM medication. Morphine and
meperidine are commonly used drugs, and an example of orders is shown in Table 13-20.
Transdermal narcotic delivery is receiving attention and may become available for postoperative
pain. The method is both practical and inexpensive and aims to maintain continuous delivery and
constant blood levels. Fentanyl has been the drug of choice and has been well received by patients. The
method appears to be safe, but there is a significant lag time between application and the attainment of
therapeutic blood levels.
The discovery of endorphins in the 1970s and recognition of their importance in modulating pain at
spinal sites led to the supposition that it would be possible to selectively apply opioids directly to
440
receptors. This led to the development of epidural opiate analgesia, in which opioids are applied
directly to the receptors at spinal sites. The goal of epidural analgesia is to obtain maximal analgesia
while minimizing systemic side effects. For severe acute postoperative pain caused by major surgery,
epidural analgesia has proved to be a superior modality for pain control. In high-risk cases, there is
evidence that it has an overall beneficial effect on morbidity.43
Table 13-20 Example of Orders for Patient-Controlled Analgesia (PCA)
Table 13-21 Opioid Protocols in Epidural Opiate Analgesia
The effective use of this sophisticated modality requires education and the establishment of protocols
with rigorous attention to detail. The potential for respiratory depression demands adherence to
monitoring standards. Morphine and fentanyl, often in combination with a dilute local anesthetic
solution, are most often prescribed. A typical order form with monitored parameters is shown in Table
13-21.
A comprehensive postoperative pain management service demands resources and must use the
physical and pharmacologic modalities available while recognizing the significant subjective component
of any individual’s pain problem. The ability to recognize the impact of acute pain or an underlying
chronic pain disorder requires that experience be brought to bear on difficult problems. The active
involvement of nursing staff and surgeons is essential for the patient to achieve maximal benefit. It is
incumbent on the pain-management service to render efficient, continuous, and cost-effective care.
16 Postoperative acute pain management may require a multimodal approach that incorporates
opioids, PNB, and nonopioid analgesics. Chronic pain patients can be particularly difficult to manage
and may require preoperative optimization by an anesthesiologist. These patients require very large
doses of IV analgesics and need to be maintained orally. The best way to evaluate an appropriate
starting dose is to convert the preoperative opioid regimen to an IV morphine equivalent, then add what
would be required to treat the acute surgical pain (Table 13-4). The use of nonopioid and
nonpharmacologic treatments is essential in the management of acute postoperative pain in this patient
population. PNB, aggressive use of acetaminophen and nonsteroidal anti-inflammatory agents, and
novel agents such as dexmedetomidine may be necessary to minimize the adverse effects associated
with uncontrolled postoperative pain. As mentioned earlier, these patients may need to be evaluated by
an anesthesiologist prior to the day of surgery. This should be an institutional requirement for patients
on chronic buprenorphine therapy, as demonstrated in Algorithm 13-2.
Acknowledgements: The authors would like to thank Kevin K. Tremper and Timothy W. Rutter for
their contributions to earlier editions of this chapter.
References
441
1. Calverly R. Anesthesia as a specialty: Past, present and future. In: Barash P, Cullen B, Stoelting R,
eds. Clinical Anesthesia. Philadelphia, PA: JB Lippincott; 1992.
2. Brueckmann B, Sasaki N, Grobara P, et al. Effects of sugammadex on incidence of postoperative
residual neuromuscular blockade: A randomized, controlled study. Br J Anaesth 2015;115(5):743–
751.
3. Kam PC, Cardone D. Propofol infusion syndrome. Anaesthesia 2007;62:690–701.
4. Himmelseher S, Durieux ME. Ketamine for perioperative pain management. Anesthesiology
2005;102:211–220.
5. Rosenberg JM, Wahr JA, Sung CH, et al. Coronary perfusion pressure during cardiopulmonary
resuscitation after spinal anesthesia in dogs. Anesth Analg 1996;82:84–87.
6. Drasner K, Smiley R. Continuous spinal analgesia for labor and delivery: A born-again technique?
Anesthesiology 2008;108:184–186.
7. Standl TG. Catheter tip position and baricity of the local anesthetic have an impact on
maldistribution in microcatheter CSA. Anesthesiology 1999;90:1227–1229.
8. JCAHO. Comprehensive accreditation manual for hospitals: The official handbook: Conscious
sedations. Oakbrook Terrace, IL: 1999.
9. Malviya S, Naughton N, Tremper K, eds. Sedation analgesia for diagnostic and therapeutic
procedures. New Jersey: Human Press; 2003.
10. American Society of Anesthesiologists Task Force on Management of the Difficult Airway. Practice
guidelines for management of the difficult airway: An updated report by the American Society of
Anesthesiologists Task Force on Management of the Difficult Airway. Anesthesiology 2003;98:1269–
1277.
11. Kheterpal S, Han R, Tremper KK, et al. Incidence and predictors of difficult and impossible mask
ventilation. Anesthesiology 2006;105:885–891.
12. Mallampati SR, Gatt SP, Gugino LD, et al. A clinical sign to predict difficult tracheal intubation: A
prospective study. Can Anaesth Soc J 1985;32:429–434.
13. Lienhart A, Auroy Y, Pequignot F, et al. Survey of anesthesia-related mortality in France.
14. Sparicio D, Landoni G, Zangrillo A. Angiotensin-converting enzyme inhibitors predispose to
hypotension refractory to norepinephrine but responsive to methylene blue. J Thorac Cardiovasc
Surg 2004;127:608.
15. Medel J, Boccara G, Van de Steen E, et al. Terlipressin for treating intraoperative hypotension: Can
it unmask myocardial ischemia? Anesth Analg 2001;93:53–55, TOC.
16. Talbot MP, Tremblay I, Denault AY, et al. Vasopressin for refractory hypotension during
cardiopulmonary bypass. J Thorac Cardiovasc Surg 2000;120:401–402.
17. Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued
before surgery? Anesth Analg 2001;92:26–30.
18. Comfere T, Sprung J, Kumar MM, et al. Angiotensin system inhibitors in a general surgical
population. Anesth Analg 2005;100:636–644, table of contents.
19. Augoustides JG. Angiotensin blockade and general anesthesia: So little known, so far to go. J
Cardiothorac Vasc Anesth 2008;22:177–179.
20. Kheterpal S, Khodaparast O, Shanks A, et al. Chronic angiotensin-converting enzyme inhibitor or
angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased
episodes of hypotension in noncardiac surgery. J Cardiothorac Vasc Anesth 2008;22:180–186.
21. Stoelting R. Anesthesia and Co-Existing Disease. 3rd ed. New York, NY: Churchhill Livingstone; 1993.
22. Padma S, Sundaram PS. Current practice and recommendation for presurgical cardiac evaluation in
patients undergoing noncardiac surgeries. World J Nucl Med 2014;13:6–15.
23. Davenport DL, Ferraris VA, Hosokawa P, et al. Multivariable predictors of postoperative cardiac
adverse events after general and vascular surgery: Results from the patient safety in surgery study.
J Am Coll Surg 2007;204:1199–1210.
24. Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990;72:153–184.
25. Fleisher LA, Poldermans D. Perioperative beta blockade: Where do we go from here? Lancet
2008;371:1813–1814.
442
26. Mangano DT, Browner WS, Hollenberg M, et al. Association of perioperative myocardial ischemia
with cardiac morbidity and mortality in men undergoing noncardiac surgery. The Study of
Perioperative Ischemia Research Group. N Eng J Med 1990;323:1781–1788.
27. Rao TL, Jacobs KH, El-Etr AA. Reinfarction following anesthesia in patients with myocardial
infarction. Anesthesiology 1983;59:499–505.
28. Tarhan S, Moffitt EA, Taylor WF, et al. Myocardial infarction after general anesthesia. JAMA
1972;220:1451–1454.
29. Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery: A large,
international, prospective cohort study establishing diagnostic criteria, characteristics, predictors,
and 30-day outcomes. Anesthesiology 2014;120:564–578.
30. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable
coronary disease. N Eng J Med 2007;356:1503–1516.
31. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major
vascular surgery. N Eng J Med 2004;351:2795–2804.
32. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative
cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of
the American College of Cardiology/American Heart Association Task Force on practice guidelines.
J Am Coll Cardiol 2014;64:e77–e137.
33. Group PS, Devereaux PJ, Yang H, et al. Effects of extended-release metoprolol succinate in patients
undergoing non-cardiac surgery (POISE trial): A randomised controlled trial. Lancet
2008;371:1839–1847.
34. Lindenauer PK, Pekow P, Wang K, et al. Perioperative beta-blocker therapy and mortality after
major noncardiac surgery. N Eng J Med 2005;353: 349–361.
35. Le Manach Y, Coriat P, Collard CD, et al. Statin therapy within the perioperative period.
36. Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing noncardiac surgery. N
Eng J Med 2014;370:1494–1503.
37. Devereaux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing noncardiac surgery. N
Eng J Med 2014;370:1504–1513.
38. Rabbitts JA, Nuttall GA, Brown MJ, et al. Cardiac risk of noncardiac surgery after percutaneous
coronary intervention with drug-eluting stents. Anesthesiology 2008;109:596–604.
39. Nuttall GA, Brown MJ, Stombaugh JW, et al. Time and cardiac risk of surgery after bare-metal
stent percutaneous coronary intervention. Anesthesiology 2008;109:588–595.
40. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac
surgical procedures. N Eng J Med 1977;297:845–850.
41. Maile MD, Engoren MC, Tremper KK, et al. Worsening preoperative heart failure is associated with
mortality and noncardiac complications, but not myocardial infarction after noncardiac surgery: A
retrospective cohort study. Anesth Analg 2014;119:522–532.
42. Popping DM, Elia N, Marret E, et al. Protective effects of epidural analgesia on pulmonary
complications after abdominal and thoracic surgery: A meta-analysis. Arch Surg 2008;143:990–999;
discussion 1000.
43. Yeager MP, Glass DD, Neff RK, et al. Epidural anesthesia and analgesia in high-risk surgical
patients. Anesthesiology 1987;66:729–736.
44. Abdelmalak BB, Bonilla A, Mascha EJ, et al. Dexamethasone, light anaesthesia, and tight glucose
control (DeLiT) randomized controlled trial. Br J Anaesth 2013;111:209–221.
45. Kheterpal S, O’Reilly M, Englesbe MJ, et al. Preoperative and intraoperative predictors of cardiac
adverse events after general, vascular, and urological surgery. Anesthesiology 2009;110:58–66.
46. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple
index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100:1043–1049.
47. Garg AX, Kurz A, Sessler DI, et al. Perioperative aspirin and clonidine and risk of acute kidney
injury: A randomized clinical trial. JAMA 2014;312:2254–2264.
48. Memtsoudis SG, Stundner O, Rasul R, et al. The impact of sleep apnea on postoperative utilization
of resources and adverse outcomes. Anesth Analg 2014;118:407–418.
49. Memtsoudis SG, Besculides MC, Mazumdar M. A rude awakening–the perioperative sleep apnea
443
epidemic. N Eng J Med 2013;368:2352–2353.
50. Tagaito Y, Isono S, Tanaka A, et al. Sitting posture decreases collapsibility of the passive pharynx in
anesthetized paralyzed patients with obstructive sleep apnea. Anesthesiology 2010;113:812–818.
51. Brown KA, Laferriere A, Lakheeram I, et al. Recurrent hypoxemia in children is associated with
increased analgesic sensitivity to opiates. Anesthesiology 2006;105:665–669.
52. Mutter TC, Chateau D, Moffatt M, et al. A matched cohort study of postoperative outcomes in
obstructive sleep apnea: Could preoperative diagnosis and treatment prevent complications?
53. Abdelsattar ZM, Hendren S, Wong SL, et al. The Impact of Untreated Obstructive Sleep Apnea on
Cardiopulmonary Complications in General and Vascular Surgery: A Cohort Study. Sleep
2015;38:1205–1210.
54. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving
antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain
Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med 2010;35:64–101.
55. Wijeysundera DN, Duncan D, Nkonde-Price C, et al. Perioperative beta blockade in noncardiac
surgery: A systematic review for the 2014 ACC/AHA guideline on perioperative cardiovascular
evaluation and management of patients undergoing noncardiac surgery: A report of the American
College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll
Cardiol 2014;64:2406–2425.
56. Roberts DM, Meyer-Witting M. High-dose buprenorphine: Perioperative precautions and
management strategies. Anaesth Intensive Care 2005; 33:17–25.
57. Barker SJ, Badal JJ. The measurement of dyshemoglobins and total hemoglobin by pulse oximetry.
Curr Opin Anaesthesiol 2008;21:805–810.
58. Wahr J, Parks R, Boisvert D. Pulse oximetry. In: Blitt H, ed. Monitoring in Anesthesia and Critical
Care Medicine. 3rd ed. New York, NY: Churchill Livingstone; 1994:385.
59. Coriat P, Vrillon M, Perel A, et al. A comparison of systolic blood pressure variations and
echocardiographic estimates of end-diastolic left ventricular size in patients after aortic surgery.
Anesth Analg 1994;78:46–53.
60. Minto G, Scott MJ, Miller TE. Monitoring needs and goal-directed fluid therapy within an enhanced
recovery program. Anesthesiol Clin 2015; 33:35–49.
61. Wuethrich PY, Burkhard FC, Thalmann GN, et al. Restrictive deferred hydration combined with
preemptive norepinephrine infusion during radical cystectomy reduces postoperative complications
and hospitalization time: A randomized clinical trial. Anesthesiology 2014;120:365–377.
62. Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the bispectral index. N Eng J
Med 2008;358:1097–1108.
63. Myles PS, Leslie K, McNeil J, et al. Bispectral index monitoring to prevent awareness during
anaesthesia: The B-Aware randomised controlled trial. Lancet 2004;363:1757–1763.
64. American Society of Anesthesiologists Task Force on Intraoperative Awareness. Practice advisory
for intraoperative awareness and brain function monitoring: A report by the American society of
anesthesiologists task force on intraoperative awareness. Anesthesiology 2006;104:847–864.
65. Bonner S. Admission and discharge criteria. Post anesthesia care. Connecticut: Prentice Hall
International; 1990.
66. Avidan MS, Jacobsohn E, Glick D, et al. Prevention of intraoperative awareness in a high-risk
surgical population. N Eng J Med 2011;365:591–600.
67. Mashour GA, Shanks A, Tremper KK, et al. Prevention of intraoperative awareness with explicit
recall in an unselected surgical population: A randomized comparative effectiveness trial.
68. Hines R, Barash PG, Watrous G, et al. Complications occurring in the postanesthesia care unit: A
survey. Anesth Analg 1992;74:503–509.
69. Breslow MJ, Miller CF, Parker SD, et al. Changes in T-wave morphology following anesthesia and
surgery: A common recovery-room phenomenon. Anesthesiology 1986;64:398–402.
70. Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of
postoperative nausea and vomiting. N Eng J Med 2004;350:2441–2451.
71. Charbit B, Funck-Brentano C. Droperidol-induced proarrhythmia: The beginning of an answer?
444
72. Nuttall GA, Eckerman KM, Jacob KA, et al. Does low-dose droperidol administration increase the
risk of drug-induced QT prolongation and torsade de pointes in the general surgical population?
73. Marks RM, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern
Med 1973;78:173–181.
74. Hubner M, Blanc C, Roulin D, et al. Randomized clinical trial on epidural versus patient-controlled
analgesia for laparoscopic colorectal surgery within an enhanced recovery pathway. Ann Surg
2015;261:648–653.
75. ERAS Compliance Group. The Impact of Enhanced Recovery Protocol Compliance on Elective
Colorectal Cancer Resection: Results From an International Registry. Ann Surg 2015;261:1153–
1159.
76. Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965;150: 971–979.
77. Tverskoy M, Cozacov C, Ayache M, et al. Postoperative pain after inguinal herniorrhaphy with
different types of anesthesia. Anesth Analg 1990;70:29–35.
445
Chapter 14
Oncology
Adam C. Yopp and John C. Mansour
Key Points
1 Cancer is responsible for nearly 1 in 4 deaths within the United States and is the second leading all-
age cause of death, regardless of gender.
2 Five percent to 10% of reported cancers are secondary to familial cancer syndromes.
3 Tobacco use and dietary factors are the two most common environmental risk factors associated
with cancer.
4 Population-based screening tests are available for the following cancers: cervical, colon, breast, and
prostate.
The earliest known description of cancer is documented in a series of Egyptian papyri, the Edwin Smith
and George Ebers papyri, written circa 1500 BC. These scrolls detail events approximately 1,000 years
earlier, documenting surgical, pharmacologic, mechanical, and magical treatments of cancer. Although
illustrated in the papyri, the word “cancer” is first attributed to Hippocrates (460 to 370 BC) nearly a
thousand years later. Cancer, the Greek term for crab (“karkinoma”) describes the finger-like spreading
projections of an ulcer-forming tumor. Later the Roman physician, Celsus (28 to 50 BC), translated
karkinoma into the Latin term cancer, the term most commonly used today. The study of cancer or
oncology is attributed to another Greek physician, Galen (130 to 200 AD), who used the Greek word for
swelling, oncos, to describe tumors.
EPIDEMIOLOGY
1 Cancer is responsible for nearly 1 in 4 deaths within the United States and is the second leading all-
age cause of death, regardless of gender. In 2015, an estimated 1.6 million new cases will be diagnosed
and over a half million patients will die of cancer within the United States. In men, the most common
forms of cancer are from prostate, lung and bronchus, and colorectal origins. In women, the most
common forms are breast, lung and bronchus, and colorectal. Cancers of the lung and bronchus,
prostate, and colorectum in men and cancers of the lung and bronchus, breast, and colorectum in
women are, in order, the most common cause of cancer-related deaths (Table 14-1).1
Although, the overall incidence rate of cancer has been 23% lower among women compared with men
since 1992, the rate in men has also declined by −0.6% over the period from 2006 to 2011, largely due
to decreases in colorectal, prostate, and lung cancers. During the same time period there was no change
in incidence of cancer among women, largely due to the stable rate of breast cancer (Fig. 14-1).1
The decline in incidence for the most common cancer types is secondary to improvements in both
cancer control and prevention. The long-term decline in colorectal cancer incidence rates since 1985 can
be attributed to both changes in associated risk factors and the introduction of effective screening
programs. For example, increased rates of diagnostic and therapeutic polypectomies during screening
colonoscopies have contributed to declining colorectal cancer incidence rates by interrupting the
adenoma to carcinoma sequence.2–4 Similarly, lung cancer incidence rates declined in the mid-1980s in
men and in the late 1990s in women as a direct result of changed smoking habits.1,5,6 In contrast to
stable or declining incidence rates in the leading cancer subtypes, increased incidence rates for skin
melanoma, esophageal adenocarcinoma, thyroid carcinoma, primary liver carcinoma, kidney carcinoma,
pancreas carcinoma, and human papillomavirus (HPV)-related oropharyngeal cancers were observed
over the past two decades. Among both men and women the largest increase in annual incidence rates
over the last decade was in thyroid cancer and primary liver cancer (Fig. 14-2).1,7
Throughout most of the 20th century overall mortality rate associated with cancer rose secondary to
446
smoking-related lung cancer deaths, especially in men, peaking at 215.1 deaths per 100,000 persons in
1991.1 However, over the past two decades the mortality rate has steadily declined as a direct result of
advances in prevention, early detection, and treatment.1 The most current, 2010 cancer mortality rate
estimate is 171.8 deaths per 100,000 persons.1 Mortality rates for the most common cancers: breast,
prostate, and colorectal cancers are down from peak rates by 34%, 45%, and 46%, respectively.3,8,9 In
contrast, mortality rates are rising for cancers of the oropharynx, anus, liver, pancreas, skin melanoma,
and soft tissue. Although thyroid cancer is increasing in incidence the observed mortality rate is stable
over time, likely a result of indolent underlying tumor biology and a lead time screening bias (Figs. 14-
1, 14-2).1
RISK FACTORS
Genetic Risk Factors
In 1971, Alfred Knudson described his “two-hit hypothesis” model for retinoblastoma, a rare form of
childhood retinal cancer affecting 11.8 patients per one million live births in the United States.10,11 In
his hypothesis, Knudson postulated that familial retinoblastoma required a first “hit” in the form of an
inherited germline mutation and a second “hit” through an acquired mutation for development of retinal
tumors.10 This hypothesis was validated more than two decades later following cloning of RB1 as the
tumor suppressor gene implicated in familial retinoblastoma, thereby ushering in a new frontier of
study: cancer susceptibility or familial cancer syndromes.12
Table 14-1 Ten Leading Cancer Types for Men and Women by Incidence and
Mortality, United States, 2015
Familial Cancer Syndromes
447
2 The discovery of inherited mutations of genes associated with an increased risk of cancer provides
important opportunities for early detection and prevention of common and rare forms of human
malignancies. Genetically related cancer is a spectrum, ranging from common variants with low
penetrance to rare variants with either moderate or high penetrance (Fig. 14-3). Linkage studies have
successfully identified the majority of familial cancer syndromes through DNA analysis of large families
with affected individuals, linking disease phenotypes or cancer subtypes to regions of the genome, with
candidate genes subsequently sequenced for a causative mutation. These linkage studies have identified
the rare, highly penetrant cancers of hereditary cancer syndromes that account for about 5% to 10% of
reported cancers (Table 14-2).12 The more common, but lower-penetrant variants of genetic-,
nonsyndrome-related cancers are typically found through large, genome-wide analysis of unrelated
persons with common cancers. In genome-wide association studies (GWAS) the entire genome is
sequenced and single alterations, or single-nucleotide polymorphisms (SNPs), are used to delineate
increased risks of cancer related to genetic risks.13
In both high and low penetrant genetically related cancers a high clinical suspicion is necessary for
diagnosis and to formulate appropriate screening and treatment plans. To aid the clinician, tools have
been developed to obtain an accurate family history, thereby assessing the risk of genetically related
cancers (Table 14-3).14 If the clinician has a reasonable suspicion that a patient may be either at risk for
or has a genetically related cancer, further follow-up with a dedicated genetic counselor is
recommend.15 We herein summarize the five most prevalent familial cancer syndromes with regard to
genetic mechanism and diagnosis.
Hereditary Nonpolyposis Colon Cancer

Hereditary nonpolyposis colon cancer (HNPCC), previously known as Lynch syndrome, is the most
prevalent familial cancer syndrome and is responsible for 2% to 5% of all colorectal cancer.16 An
autosomal dominant syndrome, HNPCC is caused by a germline mutation in one of six genes: MLH1,
MSH2, MSH3, MSH6, PMS1, or PMS2.17–21 All six of the genes function in DNA mismatch repair and
between 45% and 70% of HNPCC families have mutations in the most common gene variants: MLH1,
MSH2, or MSH6. Patients with mutations in mismatch repair genes exhibit microsatellite instability,
with errors in replication of highly repetitive sequences unable to be repaired, resulting in alterations of
the length of the total repeat sequence.
Figure 14-1. Trends in age-adjusted cancer incidence and death by gender, United States, 1975 to 2011. (From Siegel RL, Miller
KD, Jemal A. Cancer statistics, 2015. Ca Cancer J Clin 2015;65:5–29.)
448
Figure 14-2. Trends in age-adjusted cancer incidence by gender and site, United States, 1975 to 2011. (From Siegel RL, Miller KD,
Jemal A. Cancer statistics, 2015. Ca Cancer J Clin 2015;65:5–29.)
Figure 14-3. Genetic architecture by cancer risk.
Clinically, HNPCC is associated with right-sided colonic tumors with histopathology demonstrating
poorly differentiated adenocarcinoma and signet ring features. Patients with HNPCC have a 50% to 80%
lifetime risk of colorectal cancer, with a median age of diagnosis in the mid-40s. An increased risk of
endometrial cancer, ovarian cancer, stomach cancer, small intestine cancer, ureteral cancer, and kidney
cancer is also seen in HNPCC kindreds.22–24
Currently, testing for HNPCC is recommended for all newly diagnosed cases of colorectal cancer that
fulfill the revised Bethesda guidelines, in families that meet the Amsterdam II criteria, in patients with
endometrial cancer diagnosed before age 50, or in families with known HNPCC (Table 14-4).25,26
Table 14-2 Familial Cancer Syndromes
449
Table 14-3 Clinical Aid Suggesting the Presence of a Hereditary Cancer
Disposition
Table 14-4 Amsterdam II and Revised Bethesda Guidelines for the Testing of
Hereditary Nonpolyposis Colorectal Cancer
450
Familial Adenomatous Polyposis
Familial adenomatous polyposis (FAP) is a highly penetrant, autosomal dominant syndrome with an
incidence between 1 in 5,000 and 1 in 10,000 and is responsible for approximately 1% of all colon
cancer cases.27 Arising from a mutation in the antigen-presenting cell (APC) gene on chromosome 5q,
nearly 75% of cases are due to familial germline mutations with the remainder secondary to first-
generation de novo mutations.28
Clinically, FAP manifests with hundreds to thousands of adenomatous polyps at a young age with a
resultant risk of colon cancer of 90% by age 45.29 In addition to colonic manifestations, duodenal and
gastric polyps are also prevalent with a lifetime risk of duodenal cancer ranging from 5% to 12%,
typically periampullary in location. Benign, extraintestinal manifestation of FAP includes desmoid
tumors, mesenteric fibrosis, epidermoid cysts, osteomas, congenital retinal pigment epithelium, and
dental anomalies and typically accompanying adenomatous polyp formation.29
Hereditary Breast and Ovarian Syndrome

Hereditary breast and ovarian syndrome (HBOC) occurs at an incidence rate of 1 in 500 or 1,000 and is
inherited in an autosomal dominant fashion with a penetrance of nearly 85%.30,31 Germline mutations in
BRCA1 (chromosome 17q) or BRCA2 (chromosome 13q) are responsible for approximately 60% of
HBOC, with mutations in ATM, NBM, BRIP1, CHEK2, TP53, PTEN, and RAD51C responsible for the
remaining cases.32,33 BRCA1 and BRCA2 are DNA damage repair genes and more than 1,000 variants
have been identified with founder BRCA mutations documented in genetically isolated populations.34 In
the United States, the most common founder mutations occur in Ashkenazi Jewish lineage with nearly 1
in 40 carrying the common BRCA1 or BRCA2 mutations.34 Genetic linkage studies of families with
HBOC syndrome demonstrate that the lifetime risk of developing breast and ovarian cancers by age 70
is 56% and 17%, respectively.30,32
Familial Gastric Cancer

Hereditary diffuse gastric cancer (HDGC) is autosomal dominant in nature and is characterized by
diffuse gastric cancer and lobular breast cancer with a nearly uniform penetrance and an 80% lifetime
risk of gastric cancer.35 The average age of developing hereditary gastric cancer is 38 years. Thirty to
40% of families with HDGC have germline mutations in CDH1 at chromosome 16q, a gene producing
the E-cadherin protein necessary for cell proliferation and adhesion within the stomach mucosa.36
Currently, the diagnosis of HDGC is suspected if a person or family meets any of the below criteria37:
At least two cases of stomach cancer in a family, with at least one being diffuse gastric cancer
diagnosed before age 50
At least three cases of stomach cancer at any age
Diagnosis of diffuse gastric cancer before the age of 45
Diagnosis with both diffuse gastric cancer and lobular breast cancer
von Hippel–Lindau Disease

von Hippel–Lindau Disease (VHL) is an autosomal dominant syndrome characterized by the formation
of hemangioblastomas of the brain, spinal cord, and retina.38 In addition, individuals with VHL disease
may develop renal or pancreatic cysts and are at an increased risk for clear cell renal cell carcinoma,
pheochromocytomas, and pancreatic neuroendocrine tumors. Arising from a germline mutation of the
451
VHL gene on chromosome 3p, the protein product degrading hydroxylated hypoxia inducible factor-1α,
nearly 80% of cases are familial.39 Unlike most autosomal dominant disorders, VHL disease subscribes
to the Knudson “two-hit hypothesis” with mutation of both VHL alleles necessary for tumor or cyst
formation.38
Environmental Risk Factors

Although the cause of most human cancers remains unidentified, the causal association between
carcinogenesis and exposure to environmental risk factors is significant. The first known documented
link between cancer and exposure to a carcinogen was documented in the treatises of the English
surgeon Percivall Pott.40 In 1775, Pott documented the high incidence of scrotal cancer among chimney
sweeps secondary to soot lodging in scrotal skin. Subsequent preventive measures aimed at increasing
bathing and use of protective clothing led to a dramatic decline in the incidence of scrotal cancer. It was
not until the 20th century that the active carcinogens in soot were shown to be polycyclic aromatic
hydrocarbons.41 Table 14-5 lists the most common carcinogens associated with human cancers.
Table 14-5 Preventable Exposures Associated with Human Solid Organ Cancers
Tobacco and Cancer

Tobacco use is associated with more cancer-related deaths worldwide than any other environmental risk
factor. There are now 19 cancers for which causal evidence exists between cancer formation and
cigarette smoking: lung, oral cavity, nasopharynx, nasal cavity, larynx, esophagus, liver, stomach,
colorectum, pancreas, kidney, ureter, urinary bladder, cervix, ovary, and bone marrow. Three cancers
have known causality with smokeless tobacco use: oral cavity, esophagus, and pancreas.42 Table 14-6
details the relative risks by cancer site of tobacco smoking.
The causative carcinogens in tobacco products are broad and heterogeneous. In fact, the International
Agency for Research on Cancer (IARC) working group has identified 72 carcinogens contained in
cigarette smoke linked to cancer development.43 The underlying pathophysiology for smoking-related
cancer is organ specific but likely dependent on the oxidative damage caused by the carcinogens
producing free oxygen radicals and redox cycling.44
Viral Risk Factors

Nearly 15% of cancers or 1.3 million cancer cases worldwide can be attributed to viral infection.45 The
search for human tumor viruses is accentuated by a long appreciation of viral-linked cancers in birds
452
and rodents. Peyton Rous in 1911 demonstrated spindle cell sarcomas could be readily transmitted from
diseased to healthy chickens using tumor cell infiltrates.46 This observation led to the identification of
the Rous sarcoma virus (RSV), a member of the Retroviridae family, as causative agent responsible for
Rous’ original observation decades earlier.46
The lack of convincing animal models confirming epidemiologic studies coupled with the lack of
oncogene expression by human tumor–associated viruses has delayed recognition of virus-induced
human cancers. Using both epidemiology and molecular biology analysis, six viruses are established as
causative agents of cancer (Table 14-7). Hepatitis B and C viruses (HBV and HCV), HPV, and the human
herpes virus 8 (HHV-8) (Kaposi sarcoma-associated herpes virus) will be discussed in further detail.
Table 14-6 Cancer Sites Associated with Tobacco Smoking by Relative Risk
According to the International Agency for Research on Cancer
Working Groups
Table 14-7 Human Tumor–Associated Viruses
Hepatitis B and Hepatitis C Viruses

HBV and HCV are hepatotropic viruses causing both acute and chronic viral hepatitis and are
responsible for nearly 90% of hepatocellular carcinoma (HCC) cases diagnosed worldwide.47 HBV, a
member of the Hepadnaviridae family, is a circular double-stranded DNA that incorporates into the
cellular DNA of hepatocytes at random sites. Although the exact mechanism for induction of HBV-
related HCC remains unknown due to the long latency period between viral infection and cancer
appearance it is postulated to occur through either (1) induction of chronic liver cell injury leading to
random chromosomal and genetic injury or (2) expression of X protein from the incorporated HBV
activating the mitogen-activated protein kinase, c-jun N-terminal kinase, protein kinase C,
phosphatidylinositol 3-kinase, protein kinase B, and JAK/STAT pathways.48–51
HCV is a single-stranded RNA virus from the Flaviviridae family, unique as the only human tumor virus
utilizing RNA as genetic material. Responsible for the vast majority of HCC cases within the United
States, HCV has six known genotypes and has a latency period from infection to HCC formation
typically more than two decades. The actual pathophysiologic mechanism for HCV-related HCC
development is unknown but like HBV-related HCC is thought to occur secondary to creating a state of
chronic inflammation and regeneration within the liver parenchyma at the hepatocyte level.52,53
With the development of a HBV vaccine in the late 1970s the incidence of HBV-related HCC has
decreased worldwide. Although there is no commercially available HCV vaccines, since 2010 there are
orally bioavailable drugs that dramatically decrease the HCV viral load. However, it is unclear whether
453
HCV treatment will impact HCC incidence rates as many patients have already progressed to cirrhosis
prior to actual HCV diagnosis.
Human Papilloma Virus

HPV is a nonenveloped double-stranded DNA tumor virus that is responsible for a variety of epithelial
disorders ranging from benign to malignant. Although consisting of over 100 known variants, HPV-16
and HPV-18 are designated high risk for tumor induction and are responsible for over 70% of known
cervical and anal cancers.54,55 The molecular pathogenesis of HPV-related cancers is better understood
than other viral-associated cancers and occurs following HPV infection of keratinocytes at the basal
epithelial layer of the stratified squamous epithelium. Upon HPV integration into host DNA, two viral
genes, E6 and E7, are expressed and their products bind to a p53 tumor suppressor gene (E6) and/or
retinoblastoma suppressor protein (E7) to deregulate cell growth and inhibit apoptosis leading to the
accumulation of mutations and the development of cancers following a length latency period.56,57 The
recent development of quadrivalent and bivalent HPV vaccines is expected to have a significant impact
on the development of HPV and subsequent cervical and anal cancer incidence.58
Human Herpes Virus 8

HHV-8, also known as Kaposi sarcoma-associated herpes virus, is a double-stranded DNA virus from the
Herpesviridae family associated with the development of Kaposi sarcoma, primary effusion lymphoma,
and multicentric Castleman disease. HHV-8 has a latent and lytic phase persisting in B-lymphocytes.
During the latent phase HHV-8 evades the host immune system and has only minimal expression of gene
products. However, in the lytic phase innumerable viral proteins are produced including viral G
protein–coupled receptor, K1, v-cyclin, and v-Bcl-2 that modulates cell growth, induces vascular
endothelial growth factor (VEGF) expression, and inhibits apoptosis, respectively, leading to induction
of cancer.59,60
Dietary Risk Factors and Obesity

3 Dietary factors are thought to account for nearly 30% of cancer cases in developed countries, making
dietary factors second only to tobacco use as the most preventable cause of cancer.61 The contribution
of diet to cancer risk in developing countries is considerably lower, most estimates indicate a 20%
causal rate.62 Attaining definitive evidence to confirm or refute effects of specific dietary factors on
cancer incidence is oftentimes difficult with causal associations relying on migration patterns of
immigrants. Migration studies have demonstrated that the incidence of many cancers change as much as
5- to 10-fold among immigrants over time, approaching that of the host country. The age at migration
appears linked to cancer development among first-generation immigrants, suggesting that the
susceptibility to environmental carcinogenic influences varies with age by cancer type.63–65 Table 14-10
lists cancer sites with causal associations with dietary factors.
Obesity
The most important impact of diet on the risk of cancer is mediated through body weight. The IARC
working group on weight control and physical activity estimates in developed countries a body mass
index over 25 kg/m2 accounts for approximately 39% of endometrial, 25% of kidney, 11% of colon, 9%
of postmenopausal breast cancer, and 5% of total cancer incidence.66
The mechanisms linking obesity and cancer development are largely unknown but likely
multifactorial. An example of a causal association between cancer and obesity is in postmenopausal
breast cancer. A weight gain of 10 kg or more is associated with a significant increase in breast cancer
incidence among women who have never used hormone replacement therapy.67 This is likely secondary
to large increases in endogenous estrogen levels, also leading to increased incidence of endometrial
cancer.68 The mechanism for obesity-related nonbreast or nonendometrial cancers remains unclear and
is under clinical investigation.
Table 14-8 Human Cancers Associated with Dietary Factors and Nutrition
454
Cell Cycle
Control of the cell division cycle is central for governing when the cell should progress to DNA synthesis
and proliferation versus growth arrest, DNA repair, or apoptosis. Cell division proceeds through a well-
defined series of stages with tightly regulated and balanced processes dependent on oncogene and
tumor suppressor gene expression (Fig. 14-4). When cells leave quiescence (G0), they enter a first gap
phase (G1) where an explosion of growth factors and macromolecules is transcribed and translated
allowing cells to divide but not lose overall size. Toward the end of G1, cells reach a restriction point
governed by cell cycle checkpoint genes where thereafter they are now committed to division. It is at
this restriction point where DNA repair or programmed cell death (apoptosis) occurs and where
phosphorylation of the tumor suppressor product, RB protein, allows entry into the S phase. During the
S phase, DNA is synthesized and progression to second gap phase (G2) follows. Within the middle of the
G2 phase yet another restriction point or cell cycle checkpoint occurs prior to cell entry into mitosis
(M), the actual cell division phase.69
Proto-oncogenes code for proteins that send signals to the cell nucleus promoting cell division,
especially at the G1–S and G2–M transition points. Oncogenes are altered versions of proto-oncogenes
also coding for signaling proteins but in a continuous fashion leading to incontrollable cell division and
thus, tumor development. The conversion of proto-oncogenes into oncogenes occurs through three basic
methods: (1) a mutation within a proto-oncogene producing an increase in protein activity (seen in the
conversion of the Ras proto-oncogene), (2) an increase in the amount of protein within the cell resulting
in amplified expression (i.e., c-MYC proto-oncogene), and (3) a chromosomal translocation where fusion
proteins are produced or protein expression is altered (i.e., Philadelphia chromosome, BCR/ABL).70
Tumor suppressor genes also play a crucial role in the cell division cycle serving as a brake for
division in response to DNA damage. The tumor suppressor genes, p53 and RB, play a critical role in
maintaining the checkpoint at the G1–S transition point.71,72 Homozygous loss of p53 is found in 65% of
colon cancers, 30% to 50% of breast cancers, and 50% of lung cancers. In addition, p53 germline
mutations are associated with Li–Fraumeni syndrome, an autosomal dominant disorder associated with
sarcomas, breast cancer, leukemia, and adrenal gland cancers.73
Cancer Immunology
The fundamental tenet of the immune surveillance hypothesis, postulated by Thomas and Burnet nearly
five decades ago, is that the underlying function of the immune system is to survey the human body,
recognize and then eliminate tumors based on tumor antigen expression.74,75 Well documented in
nonhuman animal models, the role of the immune system as a surveillance and treatment response in
human malignancies is debatable and is best supported by tangential clinical evidence. In humans,
cancer incidence rates correlate to advancing age presumably due to increased cell division and error
rates in chromosomal replication over time that the immune system simply cannot overcome.
A corollary to the immune surveillance hypothesis is that immunodeficient individuals have an
increased rate of cancer development.76 Epidemiologic studies of patients with heritable
immunodeficiencies demonstrate mixed results for this hypothesis. Incidence rates of traditional
noncommon cancers including Kaposi sarcoma and lymphoblastic lymphoma have demonstrated
increased frequency in heritable immunodeficiencies.77 However, common epithelial-based cancers,
including lung, colorectal, and breast, have similar incidence rates as the general population.77 The
initial epidemiologic studies were conducted at a time when patients with heritable immunodeficient
disorders rarely lived past 30 years of age, so it is difficult to ascertain whether subtle changes in
incidence seen in the more common epithelial cancers are more obvious as patients age. A similar
phenomenon is seen in acquired immunodeficiencies, including acquired immunodeficient syndrome
(AIDS), where uncommon cancers such as Kaposi sarcoma and non-Hodgkin lymphoma and not
epithelial-based tumors remain the most common AIDS-related cancers.78 As HIV-positive individuals
are living longer due to more efficacious antiretroviral treatments, common epithelial cancers as well as
455
cancers secondary to viral coinfectivity, with hepatitis viruses and/or HPV have increased in
incidence.79,80
Figure 14-4. Mammalian cell cycle. Rb, a tumor suppressor gene, is complexed to E2F and is thereby unable to enter from G1 to S
phases. Upon signaling from the checkpoint genes, CDK4, 6, and cyclin D, Rb is phosphorylated allowing passage into S phase.
Another cohort, with an acquired immunodeficiency, demonstrating increased incidence rates of

common and noncommon cancers are patients receiving immunosuppressive drugs following
transplantation. A recent study examining cancer incidence in patients following heart and/or lung
transplantation receiving immunosuppression therapy demonstrated a sevenfold increased incidence of
cancer compared to the general population, with leukemia and lymphoma being the most prevalent.81
Additionally, nearly a 200-fold increase in basal and squamous cell carcinomas is demonstrated
following renal transplantation, secondary to immunosuppression and UV radiation damage.82
Tumors differ fundamentally from their normal cell counterparts through the production of tumor
antigens, thereby allowing the immune system to differentiate self versus nonself. Tumor antigens are
generated by the tumor cell and have historically been broken into two groups, tumor-specific antigens
and tumor-associated antigens.76 Tumor-specific antigens are molecules, typically proteins produced by
the tumor secondary to a mutation of a proto-oncogene or tumor suppressor gene. Tumor-associated
antigens are proteins produced following gene mutations unrelated to tumor formation. Due to lack of
specificity between the two historical terms, tumor antigens are more accurately classified according to
mutation of normal self-proteins, overexpression or aberrant expression of normal self-proteins,
glycoproteins, or glycolipids, and formation of protein products of oncogenes or oncoviruses.76
The innate immune system response to tumors can be divided into two general compartments: a set of
barriers and cell activity.83 The barriers are comprised of mechanical factors including the skin and
mucous membrane, chemical factors including high gastric acidity, and biologic barriers including
commensal microbes. Natural killer cells, macrophages, and dendritic cells comprise the cellular
component of the innate immune system response.
Natural killer cells constitute the primary innate immune cell type responsible for killing nonmajor
histocompatibility complex (MHC) expressing cancer cells. Many tumors lose MHC class I molecules
during malignant transformation while continuing to express ligands such as MICA and MICB that
constitutively bind NK receptors, including NKG2D, inducing tumor cell apoptosis through perforin and
granzyme release.84 Macrophages can efficiently eliminate apoptotic tumor cells through the release of
lysosomal enzymes, reactive oxygen intermediaries, and nitric oxide. Dendritic cells link the innate
immune system to the adaptive immune system. Residing in specific tissues according to dendritic cell
lineage, dendritic cells phagocytize tumor antigens and carry the proteins to draining lymph tissue
presenting to tumor-specific T cells. Depending on the state of dendritic cell maturity caused by
costimulatory molecule signaling, either a state of anergy/tolerization (immature) or activation
(mature) of tumor-specific T cells and the adaptive immune system response occur.76
Evidence supporting activation of the adaptive immune system response in mouse tumor cell models
is well documented. However, its role in human malignancies is not as clearly defined due to the
heterogeneity of the tumor microenvironment and the obvious lack of immunodeficient human models.
Nevertheless, compelling clinical data supports the hypothesis that an adaptive immune system response
serves as a mechanism for tumor cell death in humans. Tumor infiltrating lymphocytes (TILs) including
456
CD8+ T cells, natural killer cells, or natural killer T cells have been associated with improved prognosis
for a number of different tumor types.85–88 The initial association between favorable prognosis and TILs
was first observed in melanoma patients where it was reported that patients with higher levels of CD8+
T cell tumor infiltration survived longer than patients with tumors containing lower numbers.85 The
mechanism of TILs and especially CD8+ T-cell–mediated tumor elimination requires tumor antigen
presentation by APCs, typically dendritic cells. Activation of CD8+ T cells occurs following binding of
MHC class I molecules expressed by APCs and costimulatory molecule expression. The most widely
studied costimulatory molecule pathway is the B7-CD28 interaction with B7 expressed on APCs and
CD28 on CD8+ T cells. Following CD8+ T-cell activation, intracellular signaling activation of the NF-
AT, NF-kb, and AP1 pathways leads to further CD8+ T-cell activation and promotion of tumor cell
death.76
Although the original immune surveillance hypothesis is critical to understanding cancer cell
eradication it is likely that tumor cell tolerance and evasion play a much more important role in tumor
cell growth, thus offering opportunities for development of novel immunotherapies. The most successful
molecules to be targeted in clinical cancer immunotherapy are the immune checkpoint receptors,
cytotoxic T-lymphocyte–associated antigen 4 (CTLA4), and programmed cell death protein 1 (PD1).
Both PD1 and CTLA4 are inhibitory receptors that regulate immune responses at different levels and via
different mechanisms (Fig. 14-5).89
CTLA4, the first immune checkpoint receptor to be clinically targeted, is expressed exclusively on T
cells, where it primarily regulates the amplitude of the early stages of T-cell activation. Although
expressed on activated CD8+ T cells, the major physiologic role of CTLA4 appears to be through effects
on CD4+ regulatory (Treg) and helper cells. Thus, blockade of CTLA4 appears to switch the tumor
microenvironment from immunosuppressive to immunoreactive.90,91 An antihuman CTLA4 antibody,
ipilimumab, was shown in a cohort of patients with advanced melanoma to induce an objective response
rate in tumors previously treated with IL-2. Although there is significant immune-related toxicity
involving skin, liver, or colon, ipilimumab has gained FDA approval for the treatment of advanced
melanoma.92
In contrast to CTLA4, the major role of PD1 is to limit the activity of T cells in peripheral tissues at
the time of T-cell activation to tumor antigen presentation. Similar to CTLA4, PD1 is highly expressed
on Treg cells acting as a suppressor mechanism to effector T cells (CD8+ T cells).93 Currently, two anti-
PD1 inhibitors, pembrolizumab and nivolumab, have demonstrated efficacy in advanced melanoma
patients with disease progression following ipilimumab treatment.94,95
The Role of the Surgeon in Cancer Management

For many patients, surgeons are the entry point into the healthcare system when managing cancer and
cancer-related illness. For many surgeons, palliative or supportive care for patients with incurable
malignancy comprises a significant portion of their practice. Surgeons are involved in every phase of
cancer care from diagnosis to palliation. Many of the concepts covered in this chapter are covered on a
disease-specific basis elsewhere in the textbook. Understanding the concepts underpinning many of the
treatment approaches can help surgeons understand the rationale for current practice, and can also
potentiate the development of new therapeutic strategies.
457
Figure 14-5. A: Upon antigen expression to the T cell receptor on memory or naïve T cells and subsequent stimulation, CTLA4 is
transported to the T cell surface dampening further T cell activation. B: The activity of PD1 is further downstream in the
inflammation process. PD1 is induced by activated T cells within peripheral tissues and signals to dampen further effector T-cell
activation-limiting inflammatory cascade. (Adapted from Pardoll DM. The blockade of immune checkpoints in cancer
immunotherapy. Nat Rev Cancer 2012;22:252–264.)
Surgical Intent
Although a significant portion of oncologic surgery practice focuses on curative resection of disease, the
intent for many surgical situations does not include cure. Recognizing the goals of therapy prior to
initiating a treatment course can help surgeons maintain a patient-centered approach with appropriate
patient preoperative counseling and consent.
Diagnosis and Staging

The role of surgical biopsy to confirm the diagnosis of cancer prior to definitive therapy has been
diminished recently by the advances of image-guided and endoscopic biopsy techniques. These
techniques allow high levels of diagnostic accuracy with reduced patient discomfort, expense, and use of
hospital resources. Procedures such as punch biopsy for suspicious cutaneous lesions or excisional lymph
node biopsy for characterization of lymphoma still remain a common diagnostic procedure for many
surgeons.
A key aspect of these biopsies is a clear communication with the responsible pathologist regarding
specialized tissue handling or preservation prior to initiation of the procedure. Specimen marking and
orientation are critical for subsequent resection needs. Incorrect preservation of the biopsy specimen
may obviate the possibility for flow cytometry when attempting to characterize lymph node suspicious
for lymphoma. Intraoperatively, surgeons need to plan for a subsequent definitive resection when
appropriate. Forethought in the selection of an incision or the extent of tissue plane dissection and
disruption can make a subsequent definitive resection less morbid and less complex for the patient and
surgeon. For instance, on occasion, extremity soft tissue tumors may require excisional biopsy. A
longitudinal incision in the orientation of the affected limb can minimize the size of the incision during
the subsequent definitive resection.
Surgeons may also play a key role in the staging of cancers. As entry points into the healthcare
system for patients dealing with cancer, surgeons are often responsible for distilling the physical
examination, radiologic, endoscopic, and surgical findings into a clinical stage assignation. For cancers,
such as pancreatic adenocarcinoma, gastric adenocarcinoma, and ovarian cancer, the operative
assessment of the peritoneum may identify radiographical occult carcinomatosis 10% to 25% of the
time.96–99 When performed laparoscopically in well-selected patients, this minor procedure can avoid
the patient impact of a nontherapeutic laparotomy in the setting of metastatic, incurable cancer. In
addition, lymphadenectomy, which will be discussed more fully elsewhere, serves an important
prognostic role by allowing for complete staging of the nodal basins. The status of the nodal basins not
only has important prognostic impact, but also defines the role of adjuvant therapy for many different
cancer types.
Curative Resection
The ability to completely resect all viable tumors requires consideration of technical, oncologic, and
functional resectability. A small number of tumor types are associated with surgical survival benefit in
the setting of incomplete resection. Patients with cancers such as ovarian cancer and mucinous
appendiceal cancer may benefit from cytoreduction with the possible addition of intraperitoneal
chemotherapy.100–104 Patients with life-limiting hormonal symptoms related to metastatic
neuroendocrine tumors may gain survival benefit from cytoreduction and the resulting decrease in
circulating hormones, such as insulin and somatostatin.105,106 However, for the vast majority of cancers,
survival benefit of resection is only associated with complete resection.107–110 For that reason, a plan for
resection should include extirpation of all viable tumor for patients with a treatment goal of cure.
The goals for curative resection should include not only complete removal of tumor, but also
preservation of adequate patient function and the possibility of prolonged disease-free survival (DFS).
These functional and oncologic aspects of resectability are the metrics by which any planned resection
can be judged successful. For instance, the role of resection of hepatic colorectal metastases or
hepatocellular cancer is defined to a great degree by the amount of healthy residual liver and not
necessarily the volume of liver tumors.111–113 Conversely, even small-volume hepatic metastasis in the
458
setting of pancreas adenocarcinoma precludes resection for curative intent.114 Resectability for patients
with colorectal hepatic metastases relies on functional preservation; resection for patients with pancreas
cancer metastases is limited by oncologic outcomes.
Palliative Surgery
Symptoms related to the progression of malignant disease are a common problem faced by surgeons. A
significant proportion of a surgeon’s oncologic practice can be dedicated to providing palliation for
patients with incurable conditions. This need is not limited to patients with malignancy; however, the
principles associated with surgical palliation of cancer-related symptoms are a sound model for
discussion regarding surgical palliation in general.
The primary concept driving decision-making for patients with palliative needs is the critical starting
point of goal assessment. In order to deliver the most individualized, risk-appropriate, effective
palliation to any given patient, surgeons need to ascertain the goals of therapy for each individual
patient at that given time. This assessment transcends diagnosis-based treatment algorithms or
pathways. Patients with gastric outlet obstruction related to metastatic gastric cancer may seem like a
homogeneous group; however, the primary therapeutic goals of individual patients may vary
dramatically. Treatment goals in that setting may include resolution of nausea, eating independently,
long-term maintenance of nutrition, or improving performance status sufficiently to enter home hospice.
These variable treatment goals can lead to variable treatment strategies, such as placement of a
nasogastric decompression tube, a percutaneous gastrostomy tube, gastrojejunostomy, and/or
antiemetic medications.
A second factor particularly relevant to palliative surgery for patients with cancer is the increased risk
for many procedures in a population with incurable malignancy. Many patients eligible for palliative
operations or procedures have been debilitated by malnutrition, physical deconditioning, prolonged
hospitalization, or cytotoxic chemotherapy.115,116 These factors, as well as the presence of metastatic
disease, have all been associated with poor short-term outcomes following operations. Understanding
the increased risks of even simple operations for this patient population can help the surgeon guide the
patient and family conversations regarding the risks and benefits of a procedure. Making a decision with
a patient and family regarding strategies for surgical palliation requires both an individualized
assessment of the needs of those involved as well as a generalized awareness of the risks for that
procedure based on associated risk factors.
Extent of Resection
For malignancies such as melanoma, breast cancer, or sarcoma, the requirement for radical resection has
decreased significantly over the past several decades.117–121 Conversely, for diseases such as pancreas
cancer and liver tumors, the frequency and safety of radical resections have increased dramatically over
that same time period.122 A key point of judgment for surgeons involved in cancer operations is not
only deciding when to operate, but also how extensive that operation should be.
Pathologic Margins
An important distinction must be made between surgical and pathologic margins. Surgical margins are
the planned lines or planes of resection around a grossly visible tumor. The aim of this strategy is not to
ensure a wide swath of healthy tissue around the tumor specimen, but to ensure a final negative
pathologic margin. Pathologic margins are the histologically assessed borders of uninvolved tissue
around the microscopic tumor. Tumors with infiltrative behavior may extend up to the pathologically
assessed margin even though the grossly assessed surgical margin appears to be uninvolved. An example
of this discrepancy occurs in the management of melanoma. Resection with a 1-cm surgical margin is
generally considered adequate for a nonmetastatic extremity lesion with a tumor thickness of 1 to 2
mm. If the final pathologic margin is only 0.3 mm, this is considered a negative, and adequate,
pathologic margin.
Table 14-9 Terms Typically Used to Describe Pathologic Margins for Cancer
Resections
459
The terms typically used to describe pathologic margins for cancer resections are defined below
(Table 14-9). An R0 margin is typically considered negative and an R2 margin is considered grossly
positive. For many, but not all, types of cancer, the presence of an R1 margin is associated with
increased risk of recurrence. Management of a positive pathologic margin is dependent on technical and
oncologic factors associated with that particular tumor. For instance, some early-stage cutaneous
malignancies such as dermatofibrosarcoma protuberans or basal cell cancer are characterized by limited
risk of distant disease dissemination and a high risk of local recurrence in the setting of positive
pathologic resection margins. In a location where additional local excision may not be limited by
adjacent structures, an effort for reexcision of a positive margin may be reasonable. Alternatively, the
presence of cancer at the superior mesenteric artery (SMA) resection margin at the time of
pancreaticoduodenectomy does not lead to an additional operative attempt to achieve a negative final
margin for patients with pancreas adenocarcinoma. The hesitation to attempt reresection is driven not
only by the technical challenges of attempting to achieve a broader margin along the SMA, but also by
the very high risk of distant recurrence for those patients and the relatively lower impact of local
recurrence in this setting.123–125
Lymphadenectomy
The removal of regional lymph nodes at the time of resection of the primary tumor has been the focus
of significant investigation and controversy throughout the contemporary history of surgical
management of cancer. The surgical principles attributed to William Halsted regarding the surgeon’s
role in interrupting the progression of cancer from the primary tumor through lymphatic channels to
regional lymph nodes and then to distant sites form the traditional rationale for regional
lymphadenectomy.126,127 However, more contemporary studies such as MSLT-1, the Dutch Gastric
Cancer Lymphadenectomy, and ACOSOG Z0011 clinical studies have raised questions regarding the
survival benefit of lymphadenectomy for patients with melanoma, gastric cancer, and breast cancer,
respectively.128–131
The potential prognostic benefits of lymphadenectomy undoubtedly are more germane than
therapeutic advantages. For almost all types of malignancy, the presence of cancer within regional
lymph nodes portends a worse prognosis for patients, as a harbinger of systemic cancer spread. The
accuracy of the assessment of the regional lymph node basin can be increased with either focused
evaluation of the most at-risk lymph nodes (i.e., sentinel lymph node biopsy) or thorough sampling of a
large number of nodes (i.e., lymphadenectomy). Accuracy of cancer staging, for example in colorectal
cancer, is oftentimes increased through the sampling of a sufficient number of lymph nodes. The
threshold for quality assurance through adequate lymph node sampling has been established for
surgeons who perform colorectal cancer resections, however, that well-defined performance metric is
not common to all types of resection and all types of cancer.132–135
For patients with bulky involved regional lymph nodes, the benefits of node removal are not likely
prognostic. In selected patients, removal of these lymph nodes may provide some palliation from local
symptoms. The role of “prophylactic palliation” or removal of lymph nodes, which may develop and
cause local problems is less clear. For example, in melanoma or rectal cancer, eliminating all of the
regional lymph nodes in the setting of positive microscopic nodal burden decreases the potential of
future development of bulky, symptomatic nodes.128,136–138 The therapeutic benefit of avoiding local
recurrence in a subset of the operative population needs to be balanced against the potential adverse
effects of lymphadenectomy. For many nodal basin sites, the adverse impact of interrupting lymphatic
flow can have significant deleterious effects on patients following lymphadenectomy, including
lymphedema, paresthesias, and even development of secondary malignancies, such as angiosarcoma
(Stewart–Treves syndrome).139–142
In general, lymphadenectomy is an important aspect of surgical cancer care when any of the
following criteria are met: (1) removal of regional lymph nodes will provide important information to
either guide adjuvant therapy decisions or provide prognostic clarity (e.g., colon cancer, gastric cancer);
(2) lymphadenectomy can eliminate a predictably involved site of disease involvement which can lead
to local regional complications in the setting of nodal recurrence (e.g., rectal cancer, esophageal
460
cancer); (3) removal of at-risk lymph nodes is a minor adjunct of the procedure for primary tumor
removal (e.g., pancreatectomy). The extent of our operative management for cancer is likely to change
as we learn more about the therapeutic benefit of regional nodal removal. Perhaps more strikingly, the
prognostic information gained by evaluating a nodal basin is likely to diminish as our ability to profile
tumors and their behavior becomes more dependent on genomic, proteomic, and other expression
profiling.
Resection of Metastatic Disease

Outside the palliative setting, the indications for resection of metastatic disease are relatively narrow.
Despite the growing awareness and increased frequency of resection for metastatic colon cancer,
endocrine tumors, and gastrointestinal stromal tumors, the vast majority of patients with metastatic
disease are not eligible for metastasectomy. Although it is important to recognize the diverse spectrum
of presentations for malignant disease and to be wary of absolute contraindications against surgical
management of metastases, several general principles do apply to the overwhelming majority of
patients with metastatic disease.
Complete elimination of all sites of disease is generally associated with dramatically improved
survival compared to incomplete resection. In addition, the outcomes for patients with incompletely
resected disease are frequently comparable to outcomes for patients who underwent no resection at
all.108–110,143–145 For these reasons, resection or ablation of all sites of disease is a common requirement
when making a decision to proceed with resection of metastatic disease. This principle applies to
patients with primary tumors in place as well; therefore, patients with unresectable primary tumors are
generally not eligible for curative intent resection of their metastatic sites.
The behavior or biology of an individual’s cancer may suggest a less aggressive phenotype and
warrant consideration of metastasectomy. Oftentimes characteristics of favorable cancer biology are
associated with improved survival outcomes following resection. A prolonged period of progression-free
survival (PFS) or DFS is commonly associated with improved outcomes following resection of
metastatic disease.143–145 Progression of metastatic sites while receiving first-line systemic
chemotherapy is often a harbinger of early systemic failure among patients undergoing resection of
metastatic disease.146,147 As systemic chemotherapy has grown more effective over the last decades, the
impact on tumor progression and control of systemic disease has led to increased opportunities for
resection of metastatic sites. This concept has been most plainly demonstrated in the context of hepatic
colorectal metastases. The frequency of hepatectomy in that setting has increased in harmony with the
increased effectiveness and availability of both cytotoxic and targeted chemotherapy agents.122 Surgical
management of metastatic disease may increase in frequency for other diseases as we develop more
effective systemic therapy options.
Cancer-Related Surgical Outcomes

The short-term outcomes for surgical patients commonly include metrics, such as complication rates,
length of stay, mortality rate, and overall survival (OS). These metrics are certainly important measures
of quality and efficacy for patients undergoing operations for cancer. Similar to other surgical
specialties, cancer-related surgery also carries specific outcome measures, which are particularly
relevant to these clinical scenarios. Understanding these metrics is critical to balancing risk and benefit
for individual patients as well as for evaluating the role of new therapeutic strategies and approaches.
Disease Recurrence
Many surgical specialties are directed at the eradication of a tangible, anatomically identifiable lesion.
Peripheral and coronary vascular bypass, gastroesophageal fundoplication, and parathyroidectomy are
all measured by how effectively the treatment eliminates the arterial plaque, gastroesophageal reflux,
or hyperparathyroidism. Early recurrence of the condition suggests a failure of therapy or poor patient
selection for the procedure. Disease recurrence is also a critical measure of the effectiveness of surgical
therapy for cancer patients.
A prerequisite for disease recurrence as a measure of outcome is the initial eradication of all visible
cancer. Recurrence can be measured by development of symptoms, physical examination, radiographic
evaluation, biochemical evaluation, or operative exploration. Unique to the practice of surgery for
cancer patients is the distinction between locoregional and distant disease recurrence. Locoregional
recurrence is typically defined as recurrence in the resection bed or region of the draining regional
lymph nodes. Distant recurrence is typically defined as occurrence of malignant cells outside of the
461
initial primary tumor and lymphadenectomy resection field.
Although resection is traditionally considered a means to achieve locoregional control, and adjuvant
systemic therapy is employed to control distant disease recurrence, a decision to proceed with an
operation should consider how the operation impacts both locoregional and distant recurrence. A well-
performed, radical, margin-negative operation can only lead to prolonged DFS if it is performed with
appropriate patient selection. This distinction is the underpinning behind the approach for patients with
small-volume metastatic disease in the setting of pancreatic adenocarcinoma, gastric cancer, or biliary
tract cancers. Many patients, when faced with this scenario, will ask their surgeon, “Why can’t you just
take out all of it?” Patients with easily resectable, distant disease are poor candidates for resection not
because they cannot be rendered free of all visible disease but rather because the findings of metastases
are highly predictive of early distant disease recurrence even if local control can be achieved. The trade-
off for a short period of DFS after a radical operation is the chance at a more prolonged PFS or OS with
the immediate initiation of effective systemic chemotherapy.
Progression-Free Survival
For patients who cannot have all visible tumor resected due to locally advanced disease or metastases,
PFS is an important measure for subsequent therapy. The propensity for a treatment to control, but
perhaps not eliminate, a measurable volume of tumor is the critical measure for defining the
effectiveness of that therapy. For many types of cancer, PFS is a reliable surrogate for OS.148,149
Typically, when patients experience disease progression while receiving a particular regimen of
systemic therapy, the treating physician will consider initiating the next line of systemic treatment.
Radiographic progression of measurable lesions is measured by a well-defined set of criteria referred
to as RECIST or modified RECIST criteria. Response Evaluation Criteria in Solid Tumors (RECIST) was
developed in 2000 and subsequently modified in 2009 as a system for measuring tumor response or
progression.150 These criteria are commonly employed in clinical trials as a standardized way to
determine when a tumor has progressed on therapy. A simplified description of the criteria is included
in Table 14-10. This strategy requires the upfront identification of index lesions, which are measurable
radiographically. RECIST has proven to be a useful measure of potential treatment benefit in phase II
clinical trials. Although useful in clinical trials, stringent application of RECIST measures of progression
is not as readily used outside trial settings. Even small changes in the one-dimensional measurements or
characteristics of measurable lesions may be considered evidence for clinical progression and
justification for a change in treatment course.
Return to Intended Oncologic Treatment

A novel measure for the quality of surgical management of cancer patients is return to intended
oncologic treatment (RIOT).151 This metric considers the place that resection holds in the
multidisciplinary care of a cancer patient. Although surgical resection is required for a curative intent
pathway for the majority of solid tumors, important oncologic adjuncts such as adjuvant chemotherapy,
radiotherapy, and maintenance hormonal therapy can reduce the chances of recurrence and prolong
survival for many patients. Delays or disqualifications due to operative adverse events may negatively
impact the overall outcomes of patients. An important element in the assessment of the quality of
cancer care is the ability for a health system to deliver all of the treatment modalities demonstrating
benefit for a particular malignant condition. Recognizing that the definitive resection of a cancer is part
of a larger treatment strategy is one of the important considerations for assessing surgical outcomes for
patients with cancer.
Table 14-10 Common Criteria Used to Determine Therapy-Related Progression
462
The Role of Radiation Therapy in Cancer Management
Surgery is complemented by the modality of radiation therapy as part of a multimodal approach for
many types of cancer. Like surgery, radiotherapy is typically focused on locoregional disease control.
For that reason, many of the same principles apply to surgery and radiation oncology, such as patient
selection, recognition of the behavior or tumor biology for a particular patient and cancer, and
assessment of both short-term and long-term toxicities of therapy.
Mechanisms of Radiation Delivery

Energy emitted from a source travelling through space is termed “radiation.” As the energy passes
through materials it interacts with those substances in one of two forms: photons or freely propagating
particles. Photons are packets of electromagnetic fields travelling through space at the speed of light.
The shorter the wavelength of the photon the greater the frequency of the oscillation and the higher the
energy contained within the photon packet. Lower-energy photons make up the energy in visible light
and only interact with the surfaces of objects. Higher-energy photons are used in diagnostic and
therapeutic radiology and can pass through tissues to interact with deeper material and either reveal or
impact underlying structures. Freely propagating particles carrying kinetic energy can be protons,
electrons, or alpha-particles. These charged particles interact with other charged particles as they travel
along their path. As photons or charged particles interact with biologic materials within the target area
in the setting of therapeutic radiation, the interactions lead to ionization and subsequent biologic
damage.
Linear accelerators (linacs) are the most common means for generating radiation in a manner
allowing focused delivery of energy to a target tissue. Linacs can be used to generate either photon
radiation or electron particles to be used as the ionizing agent. The linac uses oscillating electric fields
to accelerate electrons toward a metal target converting the electron beam into a spray of photons. The
photons are focused through filters and shaping elements to sharpen the beam of energy being
delivered. A higher energy level of the photons travelling through the shaping process will lead to a
higher level of energy delivered to the surface of the treatment target. As the photon beam travels
across distance through a material, the dose will attenuate as the depth of penetration increases.
Photons with higher energy penetrate more deeply into any given material and maintain the energy
level for a greater distance. As this ionizing radiation travels through tissues, the photons deposit
energy into the materials through which it passes. The total amount of energy delivered to a biologic
system is measured in terms of joules per kilogram. The dose corresponding to the amount of energy
delivered is expressed in terms of Gray (units of dose).
Tissue Response to Radiation

The therapeutic effects of radiation are contingent on the damage caused to the cells through which the
ionizing radiation beam passes. The mechanism of action of cellular damage can be categorized into
direct and indirect effects of radiation (Fig. 14-6). Both effects lead to the damage of DNA molecules.
The direct effect of ionizing radiation is ionization of DNA molecules and the downstream effects of the
damage to this critical cellular molecule. The indirect effect of ionizing radiation is best exemplified by
the radiolysis of water molecules leading to the generation of free radicals. Free reactive species
interact with DNA molecules causing indirect damage. The majority of total DNA damage is from this
second, indirect effect. The proportional relationship between oxygen tension within tissues and the
resultant damage caused by ionizing radiation is termed the oxygen effect.152 The phenomenon is
explained by the capacity to generate a greater concentration of free radicals in oxygen-rich tissues than
in hypoxic environments.
463
Figure 14-6. The mechanism of action of cellular damage can be categorized into direct and indirect effects of radiation.
Ionizing radiation can lead to multiple types of DNA damage: cross-linking of two DNA strands, loss
of a DNA base or entire nucleotide, and breakage of the sugar-phosphate backbone.153 Many of these
types of damage are actually a failed attempt to eliminate unpaired electrons resulting from free radical
generation. The mammalian cell has multiple DNA repair mechanisms operating with remarkable
fidelity under typical conditions. In the setting of therapeutic radiation delivery, the DNA disruption is
either too complex or too widespread to allow for normal mechanisms of repair. The generation of
flawed versions of the original DNA molecule can lead to ineffective mitosis and failed cell division.
Many cancer types are characterized by deficits in the DNA repair mechanism process.154,155 When these
processes function suboptimally, the impact of radiation-induced damage can be more potent on the
mutated cancer cells than on the DNA-repair intact nonneoplastic cells. Disruption of DNA synthesis by
fluoropyrimidines such as 5-fluorouracil and capecitabine likely contributes to the therapeutic benefit of
combining these agents to radiation. Fluoropyrimidines interfere with the capacity of cellular DNA
repair mechanisms to correct DNA lesions induced by ionizing radiation.
Of course, ionizing radiation is relatively nonselective in terms of its deposition of energy packets
into the tissues it traverses. Both normal and neoplastic cells are targets for the effects of radiation if
the tissues lie in the beam of delivery. Different types of normal tissues demonstrate different levels of
sensitivity to radiation. Breast tissue, intestinal mucosa, stem cells, lymphocytes, and bone marrow cells
are considered radiosensitive based on their response to a given dose of radiation. Conversely, muscle
cells, large arteries and veins, the heart, and neurons are considered more radioresistant based on the
relatively low degree of cell death induced by radiation. Given a high enough radiation dose, nearly any
malignancy can be destroyed. One of the key challenges of radiation therapy treatment planning is
balancing the cytotoxic dose delivered to a given tumor with the impact that treatment will have on
surrounding tissues. The therapeutic ratio is relationship between tumor killing and normal tissue
complication rates.
Strategies to broaden the therapeutic ratio have focused on both increasing effective tumor killing
and limiting the toxicity to normal tissues associated with a given dose of radiation. Approaches for
increasing effective tumor killing include the use of radiosensitizers, preoperative radiation in a high
oxygen tension environment, and fractionation. Fractionation is the division of a total therapeutic dose
of radiation into multiple radiation treatments generally given daily. The biologic impact of dividing the
total treatment dose is related to several cellular behaviors within the treatment field (Table 14-11).
Fractionation increases the effectiveness of a radiation dose by allowing for reoxygenation and cell cycle
redistribution within the tumor. Alternatively, approaches for reducing normal tissue toxicity include
rotating gantry delivery systems using multiple beams reaching a single point via different routes
through normal tissue, collimation allowing delivery of a narrow beam of energy, and fractionation.
Fractionation decreases normal tissue toxicity by allowing initiation of DNA repair mechanisms and by a
compensatory increase in cell proliferation in tissues such as stem cells in response to injury. The injury-
induced increase in cell proliferation is termed repopulation. Since repopulation does not typically start
until 4 weeks of radiation injury, most treatment plans are kept short to avoid tumor repopulation.
Understanding the deleterious effects of ionizing radiation on normal tissues is critical to
understanding the therapeutic ratio for any radiation treatment plan. Desired cytotoxic effects on
tumors are accompanied by undesirable cytotoxic effects on normal cells. Typically, treatment plans are
developed to allow for the maximum tolerated dose (MTD) to be delivered to the structures within the
treatment field. The MTD is based on the radiation tolerance of each structure or tissue type within that
field. Plans incorporating shielding or avoidance of radiosensitive normal tissues can lead to safer and
464
more effective therapy. Although radiosensitive cells generally have a lower tolerance dose than
radioresistant cells, this principle does not always hold true. The early and late effects of ionizing
radiation may not be wholly determined by the degree of cell killing. Downstream effects, such as
compensatory proliferation, cytokine-mediated responses, and radiation-induced gene expression can
lead to undesirable tissue effects within the treatment field.156
An important, although relatively uncommon, normal tissue effect of therapeutic radiation is the
development of a second cancer. Approximately 20% of these second malignancies are leukemias. The
majority of radiation-associated tumors are solid malignancies arising in the treatment field. These
cancers typically develop many years after the original treatment. The increasing number of patients
surviving disease free after an initial radiation treatment course may lead to an increasing number of
these late second cancer events. Children and immunocompromised adults are more likely to develop
second cancers.157 Importantly, the risk of developing a second cancer within the radiation field is
relatively low. In clinical scenarios where the benefit of therapeutic radiation is clearly demonstrated,
the incidence of second malignancies does not generally skew the risk/benefit assessment against
therapeutic radiation. However, an awareness of the potential for the development of a second cancer is
critical for those who care for long-term cancer survivors.
Table 14-11 The Biologic Impact of Dividing the Total Treatment Dose is Related
to Several Cellular Behaviors Within the Treatment Field
Radiation Therapy Delivery Modalities

Ionizing radiation can be delivered to an intended treatment area in a number of ways. The choice
regarding the proper treatment modality includes decisions regarding the timing of radiation, the use of
concurrent chemotherapy, and the delivery system for the radiation energy. Just as with surgical
therapy, the primary determinant for all of these decisions is the intent of any radiation treatment plan.
Therapeutic radiation can be employed as a part of a nonsurgical definitive treatment plan, as a
palliative therapy, or as a means to complement the locoregional control of a surgical resection.
Radiation Treatment Approaches

Perioperative radiation therapy with or without chemotherapy sensitizers is commonly employed for
tumors, such as rectal cancers, gastroesophageal cancers, and soft tissue sarcomas.158–160 When surgical
therapy is combined with radiation and chemotherapy, this is often referred to as trimodality therapy. In
these scenarios, radiation provides an additional element of local control by treating potential
postsurgical residual disease in the tumor bed and lymphatic system. Preoperative radiation is generally
preferred over postoperative radiation for several reasons. The normal tissue toxicity associated with
any radiation treatment is largely within a planned field of resection when radiation is delivered
preoperatively. Radiation delivered postoperatively is delivered entirely to a healing surgical bed.
Additionally, treatment of a target field with an intact vascular supply and associated increased oxygen
tension, theoretically enhances the indirect effects of the radiation energy. In clinical settings where the
tumor is large or abuts major structures, such as major blood vessels, nerves, or bony structures, the
reduction in size of a tumor may allow for preservation of critical structures and their function.
Chemotherapy is often combined with radiation as a definitive therapy for cancers that are either
unresectable or exquisitely radiosensitive. Patients with anal cancer can avoid an abdominoperineal
resection the majority of time due to the extremely high complete response rates of combined
chemoradiotherapy.161 Locally advanced cancers such as pancreas adenocarcinoma or esophageal cancer
may be treated with concurrent chemoradiation in order to alleviate local symptoms and limit the impact
of local progression.
Definitive radiation therapy is not commonly employed for these locally advanced cancers. A more
typical application of radiation alone is in the setting of certain small, radiosensitive cancers such as
prostate cancer or nonmelanoma skin cancers.162 Cutaneous tumors in sensitive areas such as the face or
head are good candidates for this approach in order to avoid the need for significant soft tissue
465
reconstruction. Patients with multiple high-risk comorbid factors or frailty may be good candidates for
definitive radiation in order to avoid general anesthesia or prolonged inpatient recovery.
Radiation Therapy Delivery

The systems and technology used to generate and focus photons and electrons toward a target field can
vary based on the requirements of each clinical scenario. Over the past several decades, techniques have
advanced to generate a more focused beam of photons with increased delivery to target tissues and
reduced collateral injury to normal tissue.
External beam radiation therapy is the most commonly employed therapeutic radiation strategy.
Multiple angles of approach are used to deliver multiple beams of radiation to a target region.
Modifiable factors with this approach include the angles of beam delivery, the shape of the beam, and
the intensity of each beam. The radiation oncologist can adjust these factors to maximize the radiation
dose focused on the target tissue while minimizing the effect on nearby, associated radiosensitive
tissues. Patients undergo simulation as an early step in treatment planning. Contemporary simulation is
typically performed with CT scan guidance. During this process, a patient undergoes a CT scan during
which the radiation oncologist identifies the intended isocenter within target area. Using an integrated
laser system to align the isocenter with sites on the patient surface, the radiation oncologist places
tattoos to ensure reproducible, accurate beam alignment for future treatments. Patients typically
undergo radiation treatment for 5 days a week for up to 6 weeks. Intensity modulated radiation therapy
(IMRT) is an enhanced version of external beam therapy. IMRT uses mechanical devices or multiple
beam integration to adjust the intensity within each beam in order to account for irregular patient
surfaces or sensitive structures near the treatment region. By modifying the intensity within the beam, a
more homogeneous dose distribution can be achieved within the target area.
Stereotactic body radiation therapy (SBRT) is a more specialized delivery system used for patients with
brain tumors, lung cancer, and liver tumors. The applications of this technique are rapidly evolving as
the expertise within the radiation oncology community grows. SBRT relies on precise motion control,
high degrees of quality insurance, hypofractionation (commonly 1 to 5 treatments), and a relatively
high dose per fraction to deliver a potentially ablative dose to the target area. Whereas conventional
external beam radiotherapy may deliver a dose of 45 to 60 Gy over a course of 25 fractions
(approximately 2 Gy per fraction), SBRT delivers 7 to 15 Gy per fraction with a lower number of total
fractions. This technique has the potential to be a more definitive therapeutic option than conventional
radiotherapy in light of the ablative intent of the treatment.
The use of radioactive implants, or brachytherapy, is common in the treatment of prostate and
gynecologic cancers. Radioactive seeds can be placed either directly into the tumor (interstitial therapy)
or within catheter-containing applicators placed in the vicinity of the tumor bed (intracavitary therapy).
Intracavitary therapy has been developed as a potential adjuvant therapy for patients following
resection of soft tissue sarcoma or partial mastectomy in the setting of breast conservation therapy.163
The use of intracavitary therapy in these clinical settings is being explored but has certainly not
achieved widespread acceptance.
In addition to intraoperative placement of radiation delivery applicators following resection, surgeons
have assisted with radiation delivery through the use of intraoperative radiation therapy. In select
environments where a specialized intraoperative irradiator is available, radiation is given directly to the
tumor bed where incomplete marginal resection has been performed. The radiation is delivered in a
single fraction of 10 to 15 Gy in combination with more traditional perioperative external beam
radiation. The most common clinical applications for this technique have been in the treatment of pelvic
and retroperitoneal tumors such as recurrent rectal cancer and retroperitoneal sarcoma.
The Role of Chemotherapy in Cancer Management

The use of chemotherapy as a modality in the treatment of cancer is almost universal and its efficacy is
based on systemic treatment of primary and metastatic cancer. Unlike surgical resection or radiation
therapy, the goal of chemotherapy is not necessarily localized or locoregional but systemic cancer
treatment.
The setting in which chemotherapy is given can be defined as neoadjuvant, conversion, adjuvant, or
palliative, dependent on the goals of the planned treatment course. Neoadjuvant chemotherapy is
administered prior to a planned curative surgical resection. The primary or metastatic tumor is
considered technically resectable at baseline but due to oncologic concerns of aggressive tumor biology
a period of chemotherapy is used. An example of neoadjuvant chemotherapy is in the treatment of
466
advanced gastric cancer. The MAGIC trial for resectable gastroesophageal cancer included a treatment
arm where patients with either node positive or locally advanced (by T tumor stage) gastric cancer
were treated with a short course of chemotherapy prior to curative gastrectomy.164 The potential
benefits of neoadjuvant chemotherapy is to treat micrometastatic disease not seen on preoperative
imaging, improve tumor-related symptoms, to allow for a period of time where metastatic disease can
present precluding unwarranted surgical resection, and an in vivo method of determining tumor
chemosensitivity. Conversion chemotherapy is also administered prior to surgical resection but the
baseline tumor is considered unresectable, typically due to technical reasons, unlike in the neoadjuvant
setting. An example of conversion chemotherapy is the administration of systemic chemotherapy to
patients with metastatic colorectal liver metastases where upfront surgical resection is precluding by a
sufficient future liver remnant.165,166 The goal of conversion chemotherapy is to downsize the baseline
tumor allowing a safe curative resection. Adjuvant chemotherapy is administered in the postoperative
setting after the primary or metastatic tumor is surgically resected. This is perhaps the most common
setting of chemotherapy administration. Palliative chemotherapy is the setting defined as unresectable
primary or metastatic cancer where the goal of chemotherapy is prolongation of life and not necessarily
conversion to a curative resection.
The choice of systemic chemotherapy regimens is oftentimes tumor specific and is based on
demonstrated efficacy in large phase III randomized controlled clinical trials. Table 14-12 lists the most
commonly administered chemotherapy regimens, the presumed mechanism of action, and the applicable
cancers treated.
The increasing knowledge of cancer genetics and biology has generated potential new targets for
systemic therapeutic regimens ushering in potential individualized cancer treatments. The best example
of a genetic abnormality with a systemic therapy specific for a molecular target is the BCR-ABL
chromosomal translocation seen in patients with chronic myelogenous leukemia (CML).167 The BCR-ABL
fusion protein is a dysregulated tyrosine kinase that has a causal role in the development of CML and
serves as the target for a new class of molecular inhibitors, tyrosine kinase inhibitors. The use of
imatinib mesylate in CML has served as a prototype for the development of molecular target agents in
other cancers, including gastrointestinal stromal tumor.168 Unfortunately, most tumors, including the
most common types, are genetically complex and do not offer a single target that serves as the critical
inhibition point for cancer cell death.
Lack of single, molecular targets has led to the development of molecular targeted agents aimed at
inhibition of pathways. An example of such a druggable pathway is the VEGF and its receptor (VEGFR).
The VEGF pathway is an important regulator of physiologic and pathologic angiogenesis and is thought
to promote tumor cell growth through increased vascular permeability, migration, differentiation of
endothelial cells, and mobilization of bone marrow–derived endothelial cell precursors.169
Overexpression of VEGF and/or VEGFR occurs in most common types of cancers and is associated with
worse tumor presentation and outcome measures.170–172 In 2004, the Federal Drug Administration
approved bevacizumab, a humanized murine monoclonal antibody directed against VEGF, for the
treatment of metastatic colorectal carcinoma.173 Subsequent approval of sunitinib, sorafenib, and
axitinib, three molecular targeted agents with activity against tyrosine kinase in addition to VEGF for
renal cell carcinoma and HCC has established targeting pathways as a viable target for cancer
therapeutics.174–177
Table 14-12 Common Systemic Therapeutic Agents for the Treatment of Cancer
467
468
Staging (Traditional and Genetic)
Cancer staging is the process of determining the cancer burden within the body and the location.
Staging describes the severity of an individual’s cancer based on the magnitude of the original or
primary tumor as well as on the extent of cancer spread via metastases. Understanding and properly
staging cancer is important as it provides a common language for communication among providers and
patients, is a prognostic marker of outcome, allows appropriate treatment decisions, and stratifies
469
patients for clinical trials.
There are four different types of staging: (1) clinical staging: based on physical examination, imaging
tests, and appropriate biopsies, (2) pathologic stage: determined following surgical excision of cancer;
both clinical and pathologic characteristics contribute to the pathologic stage, (3) neoadjuvant or
posttherapy staging: following treatment with systemic chemotherapy or radiation therapy, relying on
clinical and/or pathologic staging guidelines, and (4) restaging: the extent of recurrent disease
following definitive therapy. The formal stage of a cancer does not change over time, even if the cancer
progresses. A cancer that returns or demonstrates progression is still referred to by the stage it was
given at first diagnosis. Restaged cancer is noted with a lower case “r” indicating a restaging
designation.
Table 14-13 TNM Staging Based on AJCC and UICC Classification
Tumor staging in most solid tumors is based on four main factors: (1) location of the primary or
original tumor, (2) tumor size and/or extent of tumors, (3) lymph node involvement or spread, and (4)
presence or absence of distant metastases. The TNM staging system developed by the American Joint
Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) is the most widely
used system and is based on the extent of primary tumor (T), the extent of spread to lymph nodes (N),
and the presence of metastases (M). Table 14-13 demonstrates the general AJCC/UICC TNM staging
system; specific staging systems have been developed for each individual malignancy. Once the T, N,
and M individual stages are determined, they are combined, and an overall stage of 0, I, II, III, or IV is
assigned.
In addition to utilizing the traditional AJCC/UICC TNM staging systems, genomic data have been
recently incorporated to further fine tune and guide treatment decisions. The best-studied example is the
use of genomic tests for breast cancer staging. In four externally validated, commercially available tests,
genomic information is coupled with pathologic staging helping providers to determine the risk of
recurrence of early-stage, estrogen-receptor–positive breast cancers, and the benefit of adjuvant
chemotherapy. In addition, these genomic tests also have been validated in breast ductal carcinoma in
situ to determine the risk of recurrence following resection, the risk of a de novo cancer developing in
the same breast, and the benefits of adjuvant radiation therapy.178 Unfortunately, similar genomic tests
with proven clinical validation are lacking in other cancer subtypes and remain exploratory and useful
only in a research setting at this time.
Screening
The development of the periodic health examination in the late 19th century by medical providers was
the impetus linking cancer mortality to delay in diagnosis. In 1907, Dr. Charles Childe published the
first book, The Control of a Scourge, Or How Cancer is Curable, detailing cancer as a linear carcinogenesis
pathway that could be interrupted by identification of early warning signs and symptoms, thus
eradicating cancer.179 Although too simple, this publication and others led to the upsurge of a large-
scale health campaign in the 1940s within the United States aimed at advocating early cancer detection
programs, or cancer screening.
Technologic advances in screening and early detection are essential for progress in both the
prevention and treatment of cancer, but incorporation of such advances to useful clinical practice is
often challenging and requires careful consideration of all potential risks and benefits. For any screening
test to be useful, three tenets of screening should be met: (1) a test must exist that will detect the
470
disease earlier than routine methods, (2) evidence must exist that earlier treatment leads to improved
outcomes, and (3) benefits of screening must outweigh the risks associated with any subsequent
diagnostic and therapeutic treatments.
The Canadian Task Force on the Periodic Health Examination and the United States Preventive
Services Task Force (USPSTF) in Figure 14-7 provide the basic analytical framework necessary to
delineate the steps for evaluating the worth of a screening test.180 The framework demands a clear
identification of the population at risk that is to be screened. The importance of this starting point is due
to the potential changing nature of the screened population and extrapolation of findings from a subset
of patients to a general population. More importantly, the framework details the adverse effects of both
screening and treatment of early-stage cancers. Because screening tests are performed on healthy
individuals there is significant potential harm associated with a false-positive test. A recent meta-
analysis determined that after 3 years of screening tests, a man’s and woman’s risk of obtaining at least
one false-positive test was 60% and 50%, respectively.181,182 False-positive tests are a concern for three
reasons. First, they have the potential to generate negative psychological consequences. Second, they
can trigger a cascade of more invasive follow-up testing, which since the patient does not have cancer
and can obtain no benefit, represents pure harm to the individual. Third, false-positive tests and the
cascade of follow-up tests represent a significant burden to already strained healthcare resources.183
Figure 14-7. Analytic framework for evaluating a screening test. (Adapted from Harris RP, Helfand M, Woolf SH, et al. Current
methods of the US Preventative Task Force: a review of the process. Am J Prev Med 2001;20:21–35.)
Figure 14-8. A: With screening, the lead time in diagnosis prolongs survival even if death is not delayed. B: Screening is more
likely to detect indolent or slow-growing cancers therefore giving a length bias where survival appears improved with screening
but is secondary to the less aggressive tumor biology.
In addition to potential harms, at least two important biases, lead-time and length, need to be
accounted for prior to advocating for a screening test. The intent of screening is to advance the date of
diagnosis to an earlier point in time than it would otherwise been made. Therefore, lead-time refers to
the amount of time between screen-detected and symptom-detected diagnosis (Fig. 14-8A). This lead-
time in diagnosis appears to prolong survival in screened individuals, although mortality in this group
may not actually be delayed, creating a lead-time bias. The use of 5-year survival rates to judge the
efficacy of a cancer screening test must be used with caution. For example, the Mayo Lung Project used
chest x-ray and sputum cytology as screening modalities in a randomized controlled trial and
demonstrated that 5-year survival rates increased from 19% to 36% in the screened population.
However, lung cancer mortality rates were not significantly different between the two groups indicating
that although lung cancer was diagnosed sooner in the screened group no overall benefit was noted.184
Length-time bias refers to the tendency of screening to detect cancers that are indolent and slower
471
growing because of a longer detectable preclinical phase compared with faster-growing, more
aggressive forms of cancer (Fig. 14-8B). Consequently, in a group of screened individuals this
phenomenon creates the appearance that screening is extending survival, when in fact extended survival
is due to the more indolent nature of the cancers found in this group and not necessarily to the
screening itself. Over diagnosis is one extreme form of length-time bias and can occur in two situations:
(1) cancers that are so benign that they have virtually no growth potential and (2) cancers that grow so
slowly that the person would die of another competing cause of death before the tumor generated
symptoms. The classic indication of an over diagnosis bias is a rise in early-stage cancers coupled with a
minor or even nonexistent decline in incidence of late-stage disease. An example of over diagnosis is
seen in prostate cancer where although there is a decrease in the rate of late-stage disease, the absolute
rate of decline makes up only a tiny fraction of the associated increase in early-stage disease. Thereby,
there are more early cases being identified than late-stage cases being prevented.
4 Currently, population-based screening tests are available for the following cancers: cervical
(Papanicolaou test), colon (colonoscopy, fecal occult blood test, flexible sigmoidoscopy, and double-
contrast barium enema), breast (mammogram), and prostate (PSA test). The current recommendations
for screening by the USPSTF and/or American Cancer Society are listed in Table 14-14.185
Surveillance
Improving cancer survival rates have generated an increased focus on survivorship programs, or the
care of the cancer patient following treatment. One of the goals of these follow-up care programs is the
early detection of tumor recurrence and new primary cancers at a point where curative treatment is still
possible. Unfortunately, due to the heterogeneity of cancer treatment and outcome measures there is a
paucity of evidenced-based data concerning follow-up care, surveillance protocols, and secondary
prevention measures for survivors of cancer. Currently, there are recommended guidelines for only two
cancers, colorectal and breast, detailing survivorship programs.186,187
Surveillance following curative resection of colorectal cancer is guided by the presumed risk of
recurrence and functional status of the patient and is generally heightened in the first 4 years following
surgery.187 Current ASCO guidelines recommend the following: (1) a medical history, physical
examination, and carcinoembryonic antigen (CEA) testing every 3 to 6 months for 5 years, (2) annual
abdominal and chest imaging using computed tomography for 3 years, PET imaging is not recommend,
and (3) surveillance colonoscopy approximately 1 year following surgery with repeat procedures every
5 years if no abnormal findings.
Table 14-14 Current Population-Based Screening Recommendations
The length of surveillance following breast cancer treatment corresponds to the risk of recurrence. As
breast cancer recurrences can occur decades following curative treatment, current continual surveillance
is recommended for at least 15 years.186 Current ASCO guidelines also recommend the following: (1)
history and physical examination every 3 to 6 months for the first 3 years, then every 6 to 12 months
for the next 2 years, and then annually, (2) referral to genetic counseling for women at high risk for
familial breast cancer syndromes, (3) mammography beginning 6 months after definitive radiation
therapy, then annual mammograms following stability of mammographic findings, and (4) regular
gynecologic follow-up.
472
Cancer Biostatistics
The driving force behind the maturation of an epidemiologic approach to oncology has been the
incorporation of statistical analysis in modern medical research. This is no more evident than when
discussing survival rates following diagnosis with cancer. The most common survival statistic is OS,
which is typically defined as the time from diagnosis or treatment to death from any cause and is
measured either as a median (months) or as a percentage over 5 years (5-year OS). Disease-specific
survival (DSS) is similar to OS and is measured in months or in a 5-year percentage but where the end
measure is death due to cancer, which is oftentimes difficult to ascertain retrospectively. PFS and time
to progression (TTP) are commonly used to assess efficacy in cancer drug development. PFS is defined
as time of treatment start (or randomization in randomized clinical trials) to the time of disease
progression or death from any cause. Similarly, TTP measures the interval from time to treatment start
but concludes at time of disease progression. Unlike PFS, deaths are censored from analysis in TTP
calculations. Although, used interchangeably, PFS is likely more suitable to situations where a therapy
or intervention can produce an adverse event directly leading to death. Whereas, TTP is more
commonly used in clinical trials with high underlying patient comorbidity, where early patient death
from nontreatment-related events could negatively skew the studied treatment effects. Other commonly
used survival rates include DFS and recurrence-free survival (RFS). DFS is defined as the time from
treatment to recurrence of disease either from the treated cancer or a new primary. RFS is defined as
the time from treatment to recurrence of disease only related to the treated cancer and not a new
primary. Again, both RFS and DFS can be measured in months or time interval percentage, commonly 3-
or 5-year increments.
In a typical clinical trial or study, survival outcome data are represented as a Kaplan–Meier plot (Fig.
14-9). In constructing a Kaplan–Meier survival curve, the probability of surviving in a given length of
time is calculated. For each time interval, survival probability is calculated as the number of subjects
surviving divided by the number of patients at risk. Subjects who have died or dropped out are no
longer considered part of the at-risk population and are removed from the denominator. Within the
graphical representation of the plot, if a patient is removed or no longer participating in the study
before the final outcome is observed, death in OS analysis, the patient is censored and a small vertical
tick mark is seen. The most common statistical method comparing Kaplan–Meier estimates is the log
rank test, which calculates the chi-square for each event time for each group and sums the results giving
a p-value. In addition to the log rank test, median values of an outcome measure can be calculated from
a Kaplan–Meier plot.188
Figure 14-9. Kaplan–Meier survival curve of a hypothetical cancer. Median overall survival is plotted by the time in months of the
median or 50% patient (red line). Deaths represent the step down lines in the curve. Censored events including lost to follow-up
are represented by the vertical tick marks.
Clinical Trials
Clinical trials, in their purest form, are designed to observe outcomes of human subjects under
“experimental” conditions controlled by the researcher. Prior to initiation of human clinical trials,
preclinical investigations include the following animal studies: studying the treatment or drugs safety in
animals at doses equivalent to human exposure, pharmacodynamics, and pharmacokinetics need to be
completed. Pharmacodynamics is the study of what a drug or treatment does to the body, whereas
pharmacokinetics is the study of the body’s effect on the drug.
473
The first studies done in human are phase I trials. These are usually open-labeled studies performed in
a small number of “healthy” or “diseased” individuals with the intent on obtaining the MTD useful for
further trials. The MTD is determined by dose escalation of the study drug or treatment and closely
following patients for predetermined, dose-limiting toxicities or adverse events. Typically, there are no
therapeutic end points including survival or progression included in phase I trials.
Phase II trials, also referred to as “therapeutic exploratory” trials, are usually larger than phase I
trials, and are conducted in patients with the disease in question. They are designed to test safety,
pharmacokinetics, and pharmacodynamics as well as providing preliminary data on optimal doses and
frequencies for future phase III trials. Trial design can include a single arm with comparison to historical
controls or a randomized design comparing the study drug or treatment directly with either placebo or a
known drug or treatment. Usually the narrow scope of phase II trials prevents full approval for a study
drug or treatment and requires validation in a phase III trial.
Phase III trials, are typically large-scale studies performed in a more diverse target population in
order to confirm efficacy of earlier trials and to identify and estimate the incidence of common adverse
events. The most common type of phase III trial is comparing the intervention of interest with either a
standard therapy or placebo with a balance in treatment allocation typically through randomization.
Another feature of phase III trial design is stratification, which balances study arms by ensuring that
specific prognostic factors of presumed clinical importance are properly balanced in the arms of a
clinical trial. Following drug or treatment approval, a phase IV trial may be completed. These trials also
referred to as “postmarketing” studies are observational in nature and are aimed at identifying less
common adverse reactions and evaluating cost and/or drug effectiveness in diseases, populations, doses
similar to or markedly different from the original population. The results of phase IV studies can lead to
new black box warnings and even withdrawal of the drug or treatment for safety reasons.189
References
1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64:9–29.
2. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin 2014;64:104–117.
3. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975–
2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and
treatment) to reduce future rates. Cancer 2010;116:544–573.
4. Cress RD, Morris C, Ellison GL, et al. Secular changes in colorectal cancer incidence by subsite,
stage at diagnosis, and race/ethnicity, 1992–2001. Cancer 2006;107:1142–1152.
5. Weiss W. Cigarette smoking and lung cancer trends. A light at the end of the tunnel? Chest
1997;111:1414–1416.
6. Jemal A, Thun MJ, Ries LA, et al. Annual report to the nation on the status of cancer, 1975–2005,
featuring trends in lung cancer, tobacco use, and tobacco control. J Natl Cancer Inst 2008;100:1672–
1694.
7. Simard EP, Ward EM, Siegel R, et al. Cancers with increasing incidence trends in the United States:
1999 through 2008. CA Cancer J Clin 2012; 62:118–128.
8. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screening and adjuvant therapy on mortality from
breast cancer. N Engl J Med 2005;353:1784–1792.
9. Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate
cancer mortality decline. Cancer Causes Control 2008;19:175–181.
10. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A
1971;68:820–823.
11. Friend SH, Bernards R, Rogelj S, et al. A human DNA segment with properties of the gene that
predisposes to retinoblastoma and osteosarcoma. Nature 1986;323:643–646.
12. Lohmann DR, Gallie BL. Retinoblastoma: revisiting the model prototype of inherited cancer. Am J
Med Genet C Semin Med Genet 2004;129C:23–28.
13. Stadler ZK, Thom P, Robson ME, et al. Genome-wide association studies of cancer. J Clin Oncol
2010;28:4255–4267.
14. Lindor NM, McMaster ML, Lindor CJ, et al. Concise handbook of familial cancer susceptibility
syndromes - second edition. J Natl Cancer Inst Monogr 2008;(38):1–93.
15. Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role of risk-reducing surgery
474
in common hereditary cancer syndromes. J Clin Oncol 2006;24:4642–4660.
16. Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med 2003;348:919–932.
17. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary
nonpolyposis colorectal cancer. Cell 1993;75:1215–1225.
18. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association
with hereditary nonpolyposis colon cancer. Cell 1993;75:1027–1038.
19. Bronner CE, Baker SM, Morrison PT, et al. Mutation in the DNA mismatch repair gene homologue
hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994;368:258–261.
20. Liu B, Parsons R, Papadopoulos N, et al. Analysis of mismatch repair genes in hereditary non-
polyposis colorectal cancer patients. Nat Med 1996;2:169–174.
21. Wijnen JT, Vasen HF, Khan PM, et al. Clinical findings with implications for genetic testing in
families with clustering of colorectal cancer. N Engl J Med 1998;339:511–518.
22. Bailey-Wilson JE, Elston RC, Schuelke GS, et al. Segregation analysis of hereditary nonpolyposis
colorectal cancer. Genet Epidemiol 1986;3:27–38.
23. Vasen HF, Taal BG, Griffioen G, et al. Clinical heterogeneity of familial colorectal cancer and its
influence on screening protocols. Gut 1994; 35:1262–1266.
24. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair
genes. Int J Cancer 1999;81:214–248.
25. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal
cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC.
Gastroenterology 1999; 116:1453–1456.
26. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda Guidelines for hereditary nonpolyposis
colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 2004;96:261–
268.
27. Burt RW, Leppert MF, Slattery ML, et al. Genetic testing and phenotype in a large kindred with
attenuated familial adenomatous polyposis. Gastroenterology 2004;127:444–451.
28. Kinzler KW, Nilbert MC, Su LK, et al. Identification of FAP locus genes from chromosome 5q21.
Science 1991;253:661–665.
29. Campbell WJ, Spence RA, Parks TG. Familial adenomatous polyposis. Br J Surg 1994;81:1722–1733.
30. Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with
BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined
analysis of 22 studies. Am J Hum Genet 2003;72:1117–1130.
31. Pharoah PD, Antoniou A, Bobrow M, et al. Polygenic susceptibility to breast cancer and
implications for prevention. Nat Genet 2002;31:33–36.
32. Futreal PA, Liu Q, Shattuck-Eidens D, et al. BRCA1 mutations in primary breast and ovarian
carcinomas. Science 1994;266:120–122.
33. Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene
BRCA2. Nature 1995;378:789–792.
34. Kauff ND, Perez-Segura P, Robson ME, et al. Incidence of non-founder BRCA1 and BRCA2
mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet 2002;39:611–614.
35. Guilford PJ, Hopkins JB, Grady WM, et al. E-cadherin germline mutations define an inherited
cancer syndrome dominated by diffuse gastric cancer. Hum Mutat 1999;14:249–255.
36. Brooks-Wilson AR, Kaurah P, Suriano G, et al. Germline E-cadherin mutations in hereditary diffuse
gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet
2004;41:508–517.
37. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus
guidelines for clinical management and directions for future research. J Med Genet 2010;47:436–
444.
38. Lonser RR, Glenn GM, Walther M, et al. von Hippel-Lindau disease. Lancet 2003;361:2059–2067.
39. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with biallelic loss of fumarate
hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell
2005;8:143–153.
40. Waldron HA. On the history of scrotal cancer. Ann R Coll Surg Engl 1983; 65:420–422.
475
41. Dipple A, Pigott MA, Bigger CA, et al. 7,12-dimethylbenz[a] anthracene–DNA binding in mouse
skin: response of different mouse strains and effects of various modifiers of carcinogenesis.
Carcinogenesis 1984;5:1087–1090.
42. Sasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent
epidemiological evidence. Lung Cancer 2004;45(suppl 2):S3–S9.
43. IARC. IARC Monographs on the evaluation of teh carcinogenic risk of chemicals to humans, in IARC
(ed): IARC press. Lyon, France, IARC, 2004.
44. Cerutti PA. Oxy-radicals and cancer. Lancet 1994;344:862–863.
45. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer
2006;118:3030–3044.
46. Weiss RA, Vogt PK. 100 years of Rous sarcoma virus. J Exp Med 2011; 208:2351–2355.
47. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology
2012;142:1264–1273.e1.
48. Natoli G, Avantaggiati ML, Chirillo P, et al. Modulation of intracellular signal transduction
pathways by the hepatitis B virus transactivator pX. J Hepatol 1995;22:14–20.
49. Lee YH, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling. J Biol Chem
1998;273:25510–25515.
50. Diao J, Khine AA, Sarangi F, et al. X protein of hepatitis B virus inhibits Fas-mediated apoptosis and
is associated with up-regulation of the SAPK/JNK pathway. J Biol Chem 2001;276:8328–8340.
51. Lee YI, Kang-Park S, Do SI, et al. The hepatitis B virus-X protein activates a phosphatidylinositol 3-
kinase-dependent survival signaling cascade. J Biol Chem 2001;276:16969–16977.
52. Forns X, Purcell RH, Bukh J. Quasispecies in viral persistence and pathogenesis of hepatitis C virus.
Trends Microbiol 1999;7:402–410.
53. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the
United States, 1988 through 1994. N Engl J Med 1999;341:556–562.
54. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types
associated with cervical cancer. N Engl J Med 2003;348:518–527.
55. Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer
worldwide: a meta-analysis. Br J Cancer 2003; 88:63–73.
56. Fehrmann F, Laimins LA. Human papillomaviruses: targeting differentiating epithelial cells for
malignant transformation. Oncogene 2003;22:5201–5207.
57. Francis DA, Schmid SI, Howley PM. Repression of the integrated papillomavirus E6/E7 promoter is
required for growth suppression of cervical cancer cells. J Virol 2000;74:2679–2686.
58. Lehtinen M, Dillner J. Clinical trials of human papillomavirus vaccines and beyond. Nat Rev Clin
Oncol 2013;10:400–410.
59. Dupin N, Fisher C, Kellam P, et al. Distribution of human herpesvirus-8 latently infected cells in
Kaposi’s sarcoma, multicentric Castleman’s disease, and primary effusion lymphoma. Proc Natl Acad
Sci U S A 1999;96:4546–4551.
60. Antman K, Chang Y. Kaposi’s sarcoma. N Engl J Med 2000;342:1027–1038.
61. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the
United States today. J Natl Cancer Inst 1981;66:1191–1308.
62. Key TJ, Schatzkin A, Willett WC, et al. Diet, nutrition and the prevention of cancer. Public Health
Nutr 2004;7:187–200.
63. Kolonel LN, Hankin JH, Lee J, et al. Nutrient intakes in relation to cancer incidence in Hawaii. Br J
Cancer 1981;44:332–339.
64. Kolonel LN, Hankin JH, Nomura AM, et al. Dietary fat intake and cancer incidence among five
ethnic groups in Hawaii. Cancer Res 1981;41:3727–3728.
65. Ziegler RG, Hoover RN, Pike MC, et al. Migration patterns and breast cancer risk in Asian-American
women. J Natl Cancer Inst 1993;85:1819–1827.
66. Arnold M, Pandeya N, Byrnes G, et al. Global burden of cancer attributable to high body-mass index
in 2012: a population-based study. Lancet Oncol 2015;16:36–46.
67. Anderson GL, Neuhouser ML. Obesity and the risk for premenopausal and postmenopausal breast
cancer. Cancer Prev Res (Phila) 2012;5:515–521.
476
68. Setiawan VW, Yang HP, Pike MC, et al. Type I and II endometrial cancers: have they different risk
factors? J Clin Oncol 2013;31:2607–2618.
69. Hartwell LH, Weinert TA. Checkpoints: controls that ensure the order of cell cycle events. Science
1989;246:629–634.
70. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med 2004;10:789–799.
71. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat
Rev Cancer 2008;8:671–682.
72. Vousden KH, Lu X. Live or let die: the cell’s response to p53. Nat Rev Cancer 2002;2:594–604.
73. McBride KA, Ballinger ML, Killick E, et al. Li-Fraumeni syndrome: cancer risk assessment and
clinical management. Nat Rev Clin Oncol 2014; 11:260–271.
74. Burnet F. Cancer-a biological approach. Br Med J 1957;1:841–847.
75. Thomas L. Cellular and Humoral Aspects of the Hypersensitive States in Hoeber-Harpe (ed). New York,
NY; 1959.
76. Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol 2003;21:807–
839.
77. Penn I. Tumors of the immunocompromised patient. Annu Rev Med 1988;39:63–73.
78. Carbone A, Vaccher E, Gloghini A, et al. Diagnosis and management of lymphomas and other
cancers in HIV-infected patients. Nat Rev Clin Oncol 2014;11:223–238.
79. Yopp AC, Subramanian M, Jain MK, et al. Presentation, treatment, and clinical outcomes of patients
with hepatocellular carcinoma, with and without human immunodeficiency virus infection. Clin
Gastroenterol Hepatol 2012;10:1284–1290.
80. Rubinstein PG, Aboulafia DM, Zloza A. Malignancies in HIV/AIDS: from epidemiology to
therapeutic challenges. AIDS 2014;28:453–465.
81. Roithmaier S, Haydon AM, Loi S, et al. Incidence of malignancies in heart and/or lung transplant
recipients: a single-institution experience. J Heart Lung Transplant 2007;26:845–849.
82. Knoll GA, Kokolo MB, Mallick R, et al. Effect of sirolimus on malignancy and survival after kidney
transplantation: systematic review and meta-analysis of individual patient data. BMJ
2014;349:g6679.
83. Melvold RW, Sticca RP. Basic and tumor immunology: a review. Surg Oncol Clin North Am
2007;16:711–735, vii.
84. Waldhauer I, Steinle A. NK cells and cancer immunosurveillance. Oncogene 2008;27:5932–5943.
85. Clemente CG, Mihm MC Jr, Bufalino R, et al. Prognostic value of tumor infiltrating lymphocytes in
the vertical growth phase of primary cutaneous melanoma. Cancer 1996;77:1303–1310.
86. Lee WS, Kang M, Baek JH, et al. Clinical impact of tumor-infiltrating lymphocytes for survival in
curatively resected stage IV colon cancer with isolated liver or lung metastasis. Ann Surg Oncol
2013;20:697–702.
87. Salama P, Phillips M, Grieu F, et al. Tumor-infiltrating FOXP3+ T regulatory cells show strong
prognostic significance in colorectal cancer. J Clin Oncol 2009;27:186–192.
88. Tsoutsou PG, Bourhis J, Coukos G. Tumor-infiltrating lymphocytes in triple-negative breast cancer:
a biomarker for use beyond prognosis? J Clin Oncol 2015;33(11):1297–1298.
89. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer
2012;12:252–264.
90. Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction.
Immunol Rev 2009;229:12–26.
91. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev
Immunol 1996;14:233–258.
92. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with
metastatic melanoma. N Engl J Med 2010;363:711–723.
93. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev
Immunol 2008;26:677–704.
94. Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison
cohort of a phase 1 trial. Lancet 2014; 384:1109–1117.
477
95. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N
Engl J Med 2013;369:122–133.
96. De Andrade JP, Mezhir JJ. The critical role of peritoneal cytology in the staging of gastric cancer:
an evidence-based review. J Surg Oncol 2014;110(3):291–297.
97. Hur H, Lee HH, Jung H, et al. Predicting factors of unexpected peritoneal seeding in locally
advanced gastric cancer: indications for staging laparoscopy. J Surg Oncol 2010;102(7):753–757.
98. Childers JM, Lang J, Surwit EA, et al. Laparoscopic surgical staging of ovarian cancer. Gynecol
Oncol 1995;59(1):25–33.
99. Arnold JC, Neubauer HJ, Zöpf T, et al. Improved tumor staging by diagnostic laparoscopy. Z
Gastroenterol 1999;37(6):483–488.
100. Austin F, Mavanur A, Sathaiah M, et al. Aggressive management of peritoneal carcinomatosis from
mucinous appendiceal neoplasms. Ann Surg Oncol 2012;19(5):1386–1393.
101. Liu Y, Ishibashi H, Hirano M, et al. Cytoreductive surgery plus hyperthermic intraperitoneal
chemotherapy for pseudomyxoma peritonei arising from urachus. Ann Surg Oncol 2015;22(8):2799–
2805.
102. Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a
curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001;27(3):239–243.
103. Martinek IE, Kehoe S. When should surgical cytoreduction in advanced ovarian cancer take place? J
Oncol 2010;2010:852028.
104. van der Burg ME, van Lent M, Buyse M, et al. The effect of debulking surgery after induction
chemotherapy on the prognosis in advanced epithelial ovarian cancer. Gynecological Cancer
Cooperative Group of the European Organization for Research and Treatment of Cancer. N Engl J
Med 1995;332(10):629–634.
105. Chambers AJ, Pasieka JL, Dixon E, et al. The palliative benefit of aggressive surgical intervention
for both hepatic and mesenteric metastases from neuroendocrine tumors. Surgery 2008;144(4):645–
651; discussion 651–653.
106. Gomez D, Malik HZ, Al-Mukthar A, et al. Hepatic resection for metastatic gastrointestinal and
pancreatic neuroendocrine tumours: outcome and prognostic predictors. HPB (Oxford)
2007;9(5):345–351.
107. Tachezy M, Bockhorn M, Gebauer F, et al. Bypass surgery versus intentionally incomplete resection
in palliation of pancreatic cancer: is resection the lesser evil? J Gastrointest Surg 2011;15(5):829–
835.
108. Uzan C, Vincens E, Balleyguier C, et al. Outcome of patients with incomplete resection after
surgery for stage IB2/II cervical carcinoma with chemoradiation therapy. Int J Gynecol Cancer
2010;20(3):379–384.
109. Laramore GE, Scott CB, Schuller DE, et al. Is a surgical resection leaving positive margins of benefit
to the patient with locally advanced squamous cell carcinoma of the head and neck: a comparative
study using the intergroup study 0034 and the Radiation Therapy Oncology Group head and neck
database. Int J Radiat Oncol Biol Phys 1993;27(5):1011–1016.
110. Ratto GB, Fabiano F, Rovida S, et al. Survival after incomplete resection or exploratory
thoracotomy in patients with advanced non small cell lung cancer. Ital J Surg Sci 1988;18(4):377–
383.
111. Donadon M, Costa G, Cimino M, et al. Safe hepatectomy selection criteria for hepatocellular
carcinoma patients: a validation of 336 consecutive hepatectomies. The BILCHE score. World J Surg
2015;39(1):237–243.
112. Pulitano C, Crawford M, Joseph D, et al. Preoperative assessment of postoperative liver function:
the importance of residual liver volume. J Surg Oncol 2014;110(4):445–450.
113. Guglielmi A, Ruzzenente A, Conci S, et al. How much remnant is enough in liver resection? Dig Surg
2012;29(1):6–17.
114. Takada T, Yasuda H, Amano H, et al. Simultaneous hepatic resection with pancreato-duodenectomy
for metastatic pancreatic head carcinoma: does it improve survival? Hepatogastroenterology
1997;44(14):567–573.
115. Morrogh M, Miner TJ, Park A, et al. A prospective evaluation of the durability of palliative
interventions for patients with metastatic breast cancer. Cancer 2010;116(14):3338–3347.
478
116. Miner TJ, Jaques DP, Karpeh MS, et al. Defining palliative surgery in patients receiving
noncurative resections for gastric cancer. J Am Coll Surg 2004;198(6):1013–1021.
117. Balch CM, Soong SJ, Smith T, et al.; Investigators from the Intergroup Melanoma Surgical Trial.
Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740
patients with 1–4 mm melanomas. Ann Surg Oncol 2001;8(2):101–108.
118. Humphrey KL, Saksena MA, Freer PE, et al. To do or not to do: axillary nodal evaluation after
ACOSOG Z0011 Trial. Radiographics 2014;34(7):1807–1816.
119. Ogiya A, Kimura K, Nakashima E, et al. Long-term prognoses and outcomes of axillary lymph node
recurrence in 2,578 sentinel lymph node-negative patients for whom axillary lymph node dissection
was omitted: results from one Japanese hospital. Breast Cancer 2014.
120. Rosenberg SA, Kent H, Costa J, et al. Prospective randomized evaluation of the role of limb-sparing
surgery, radiation therapy, and adjuvant chemoimmunotherapy in the treatment of adult soft-tissue
sarcomas. Surgery 1978;84(1):62–69.
121. Martin R, Paty P, Fong Y, et al. Simultaneous liver and colorectal resections are safe for
synchronous colorectal liver metastasis. J Am Coll Surg 2003;197(2):233–241; discussion 241–242.
122. House MG, Ito H, Gönen M, et al. Survival after hepatic resection for metastatic colorectal cancer:
trends in outcomes for 1,600 patients during two decades at a single institution. J Am Coll Surg
2010;210(5):744–752, 752–755.
123. Papavasiliou P, Hoffman JP, Cohen SJ, et al. Impact of preoperative therapy on patterns of
recurrence in pancreatic cancer. HPB (Oxford) 2014; 16(1):34–39.
124. Paulino AC. Resected pancreatic cancer treated with adjuvant radiotherapy with or without 5-
fluorouracil: treatment results and patterns of failure. Am J Clin Oncol 1999;22(5):489–494.
125. Sperti C, Pasquali C, Piccoli A, et al. Recurrence after resection for ductal adenocarcinoma of the
pancreas. World J Surg 1997;21(2):195–200.
126. Halsted WS. I. A clinical and histological study of certain adenocarcinomata of the breast: and a
brief consideration of the supraclavicular operation and of the results of operations for cancer of
the breast from 1889 to 1898 at the Johns Hopkins Hospital. Ann Surg 1898;28(5):557–576.
127. Halsted WS. I. The results of operations for the cure of cancer of the breast performed at the Johns
Hopkins Hospital from June, 1889, to January, 1894. Ann Surg 1894;20(5):497–555.
128. Durham AB, Wong SL. Sentinel lymph node biopsy in melanoma: final results of MSLT-I. Future
Oncol 2014;10(7):1121–1123.
129. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up
results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11(5):439–449.
130. Roder JD, Bonenkamp JJ, Craven J, et al. Lymphadenectomy for gastric cancer in clinical trials:
update. World J Surg 1995;19(4):546–553.
131. Giuliano AE, McCall L, Beitsch P, et al. Locoregional recurrence after sentinel lymph node
dissection with or without axillary dissection in patients with sentinel lymph node metastases: the
American College of Surgeons Oncology Group Z0011 randomized trial. Ann Surg 2010;252(3):426–
132. Rhoads KF, Ackerson LK, Ngo JV, et al. Adequacy of lymph node examination in colorectal surgery:
contribution of the hospital versus the surgeon. Med Care 2013;51(12):1055–1062.
133. Kidner TB, Ozao-Choy JJ, Yoon J, et al. Should quality measures for lymph node dissection in colon
cancer be extrapolated to rectal cancer? Am J Surg 2012;204(6):843–847; discussion 847–848.
134. Mathoulin-Pelissier S, Bécouarn Y, Belleannée G, et al. Quality indicators for colorectal cancer
surgery and care according to patient-, tumor-, and hospital-related factors. BMC Cancer
2012;12:297.
135. Parsons HM, Tuttle TM, Kuntz KM, et al. Quality of care along the cancer continuum: does
receiving adequate lymph node evaluation for colon cancer lead to comprehensive postsurgical
care? J Am Coll Surg 2012;215(3):400–411.
136. Bikhchandani J, Ong GK, Dozois EJ, et al. Outcomes of salvage surgery for cure in patients with
locally recurrent disease after local excision of rectal cancer. Dis Colon Rectum 2015;58(3):283–287.
137. Guerrieri M, Gesuita R, Ghiselli R, et al. Treatment of rectal cancer by transanal endoscopic
microsurgery: experience with 425 patients. World J Gastroenterol 2014;20(28):9556–9563.
138. Ueno H, Mochizuki H, Shinto E, et al. Histologic indices in biopsy specimens for estimating the
479
probability of extended local spread in patients with rectal carcinoma. Cancer 2002;94(11):2882–
2891.
139. Beesley VL, Rowlands IJ, Hayes SC, et al. Incidence, risk factors and estimates of a woman’s risk of
developing secondary lower limb lymphedema and lymphedema-specific supportive care needs in
women treated for endometrial cancer. Gynecol Oncol 2015;136(1):87–93.
140. Farrell R, Gebski V, Hacker NF. Quality of life after complete lymphadenectomy for vulvar cancer:
do women prefer sentinel lymph node biopsy? Int J Gynecol Cancer 2014;24(4):813–819.
141. Angioli R, Plotti F, Cafà EV, et al. Quality of life in patients with endometrial cancer treated with
or without systematic lymphadenectomy. Eur J Obstet Gynecol Reprod Biol 2013;170(2):539–543.
142. Faries MB, Thompson JF, Cochran A, et al. The impact on morbidity and length of stay of early
versus delayed complete lymphadenectomy in melanoma: results of the multicenter selective
lymphadenectomy trial (I). Ann Surg Oncol 2010;17(12):3324–3329.
143. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for
metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999;230(3):309–318;
144. Kavolius JP, Mastorakos DP, Pavlovich C, et al. Resection of metastatic renal cell carcinoma. J Clin
Oncol 1998;16(6):2261–2266.
145. Kim S, Ott HC, Wright CD, et al. Pulmonary resection of metastatic sarcoma: prognostic factors
associated with improved outcomes. Ann Thorac Surg 2011;92(5):1780–1786; discussion 1786–1787.
146. Blazer DG 3rd, Kishi Y, Maru DM, et al. Pathologic response to preoperative chemotherapy: a new
outcome end point after resection of hepatic colorectal metastases. J Clin Oncol 2008;26(33):5344–
5351.
147. Yoshita H, Hosokawa A, Ueda A, et al. Predictive value of optimal morphologic response to first-
line chemotherapy in patients with colorectal liver metastases. Digestion 2014;89(1):43–48.
148. Negrier S, Bushmakin AG, Cappelleri JC, et al. Assessment of progression-free survival as a
surrogate end-point for overall survival in patients with metastatic renal cell carcinoma. Eur J
Cancer 2014;50(10):1766–1771.
149. Saad ED, Katz A, Hoff PM, et al. Progression-free survival as surrogate and as true end point:
insights from the breast and colorectal cancer literature. Ann Oncol 2010;21(1):7–12.
150. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours:
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–247.
151. Aloia TA, Zimmitti G, Conrad C, et al. Return to intended oncologic treatment (RIOT): a novel
metric for evaluating the quality of oncosurgical therapy for malignancy. J Surg Oncol
2014;110(2):107–114.
152. Jalal N, Haq S, Anwar N, et al. Radiation induced bystander effect and DNA damage. J Cancer Res
Ther 2014;10(4):819–833.
153. Murray D, McBride WH, Schwartz JL. Radiation biology in the context of changing patterns of
radiotherapy. Radiat Res 2014;182(3):259–272.
154. Dizdaroglu M. Oxidatively induced DNA damage and its repair in cancer. Mutat Res Rev Mutat Res
2015;763:212–245.
155. Bak ST, Sakellariou D, Pena-Diaz J. The dual nature of mismatch repair as antimutator and mutator:
for better or for worse. Front Genet 2014;5:287.
156. Hei TK, Zhou H, Chai Y, et al. Radiation induced non-targeted response: mechanism and potential
clinical implications. Curr Mol Pharmacol 2011;4(2):96–105.
157. Choi DK, Helenowski I, Hijiya N. Secondary malignancies in pediatric cancer survivors:
perspectives and review of the literature. Int J Cancer 2014;135(8):1764–1773.
158. Lee J, Lim do H, Kim S, et al. Phase III trial comparing capecitabine plus cisplatin versus
capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric
cancer with D2 lymph node dissection: the ARTIST trial. J Clin Oncol 2012;30(3):268–273.
159. Naing KW, Monjazeb AM, Li CS, et al. Perioperative radiotherapy is associated with improved
survival among patients with synovial sarcoma: a SEER analysis. J Surg Oncol 2015;111(2):158–
164.
160. Siegel R, Burock S, Wernecke KD, et al. Preoperative short-course radiotherapy versus combined
radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised
480
study of the Berlin Cancer Society. BMC Cancer 2009;9:50.
161. Glynne-Jones R, Nilsson PJ, Aschele C, et al. Anal cancer: ESMO-ESSO-ESTRO clinical practice
guidelines for diagnosis, treatment and follow-up. Eur J Surg Oncol 2014;40(10):1165–1176.
162. Nguyen NP, Ries T, Vock J, et al. Effectiveness of radiotherapy for elderly patients with non-
melanoma skin cancer of the head. Geriatr Gerontol Int 2014;15(5):601–605.
163. Holloway CL, Delaney TF, Alektiar KM, et al. American Brachytherapy Society (ABS) consensus
statement for sarcoma brachytherapy. Brachytherapy 2013;12(3):179–190.
164. Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for
resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.
165. Lam VW, Spiro C, Laurence JM, et al. A systematic review of clinical response and survival
outcomes of downsizing systemic chemotherapy and rescue liver surgery in patients with initially
unresectable colorectal liver metastases. Ann Surg Oncol 2012;19:1292–1301.
166. Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver
metastases: is there a possibility of cure? J Clin Oncol 2009;27:1829–1835.
167. Ben-Neriah Y, Daley GQ, Mes-Masson AM, et al. The chronic myelogenous leukemia-specific P210
protein is the product of the bcr/abl hybrid gene. Science 1986;233:212–214.
168. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a
patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–1056.
169. Folkman J. Antiangiogenesis in cancer therapy–endostatin and its mechanisms of action. Exp Cell
Res 2006;312:594–607.
170. Chao C, Al-Saleem T, Brooks JJ, et al. Vascular endothelial growth factor and soft tissue sarcomas:
tumor expression correlates with grade. Ann Surg Oncol 2001;8:260–267.
171. Tokunaga T, Oshika Y, Abe Y, et al. Vascular endothelial growth factor (VEGF) mRNA isoform
expression pattern is correlated with liver metastasis and poor prognosis in colon cancer. Br J
Cancer 1998;77:998–1002.
172. Heer K, Kumar H, Read JR, et al. Serum vascular endothelial growth factor in breast cancer: its
relation with cancer type and estrogen receptor status. Clin Cancer Res 2001;7:3491–3494.
173. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based
chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J
Clin Oncol 2008;26:2013–2019.
174. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J
Med 2008;359:378–390.
175. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final
efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation
trial. J Clin Oncol 2009;27:3312–3318.
176. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell
carcinoma. N Engl J Med 2007;356:115–124.
177. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-
refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007;8:975–984.
178. Ellis M. Genomic analysis of breast cancer heralds a changing treatment paradigm. J Natl Compr
Canc Netw 2014;12:750–752.
179. Childe C. The Control of a Scourge, or How Cancer is Curable. New York, NY: E.P. Dutton; 1907.
180. Harris RP, Helfand M, Woolf SH, et al. Current methods of the US Preventive Services Task Force:
a review of the process. Am J Prev Med 2001;20:21–35.
181. Elmore JG, Barton MB, Moceri VM, et al. Ten-year risk of false positive screening mammograms
and clinical breast examinations. N Engl J Med 1998;338:1089–1096.
182. Croswell JM, Kramer BS, Kreimer AR, et al. Cumulative incidence of false-positive results in
repeated, multimodal cancer screening. Ann Fam Med 2009;7:212–222.
183. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and
study design issues. Semin Oncol 2010;37:202–215.
184. Fontana RS, Sanderson DR, Woolner LB, et al. Screening for lung cancer. A critique of the Mayo
Lung Project. Cancer 1991;67:1155–1164.
185. Smith RA, Manassaram-Baptiste D, Brooks D, et al. Cancer screening in the United States, 2015: a
481
review of current American cancer society guidelines and current issues in cancer screening. CA
Cancer J Clin 2015;65:30–54.
186. Burstein HJ, Temin S, Anderson H, et al. Adjuvant endocrine therapy for women with hormone
receptor-positive breast cancer: american society of clinical oncology clinical practice guideline
focused update. J Clin Oncol 2014;32:2255–2269.
187. Desch CE, Benson AB 3rd, Smith TJ, et al. Recommended colorectal cancer surveillance guidelines
by the American Society of Clinical Oncology. J Clin Oncol 1999;17:1312.
188. Guller U, DeLong ER. Interpreting statistics in medical literature: a vade mecum for surgeons. J Am
Coll Surg 2004;198:441–458.
189. Umscheid CA, Margolis DJ, Grossman CE. Key concepts of clinical trials: a narrative review.
Postgrad Med 2011;123:194–204.
482
Chapter 15
Preoperative Risk Assessment

Pauline Park
Key Points
1 Preoperative risk assessment is critical to informing patients of the risk and benefits of surgical
interventions.
2 The development of postoperative complications drives patient mortality and higher health care
costs. Interventions aimed at prevention and early recognition of complications may lower surgical
risk.
3 Consideration of patient-centered outcomes may appropriately determine that noncurative surgical
intervention may be counter to the patient’s true desires.
4 National Surgical Quality Improvement Programs from the Veterans’ Administration and the
American College of Surgeons have examined large data sets in a data-driven approach to more
finely characterize risk for mortality and complications.
5 Specific comorbidities affect both the conduct of surgery and the outcome in ways that can be
anticipated and addressed.
6 Identification of patients at risk permits quality assurance monitoring and offers the opportunity to
improve care with individual- and system-level interventions.
INTRODUCTION
1 The goal of preoperative assessment is to evaluate an individual’s risk for postoperative adverse
events and to deliberately incorporate that assessment into plans for surgical intervention. It forms the
basis of the contract between the patient and the surgeon; both wish to predict future outcomes and to
balance the risks and benefits of surgery. By synthesizing clinically available data, we can attempt to
stratify and modify risk so that the equation will favor benefit, all the while prioritizing patient-
centered goals of care.
Early landmark work in cardiac preoperative evaluation by Goldman et al.1 clearly demonstrated that
high-risk surgical patients could be identified through careful assessment of clinical history, physical
examination, and laboratory data. This has been extended by further observations in specific types of
surgery and in subgroups of patients with particular disease states. Granular, patient-level analyses
using “big data” approaches have led to the development of targeted interventions aimed at reducing
the risk of a given procedure for a given patient. Thus, preoperative evaluation has evolved to include
not only prediction of risk but also consideration of potential proactive interventions at both the
individual patient and system levels. Inclusion of patient values and desired outcomes completes the
course of informed decision-making.
This chapter reviews the relevance of risk determination, examples of data-driven approaches to
individualize risk prediction, clinical aspects of preoperative evaluation, guidelines for specific disease-
related conditions, and future directions for prevention of complications and intervention should they
occur. All of these should be considered in the context of selecting the best approach for each patient.
SURGICAL MORTALITY, COMPLICATIONS, AND PATIENT-CENTERED

OUTCOMES
Mortality rates following surgery have continued to improve with innovations in surgical technique and
advances in overall quality of medical care. Since the 1950s, large reductions in intraoperative mortality
have been accomplished through anesthesiology-led initiatives championing safer operating room
483
protocols, continuous monitoring, and error reduction. By incorporating high-reliability processes into
operating room routines, the overall mortality risk attributable to a general anesthetic has been reduced
from 25 per million to 50 per million in the 1970s and 1980s to 1 per million to 5 per million.2
From the surgical standpoint, population-based mortality rate varies sharply with the extent of the
procedure and patient age.3 Overall surgical mortality in the Nationwide Impatient Sample decreased
from 1.68% in 1996 to 1.32% in 2006.4 Substantial interhospital variation exists and underscores the
possibility for additional opportunities for improvement. The Safety in Surgery Study evaluated a large
cohort of general and vascular surgical patients at 128 VA and 14 academic hospitals between 2001 and
2004.5 The overall 30-day postoperative mortality ranged between 2.19% and 2.87% over the 3 years,
with adjusted odds ratios varying between individual institutions (Fig. 15-1). Similarly, in a 7-day
cohort study of noncardiac surgery in Europe, adjusted in-hospital mortality after surgery varied widely
between countries (odds ratio = 0.44 to 6.22) when compared with the United Kingdom.6
In 2000, the Institute of Medicine suggested that preventable adverse events accounted for as many as
98,000 in-hospital deaths.7 The search for further improvement in surgical mortality has focused on
reducing the incidence of postoperative complications. Surgical complications are strongly related to
mortality,8–10 with the ability to rescue from postoperative complications an important factor in
determining eventual outcome.11 The 10 most common perioperative complications seen in the Patient
Safety in Surgery Study hospitals included infectious, pulmonary, cardiac, renal, and venous thrombotic
events (Table 15-1).
2 Postoperative complications are associated with increased health care costs and resource utilization.
Average hospital costs may double following occurrence of a complication,12 with variation in
reimbursement exerting significant effects on both hospital profit and contribution margins.13,14
Postoperative complications are also strongly linked to hospital readmissions (Table 15-2),15 with a
substantial number of complications identified only after initial discharge.16 As an example,
approximately a quarter of colon resection patients are readmitted within 90 days, at an estimated cost
of $300 million annually.17
Figure 15-1. Variation in surgical mortality.
These circumstances influence both institutional and overall health care delivery. The overwhelming
health care spending burden adds pressure to provide efficient, high-quality care. Hospital performances
on quality measures are widely available on the Internet and mandated public reporting can easily
affect market share and policy making. These system-level considerations only heighten the push
toward population-based management of surgical care.
Nevertheless, the direct impact of postoperative complications on an individual patient’s quality of life
is critical. The consequences are often unrecognized by standard hospital-based review. In 2004, Clavien
and Dindo proposed a complication grading scale based on the severity of intervention required to
address a given complication, including the presence of associated disability (Table 15-3).18 This
classification has been validated in a cohort of more than 6,000 patients, with subsequent evaluation
showing 89% interrater agreement and correlation between perceptions by patients, nurses, and
physicians.19 It is hoped that encouraging standardized complication grading will increase meaningful,
484
patient-centered outcomes reporting.
Table 15-1 Surgical Complications: Comparison of the 10 Most Frequent

Perioperative Complications Between Private Sector and VA Hospitals
Table 15-2 Number of Surgical Readmissions by Readmission Reason
Table 15-3 Grading of Surgical Complications: Clavien–Dindo Classification
485
3 Finally, the recognition that a surgical admission may represent a turning point in the overall
trajectory of a patient’s life refocuses the preoperative evaluation to look beyond the index
hospitalization. In 2008, one-third of Medicare decedents underwent a surgical procedure during their
last 12 months of life.20 The preoperative discussion should address the patient’s understanding of the
potential impact of surgical care and include expected quality-of-life outcomes. It is important to integr
ate patient-centered goals of care into treatment recommendations; an operation that does not prolong
meaningful quality of life may be counter to the patient’s expectations of surgical care.
RISK STRATIFICATION
4 The goal of risk stratification is to identify patients at risk for adverse outcomes and to target high-
risk groups for potential intervention to reduce that risk. To date, the largest organized surgical efforts
have evolved through the National Surgical Quality Improvement Program (NSQIP) and the American
College of Surgeons (ACS-NSQIP). In 1991, the Department of Veterans Affairs (VA) system responded
to criticisms of high mortality rates by initiating a program of mandatory data collection and
evaluation. The NSQIP paradigm employs local trained nurse reviewers at each site to extract
individual, patient-level data. Variables collected include demographic information, baseline physiologic
status, medical comorbidities, laboratory values, and surgical operative characteristics. Regression
models are constructed to predict the risk of postoperative morbidity and mortality based on the
collected preoperative variables (Table 15-15A,B). Ongoing system-level analysis evaluates and
benchmarks performance between institutions using observed/expected (O/E) ratios for specified
outcomes and allows for linkage of outcomes to process and structure of care.5 Success in data-driven
VA process improvement initiatives has led to validation and adoption in academic and community
centers.5
Table 15-4A Logistic Regression Models for Prediction of 30-Day Operative

Mortality Using Preoperative Variables
486
Table 15-4B Logistic Regression Models for Prediction of 30-Day Operative
Morbidity Using Preoperative Variables
Continued development has been sponsored by the American College of Surgeons (ACS) under the
ACS-NSQIP® program, combining data collection, centralized benchmarking, and regular reporting.
Reports have been utilized as catalysts for institutional-level change, with substantial improvements
seen following targeted quality improvement efforts.21 Following implementation, 66% of ACS-NSQIP
hospitals saw reduced mortality rate and 82% saw reduction in complications. The annual benefit for a
hospital enrolling in ACS-NSQIP has been estimated at 250 to 500 fewer complications and 12 to 36
fewer deaths.22 Observed improvements in outcomes appear to be sustained, with the magnitude of
quality improvement increasing over time.23 Of note, improvements in risk-adjusted outcomes at ACS-
NSQIP hospitals were not found to differ significantly from those concurrently seen in matched non-
NSQIP hospitals, suggesting that while feedback and reporting may be critical to implementing process
change, they are not by themselves required to drive improvement.24,25
Risk Calculators
Algorithm-based risk stratification based on large data sets is now available throuh the Internet or on
mobile devices. In 2011, a cardiac risk calculator based on NSQIP variables compared favorably to
performance of the Revised Cardiac Risk Index.26 In 2013, the ACS released an online decision support
tool including a perioperative risk calculator built on the NSQIP database of 1.3 million operations
(www.riskcalculator.facs.org, last accessed March 30, 2016). The calculator incorporates 21 variables
from the original VA NSQIP data collection and has excellent predictive performance for mortality,
487
morbidity, and six specific complications.27 Potential criticisms of the model include dependence on
American Society of Anesthesiology (ASA) Physical Status grading, imprecise definition of functional
outcomes, and lack of validation outside of a NSQIP cohort28; however, the ability to rapidly provide
individualized patient risk estimation is an important advance. Figure 15-2A,B demonstrate an example
of risk determination for a patient undergoing elective colon surgery, entering specific clinical variables
and reporting specific complications in an individualized fashion. The use of mobile device decision
support tools will also likely continue to increase; as an example, the Michigan Surgical Optimization
Program’s mobile app provides risk stratification for procedures derived from the Michigan Surgical
Quality Collaborative data.
GENERAL CONCEPTS OF PREOPERATIVE EVALUATION

The setting for preoperative evaluation varies with the surgical procedure and with patient
circumstances. Coordination of preoperative care at a dedicated facility has led to improved efficiency
for outpatient elective surgery29; however, this advantage may lessen as intensity of routine testing
decreases.
Patient education remains a key aspect of the initial preoperative visit. Preoperative teaching has
been shown to improve patient satisfaction and increase cooperation with postoperative
recommendations.30 The wealth of information available on the Internet has enabled patients to be
better educated, stronger consumers and has empowered many to participate more actively in their
care. Prior to the first office visit, many will have researched their disease process, surgical procedure,
as well as the scorecards of the hospital and surgeon. Forward-thinking surgeons can leverage this
engagement and increase the value of the face-to-face appointment by providing online teaching
materials ahead of the actual office visit.
Initial evaluation includes a standard medical history and complete physical examination. The
presence of allergies, current medications, chronic illnesses related and unrelated to the surgical
condition, prior procedures, as well as staging and acuity of disease all contribute to the risk and benefit
determinations.
Routine preoperative laboratory testing is no longer recommended. The majority of preoperative
laboratory tests are rarely indicated and are of limited value.31 It has been demonstrated that, even
when abnormal, preoperative testing often does not lead to change in perioperative management or
adverse postoperative outcomes.32 Despite this, preoperative testing continues to be overused in both
low risk33 and hospital settings.34
Selective laboratory testing has potential value in certain elective cases, as well as in remote
telemedicine evaluations35 and as part of risk assessment in elderly patients.36 In all cases, testing
should be based on clinical likelihood of finding and acting on abnormal results. Baseline hemoglobin
should be assessed in elderly patients, patients undergoing procedures with expected major blood loss,
and patients with underlying hematologic disorders. Renal function can be assessed in older patients, in
younger patients with suspicion of renal disease or with associated diabetes, cardiac, vascular, or
pulmonary disease, and in patients undergoing major surgery. Electrolytes, glucose, coagulation studies,
and liver function tests should be performed selectively. Adjunctive cardiopulmonary evaluation should
also be performed selectively.
Routine electrocardiogram (ECG) is not recommended before low-risk surgery. Patients with known
coronary disease or elevated risk should be evaluated, unless the procedure itself is low risk. More
invasive testing, including exercise testing, echocardiography, and cardiac catheterization should be
based on the presence of symptoms, overall functional level, procedural factors, and calculated coronary
risk (see Cardiac section). Routine chest x-ray, pulmonary function tests, and arterial blood gases are
not indicated unless specific pulmonary symptoms are identified (see Pulmonary section).
Anesthesia
For otherwise healthy patients, selective, rather than routine, evaluation by an anesthesiologist is
recommended. Use of a screening questionnaire may facilitate appropriate referral for a formal
anesthesia consultation.37 A nursing instrument identifying high-risk conditions (history of prior or
familial anesthetic difficulty, difficult airway/limited neck motion, decreased exercise tolerance, stroke,
thyroid, cardiac, asthma, and liver and renal disease) has been validated as a trigger for formal
anesthesia consult.38
488
Figure 15-2. A,B: Risk stratification: ACS-NSQIP risk calculator. (Source: www.riskcalculator.facs.org, American College of
Surgeons.)
The ASA Physical Status classification (Table 15-15) addresses the overall physical status of the
patient, exclusive of specific surgical considerations. Despite its relative imprecision and inconsistent
application, ASA class remains strongly associated with other predictors of surgical outcomes39 and
continues as a standard adjunct during preoperative evaluation. The choice of anesthetic approach
(local, monitored anesthesia care/sedation, neuraxial, and general) varies on the basis of the indicated
procedure as well as patient considerations, with general anesthesia carrying a higher risk for
pulmonary complications.40 Systematic review suggests that the use of neuraxial blockade in surgery is
associated with overall mortality reduction and decreased complications; however, it is not possible to
ascertain whether these findings were due to salutary effects of regional blockade or reduction in the
use of general anesthesia.41 The use of epidural anesthesia may decrease perioperative cardiac events in
489
patients with hip fracture and abdominal aortic aneurysm surgery,28 but it is not clear that
intraoperative neuraxial anesthesia universally reduces perioperative cardiac events.
Table 15-5 ASA Physical Status Classification
Surgical Procedure
Each surgical procedure carries its own set of specific risks. The overall physiologic impact varies
between procedures. Procedures involving the thoracic or abdominal cavity, neurosurgery, head and
neck, or vascular system carry higher risk42 than those limited to the extremities or subcutaneous tissue.
Procedural duration, often associated with complexity and extent of resection, is also associated with
increased risk.40 The extent of surgical exposure has also been correlated with physiologic impact.
Minimally invasive approaches have, in general, been associated with lower hospital length of stay,
earlier return to function, reduced postoperative pain, and patient satisfaction, but in many cases
encumber the risk of increased procedural duration and costs without clear mortality benefit. The
urgency of the procedure affects risk assessment (Table 15-16).28 Emergency surgery carries the
additional challenges of life- or limb-threatening condition without the opportunity for medical
optimization. The underlying processes are often catastrophic, with increased risk of infection,
hemorrhage, and uncorrected physiologic derangement adding to the risk of postoperative
complications43 and mortality.42
Disparities
Disparities in surgical outcomes based on racial and socioeconomic considerations still persist. The
relative rates of postoperative complications, including respiratory failure, physiologic and metabolic
derangements, are generally increased for minority patients over Caucasian patients.44 The causes are
multifactorial and, likely, patient-related factors, as well as chronic and acute health care resource
availability, play a role. In a survey of the US Nationwide Inpatient Sample involving more than 3
million oncologic procedures performed between 1999 and 2009, African American, but not Hispanic
patients had higher rates of vascular, wound, gastrointestinal (GI), and infectious complications when
compared to white patients.45 These variations in patterns of use suggest that unexploited opportunities
may exist to reduce disparities. Cultural and economic barriers to surgical care may not be readily
visible to the surgeon and should be actively considered.
Age
Patients are living longer and with more substantial comorbidities. The world’s population of people
aged 60 years and older has doubled since 1980 and is forecast to reach 2 billion by 2050.46 Demand for
surgical services continues to increase faster than the rate of population growth; in 2006, surgery on
elderly patients accounted for 35% of inpatient and 32% of outpatient surgical procedures.47
490
Table 15-6 Procedural Urgency
Normal aging reduces the ability to maintain homeostatic responses in the face of acute physiologic
stress48 such as surgery. In a series of over a million Medicare patients, operative mortality for patients
aged 80 years and older was observed to be more than twice that for patients aged 65 to 69 years.3
Compared with patients younger than 60 years, the risk of postoperative pulmonary complication was
doubled for patients between the ages of 60 and 69 years and tripled for patients aged 70 to 79 years.49
Optimization of surgery in the elderly requires recognition of their decreased tolerance for
complications. An initial infectious or pulmonary complication is associated with significantly higher
risk-adjusted failure-to-rescue rates in elderly patients when compared with younger patients.50
Attending to prevention and early recognition of complications potentially will have great impact on
these outcomes in the elderly population.
While surgical risk increases with advancing age, chronologic age alone should not be considered a
contraindication to surgery in otherwise healthy patients. The association of age with other factors such
as decreased functional status, an increased number of comorbidities, and more complex pharmacologic
history51 renders simple conclusions unfeasible. For example, in the Revised Cardiac Risk Index model
for cardiac mortality, other risk factors become more significant than age alone,52 while in cases of
advanced age, adding age to the revised cardiac risk index (RCRI) model improves its utility for
prediction.53
The ACS and American Geriatric Society have published best practice Guidelines for the Optimal
Preoperative Assessment of the Geriatric Patient.47 The guidelines highlight 13 geriatric-specific
domains to identify and address during the preoperative period (Table 15-7). Areas of focus include
traditional preoperative evaluation (cardiopulmonary risk assessment, directed preoperative testing)
and added evaluations of cognition (baseline cognition, decision-making ability, depression, risk for
postoperative delirium), functional status (mobility, fall risk, and frailty), nutrition, medication
(polypharmacy, alcohol/substance abuse screening), support systems (family and social), as well as
discussion of goals and expectations of care.
Table 15-7 Perioperative Evaluation of the Geriatric Patient
491
Few of these domains are covered in detail during traditional preoperative surgical evaluation and
further integration into routine practice is needed. Additional recommendations for geriatric patients
include screening for cognitive deficits, with referral for support if screening is positive; recognition of
risks for postoperative delirium (inadequate pain control, sleep deprivation), avoidance of
polypharmacy (specifically avoiding drugs that contribute to delirium); encouraging early return to
function with mobilization and physical therapy; and dedicating adequate time for counseling with
patient, family, and surrogate decision makers.
Medical Comorbidity
5 Hypertension, coronary artery disease, diabetes, and chronic obstructive pulmonary disease (COPD)
are the most frequently seen comorbidities in patients older than 70 years.51 More than 50% of these
patients suffer from at least one infirmity and 30% suffer from two or more.51 As a result,
polypharmacy is common. Adaptation to multiple chronic illnesses and treatments may combine to
create altered physiologic responses to surgery. For example, a patient with hypertension that is well-
controlled with diuretics and β-blockade may be chronically volume depleted and unable to mount
cardiovascular response to further blood loss in surgery.
Obesity/Obstructive Sleep Apnea

The prevalence of adult obesity is increasing in the United States, with one-third of adults in 2009–2010
considered to be obese (body mass index [BMI] >30 kg/m2).54 Paradoxically, in nonbariatric general
surgery, a J-shaped relationship of lower mortality has been reported in overweight and moderately
obese patients.55 Nevertheless, an increased risk of postoperative complications and the need for
additional operative planning is present for the bariatric patient. For this chapter, discussion centers on
risk of airway difficulty and ventilation in the high BMI patient with sleep apnea.
The American Society of Anesthesiologists updated guidelines for perioperative management of
patients with obstructive sleep apnea in 2014.56 In this report, the prevalence of sleep-disordered
492
breathing was 9% in women and 24% in men. Patients often present without formal confirmation of the
diagnosis by polysomnography. Increases in perioperative risk are noted to occur in proportion to the
severity of sleep apnea.57 Sleep apnea should be suspected in patients with history of apparent airway
obstruction during sleep, BMI >35 kg/m2, large neck circumference, craniofacial abnormalities,
snoring, frequent arousals from sleep, and unexplained daytime somnolence or fatigue. A trial of
preoperative continuous positive airway pressure may be attempted to improve nighttime airway
obstruction, particularly if obstructive sleep apnea is severe. Other potential interventions include the
use of mandibular advancement devices, oral appliances, and preoperative weight loss; however,
evidence was judged to be insufficient to make formal recommendations.
Intraoperative considerations include choice of anesthetic technique, airway management, and patient
monitoring. For appropriate procedures, regional anesthesia may be preferred over general anesthesia
and continuous monitoring should be employed because of the potential for airway obstruction. Patients
at risk for obstructive sleep apnea may have associated difficult airway and require special attention
during induction and emergence from anesthesia. Sedation and neuromuscular blockade should be
carefully monitored and fully reversed prior to extubation.
Table 15-8 METs Equivalents
Anemia
Anemia is independently associated with mortality in noncardiac surgery,58 yet it is not clear that
correction of anemia will alter mortality. Several randomized trials examining transfusion strategies in
relatively stable patients failed to demonstrate mortality benefit with higher transfusion triggers in the
ICU,59 cardiac60 and orthopedic surgery61 settings. At present, recommendations for perioperative
transfusion are general, with consideration for higher thresholds given to patients who are symptomatic
with chest pain, hypotension, or fatigue, those with known cardiac ischemia or those receiving massive
transfusion for hemorrhagic shock. The use of erythropoietin stimulating agents and intravenous iron
supplementation to facilitate perioperative transfusion management remains controversial,62 secondary
to increased risk in oncologic and nonanemic patients. Current evidence does not support aggressive
preoperative transfusion in patients with sickle cell disease.63 Conflicting evidence has been published
regarding the relationship between age of transfused cells and mortality.64,65
Preoperative Functional Status

The impact of preoperative functional status has been recognized for years. Self-reported exercise
intolerance (to walking four blocks or two flights of steps) is independently associated with higher risk
of perioperative cardiovascular, myocardial ischemia, and neurologic events after elective major
noncardiac surgery.66 The relationship is inversely related to the total number of blocks that could be
walked or flights of stairs that could be climbed. Functional ability can be quantified in terms of
metabolic equivalents (METs), with 1 MET defined as the amount of oxygen consumed while sitting at
rest and equal to 3.5 mL O2 uptake/kg/min.67 Functional status can be categorized as excellent, >10
METs; good, 7 to 10 METs; moderate, 4 to 6 METs; and poor, <4 METs. Risk is increased if unable to
perform at a level of 4 METs (Table 15-8).28 The ACS recommends a four-question survey of activities
of daily living (ADLs) as a screen to identify unsuspected functional compromise in geriatric patients
(Table 15-9A).68
493
Frailty
Separate from comorbidity, elderly patients may suffer from frailty and sarcopenia.69 In the Medicare
population, additional mortality has been related to frailty70 and the relationship has been documented
in a broad population, including patients undergoing gastric surgery,71 gynecologic oncology,72 and
cardiac surgery.73 CT-based morphomic quantitation of trunk muscle volume is associated with
decreases in functional performance on ADLs and independent activities as measured by the Vulnerable
Elder Survey74 as well as poorer outcomes in liver transplantation75 and aortic surgery.76 An operational
frailty score (Table 15-9B) has been validated in elderly surgical patients and is associated with higher
incidence of postoperative adverse events, increased length of hospital stay, and higher likelihood of
discharge to a skilled or assisted-living facility.77
Table 15-9A Short Simple Screen for Functional Assessment
Direction of Care
One of the most important discussions between a surgeon and the patient is the understanding of the
patient’s desires regarding direction of care. There is little question of aggressive interventions for a
healthy patient expecting rapid return to their preoperative level of function after elective surgery.
Nevertheless, patients with severe underlying comorbidity or limited life expectancy should have the
opportunity to direct overall goals of their care. One approach that incorporates principles of geriatric
and palliative care is to frame surgical care for these patients in the context of time-limited trials.78,79
Overall prognosis, patient priorities, and specific milestones defining improvement or deterioration are
discussed with the patient and family. A mutual decision for surgical care is crafted, outlining a specific
time-limited trial of care and potential actions that could be undertaken at the end of the trial or in the
event that complications arise. In this fashion, treatment decisions can be matched to the individual
patient’s overall priorities and goals.
Table 15-9B Frailty Scoring (Operational Definition)
MEDICATION MANAGEMENT
494
Medication management in the perioperative period is subject to general guidelines of practice. The
pharmacokinetics of drug administration, distribution, metabolism, and excretion may all be affected by
surgery. Major GI procedures limit oral intake and may require alternate routes of administration.
Patients receiving volume resuscitation may have increased drug volume of distribution. Fluctuations in
hepatic and renal function and addition of multiple new medications may alter drug metabolism and
excretion. New drug interactions may lead to increased toxicity; appropriate monitoring by drug levels
may improve drug management.
A careful medication history includes prescription and nonprescription medications and nutritional
and herbal supplements. Patients may be taking over-the-counter herbal supplements with substantial
physiologic effects80 but may not perceive these as being relevant to the conduct of their surgery. In
one series, more than 70% of patients failed to disclose herbal medicine use during routine preoperative
assessment.81 Herbal supplements are presently not subject to FDA regulation; contents may vary
substantially from manufacturer to manufacturer and frank adulteration has been documented.82
Recommendations for commonly taken herbal supplements are summarized in Table 15-10, keeping in
mind that variations in supplement content may make a 7-day holding period prudent.83
In the absence of clear evidence-based guidelines for perioperative medication management, a general
approach is to continue drugs that would cause withdrawal within the perioperative period, and to
discontinue unnecessary drugs or those with potential for adverse events, restarting them as soon as the
patient condition permits.83 Medications that are generally continued include β-blockers, clonidine,
statins, and selective serotonin reuptake inhibitors (SSRIs). Medications that can be discontinued include
diuretics, metformin, and, possibly, angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARBs) (Table 15-11).
Chronic β-blocker therapy should not be held perioperatively, as abrupt discontinuation may lead to
rebound tachycardia and hypertension. Patients not previously receiving β-blockers should not have
them initiated in anticipation of planned surgery, as this practice has been associated with an increase in
cardiovascular events and is no longer recommended. Statins should be continued in the perioperative
period when feasible. Other than β-blockers, antihypertensive medications are generally held
perioperatively and should be considered individually. ACE inhibitors and ARBs are associated with
perioperative hypotension84 and renal risk. Diuretics are associated with chronic volume depletion and
electrolyte abnormalities and should be held perioperatively.
Management of anticoagulation is of critical importance to surgeons and the indication for
anticoagulation should be weighed against the risk of procedural bleeding. Agents should be held for the
minimum interval felt safe after invasive procedure. Patients on chronic long-acting anticoagulation
who are undergoing elective operation can use preoperative bridging with unfractionated or low-
molecular-weight heparin prior to surgery.85 In the emergent setting, the American College of Chest
Physicians (ACCP) has published guidelines covering reversal of vitamin K competitors based on
urgency of procedure and risk of life-threatening hemorrhage.86 Reversal of newer direct thrombin
inhibitors may not be possible other than waiting for drug clearance; dabigatran may be removed with
dialysis; however, rivaroxaban and apixaban are highly protein bound and unlikely to be removed with
this modality. In a large series, perioperative aspirin administration was associated with an increased
risk of postoperative hemorrhage87; however, a recent meta-analysis concluded that aspirin should not
be stopped in the perioperative period unless bleeding risk outweighed thrombotic risk of holding the
drug.88 Dual antiplatelet therapy in the setting of coronary stent placement is specifically addressed in
current American College of Cardiology/the American Heart Association (ACC/AHA) guidelines28 and is
discussed separately in the Cardiac section.
Table 15-10 Potential Interactions for Some Common Herbal Medicines
495
Perioperative glucose control reduces mortality rate, hospital length of stay, and deep wound
infections in cardiac surgery.89 An adjusted dose of short-acting insulin is administered perioperatively,
with intravenous insulin infusion intraoperatively if needed. The oral hypoglycemic, metformin, is
associated with lactic acidosis and should be held prior to surgery.
Psychiatric medications should be managed on the basis of concern for withdrawal. Abrupt
withdrawal of SSRIs may lead to nausea, vomiting, and lethargy, with symptoms seen more quickly in
drugs with shorter half-life.90 The use of SSRIs may increase the risk of bleeding, particularly when used
in conjunction with nonsteroidal anti-inflammatory drugs (NSAIDs).83 Benzodiazepines may be
continued perioperatively. Older agents, including tricyclic antidepressants and monoamine oxidase
inhibitors, may precipitate hypertensive crisis in conjunction with indirect sympathomimetics.
Patients receiving daily maintenance buprenorphine will not have sufficient surgical analgesia from
usual postoperative opioid dosing regimens. Preoperative consultation with their prescriber and with
the anesthesiology pain service is recommended prior to surgery. Alternative strategies, including the
use of regional anesthesia and nonsteroidal and nonnarcotic regimens, may facilitate postoperative
management.
Immunosuppressant mediations may be reduced or discontinued prior to surgery, depending on the
extent and the presence of associated infection, although a systematic review of immunomodulators in
patients with inflammatory bowel disease has suggested no clear increased risk of total or infectious
complications with azathioprine, cyclosporine, or infliximab.91 Steroid use carries a dose-dependent
relationship with an increased risk of postoperative complications, both infectious and overall.92 Meta-
analysis of randomized controlled trials suggests that perioperative stress dose steroids are not required
unless there is dysfunction of the hypothalamic-pituitary-adrenal axis.93 Anti-VEGF inhibitors are
associated with an increased risk of GI perforation and delayed wound healing and their use is not
recommended for 28 days before or after surgery or until surgical wounds are healed.
SPECIFIC ORGAN SYSTEM GUIDELINES

Cardiovascular
Prediction of cardiac adverse events following noncardiac surgery was pioneered in the 1970s1 and risk
stratification is most refined in this area.
496
Table 15-11 Common Prescription Medications That May Require Special
Perioperative Management
Risk Stratification
The current Revised Cardiac Risk Index (Table 15-12)52 is based on risk of surgery, history of ischemic
heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative
insulin-requiring diabetes mellitus, and preoperative renal insufficiency and can be used to identify
patients at higher risk for major cardiac complications (myocardial infarction [MI], pulmonary edema,
ventricular fibrillation, primary cardiac arrest, complete heart block). The RCRI has been validated as a
predictor of increased risk, although, disappointingly, targeted interventions in high-risk groups have
not yet conclusively shown benefit. In 2007, evaluation of ACS NSQIP data in 211,410 patients
demonstrated a 0.65% rate of perioperative myocardial infarction or cardiac arrest. Five predictors
were identified: type of surgery, dependent functional status, abnormal creatinine, ASA class, and
increasing age.26 Active angina and signs of left ventricular dysfunction, such as dyspnea or worsening
heart failure; syncope; significant arrhythmias; severe valvular disease; and surgery should prompt
further preoperative evaluation.
The ACC and the AHA issued joint recommendations for perioperative cardiovascular evaluation and
management for noncardiac surgery in 2014.28 The guideline covers preoperative evaluation, risk
assessment, perioperative management, and post–percutaneous coronary intervention (PCI)
recommendations. Outcomes are defined in terms of a composite Major Adverse Cardiac Event (MACE),
which includes death or MI. Low-risk procedures are defined as carrying a predicted MACE risk of <1%
and elevated-risk procedures carrying a MACE risk of ≥1%.
Stable patients undergoing low-risk surgery and those with good exercise tolerance rarely need
further cardiac evaluation. For those at higher risk, cardiology evaluation is recommended. In urgent or
emergent situations where surgical intervention must proceed prior to any meaningful management
changes, delay for cardiac evaluation will not be of benefit and care is focused on prompt recognition
497
and treatment of any perioperative events. In this paradigm, decision-making for higher-risk patients
can be simplified to (1) initial determination if the procedure can be delayed to permit additional
evaluation and management which could significantly alter the outcome and (2) further risk
stratification and intervention if the patient condition permits. The overall ACC/AHA algorithm is
reproduced in Algorithm 15-1 and specific recommendations are summarized later.
Table 15-12 Revised Cardiac Risk Index
Preexisting Cardiac Disease

The presence of underlying coronary artery disease is associated with postoperative MACE following
noncardiac surgery. Following an acute MI, the rate of subsequent postoperative ischemia and MI
decreases as the time interval to surgery increases. The risk of perioperative stroke was also increased
with surgery occurring within 6 months of MI.94 In the absence of myocardial revascularization,
noncardiac surgery should be delayed for 60 days or more after acute MI. Coronary artery bypass
grafting (CABG) solely to reduce perioperative risk is not recommended and should be performed only
if the procedure would otherwise be indicated.
The presence of heart failure is a strong predictor of perioperative cardiac morbidity and mortality.
The stability of heart failure is likely to affect outcomes, with decompensated, symptomatic heart
failure identified on physical examination carrying higher risk. Preservation of left ventricular ejection
fraction is an independent predictor for patients undergoing elevated-risk surgery95 and patients with an
LVEF ≤29% were identified as having higher risk in vascular surgery.96
Patients with clinically suspected valvular heart disease should have review of echocardiography
evaluation performed within 1 year prior to surgery or have repeat study if there has been a significant
change in status or physical evaluation. Concomitant evaluation for ischemic disease should be
considered. If valvular intervention is clinically indicated, intervention prior to noncardiac surgery may
reduce perioperative risk.97
Postoperative arrhythmias are common and are often triggered by the stress of surgery. Patients with
heart block, implanted pacemakers, or automatic implantable cardioverter defibrillators are best served
by effective communication between surgery, anesthesiology, and cardiology to optimize perioperative
device management.
498
Although not included in most cardiac risk scoring, pulmonary hypertension is associated with
increased complications98 and patients may benefit from referral to a center with expertise for further
evaluation. In a single-institution study evaluating adult patients with pulmonary hypertension
undergoing anesthesia, specific risk factors were identified as associated with short-term morbidity
(history of pulmonary embolism, NYHA functional class ≥2, elevated-risk surgery, anesthesia >3
hours) and postoperative mortality (pulmonary embolism, right axis deviation on ECG, right ventricular
hypertrophy or right ventricular systolic pressure:systolic blood pressure >0.66, intraoperative
vasopressor and anesthesia when nitrous oxide was not used).99
Adult patients with congenital heart disease, when possible, should undergo preoperative evaluation
in a regional center specializing in congenital cardiology.100
Preoperative Testing
ECG should be considered for patients undergoing elevated risk surgery. It should also be considered in
patients with a history of CHD, significant arrhythmia, peripheral arterial disease cerebrovascular
disease, or significant structural heart disease, unless they are undergoing low-risk surgery.
More extensive evaluation, including exercise stress testing, assessment of left ventricular function, or
coronary angiography, is performed selectively after initial risk stratification and determination of
exercise tolerance. Exercise stress testing is not recommended for patients undergoing low-risk surgery
or patients able to tolerate >10 METs; patients with elevated RCRI risk, but able to tolerate >4 METs,
and patients with elevated RCRI risk, and unable to tolerate <4 METs, but for whom cardiac evaluation
will not change management. In patients with elevated RCRI risk or unable to tolerate <4 METs in
whom the opportunity exists to improve cardiac management, stress exercise testing can be useful.28
Management of Antiplatelet Therapy Following Percutaneous Coronary Intervention

Recommendations following percutaneous coronary interventions are evolving and center on not just
the cardiac risk, but also the risk of discontinuing dual antiplatelet therapy. Premature discontinuation
of antiplatelet agents increases the risk for early and late stent thrombosis and this must be weighed
against the relative risk of surgical bleeding. Dual antiplatelet therapy should not be interrupted for the
initial 4 to 6 weeks after PCI. Elective surgery should be delayed at least 14 days after balloon
angioplasty, 30 days after bare-metal stent implantation if antiplatelet agents are to be discontinued and
365 days after drug-eluting stent (DES) implantation, if feasible. Elective surgery may be considered
earlier (180 days) following DES implantation if risk of surgical delay outweighs risk of stent
thrombosis.
Management in all other situations should be determined by consensus of the surgeon,
anesthesiologist, cardiologist, and patient. In patients undergoing emergent surgical procedures that
mandate discontinuation of P2Y12 platelet receptor inhibitors, aspirin should be continued if possible
and the P2Y12 platelet receptor inhibitor resumed as soon as possible following surgery (Algorithm 15-
2).28
499
Algorithm 15-1. Stepwise Approach to Perioperative Cardiac Assessment for CAD. (From Fleisher LA, Fleischmann KE, Auerbach
AD, et al. 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing
Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation 2014;130(24):2215–2245.)
Other Cardiac Medication Management

Patients on chronic β-blockade should continue treatment during the perioperative period. Prior
recommendations for initiating β-blockade in patients without cardiac risk factors have been removed
after meta-analysis indicated increased mortality.101 In patients with intermediate or high risk for
myocardial ischemia, that is, three or more risk factors on RCRI, new initiation of β-blockers can be
considered preoperatively but enough time should be allowed to ensure stability before surgery. Statin
therapy should be continued perioperatively and new initiation can be considered for vascular102 or
elevated-risk patients clinical indications. Alpha-2 blockade with clonidine should not be administered
for prevention of cardiac events.103 Aspirin, while it has a role in acute coronary syndrome and
following PCI, is not indicated solely for prevention of perioperative cardiac events.87 No benefit has
been identified for perioperative nitroglycerine and routine use is not recommended.
500
Algorithm 15-2. Proposed algorithm for antiplatelet management in patients with PCI and noncardiac surgery. (From Fleisher LA,
Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of
Patients Undergoing Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation 2014;130(24):2215–2245.)
Surgical Considerations
The extent and invasiveness of the surgery must be considered, including anticipated blood loss, fluid
shifts, and hemodynamic instability. In general, procedures involving extremity or noncavitary surgery
pose less risk than thoracic, abdominal, or neurosurgical procedures. As hypotension and tachycardia
may decrease coronary perfusion, intraoperative hemodynamic monitoring and ICU stay may be
advisable for high-risk patients. Routine pulmonary artery catheter monitoring is not recommended but
may be of benefit in valvular disease. Transfusion triggers for patients at risk for or experiencing active
cardiac ischemia remain undefined but are generally higher than usual thresholds.
Pulmonary
Pulmonary complications following surgery are among the most frequent and costly postoperative
events and lead to similar increases in morbidity, mortality, and length of stay as cardiac
complications.40 In particular, the development of pulmonary complications in the elderly may predict
long-term mortality after surgery.104 Age-related diminution of pulmonary function is associated with
postoperative complications40 and increasing age is an independent risk factor for postoperative
pulmonary complications.49 Other factors associated with increased risk of postoperative pulmonary
complications are summarized in Table 15-13.
Risk Stratification
The 2006 American College of Physicians guideline for preoperative pulmonary evaluation includes
evaluation of patient-related, operative, and laboratory risk factors associated with increased risk of
postoperative pulmonary complications.49 Chronic lung disease was the most frequently identified risk
factor; other patient-related factors include ASA class greater than II, increasing age, congestive heart
failure, functional dependence, restrictive lung disease, and uncontrolled reactive airway disease.
Operative risk factors include surgical site, duration, choice of anesthetic, emergency procedures, and
501
low serum albumin. Other pulmonary risk stratification scales also identified elevated blood urea
nitrogen (BUN), dyspnea at rest or low levels of activity105; low preoperative arterial oxygen saturation,
acute respiratory infection during the previous month, age, preoperative anemia, upper abdominal or
intrathoracic surgery, surgical duration of at least 2 hours, emergency surgery106; and age, smoking
status, airflow limitation, ASA class, hypoalbuminemia, emergency, surgery and nonlaparoscopic
abdominal/cardiac and AAA repair107 as risk factors for pulmonary complications.
Table 15-13 Pulmonary Complications in Noncardiac Surgery
Preoperative Evaluation
History and physical examination can be used to screen for patients requiring further assessment.
Symptomatic dyspnea is a strong predictor of pulmonary complications and should be investigated
further as it may signal underlying cardiopulmonary or neuromuscular dysfunction. Chronic cough or
sputum production, particularly in the setting of chronic obstructive lung disease, cigarette smoking, or
occupational exposures, should trigger consideration of possible associated infection. Systemic diseases
may have associated pulmonary compromise. A history of restrictive chest wall disease or
neuromuscular disorders may signal impaired ventilatory reserve and may impart additional risk.
Physical examination findings of abnormal auscultation, scoliosis, chest wall deformity, and accessory
muscle use may denote decreased functional capacity. While a history of asthma has not been confirmed
to be independently associated with postoperative pulmonary complications, patients with poor control
are at increased risk.108
6 Routine chest radiography, pulmonary function tests, and arterial blood gases are not indicated for
extrathoracic surgery49 but may be considered in evaluation for resectional and nonresectional thoracic
surgery and in patients with symptoms and undiagnosed chronic lung disease. Dyspnea on exertion
should be evaluated with pulmonary function tests and chest radiography. If a cardiac etiology is
suspected by history or physical examination, echocardiography can be considered. Abnormal chest
radiography suggesting diffuse parenchymal disease should be investigated further. Preoperative
albumin and BUN are associated with increased complications and should be obtained as part of
evaluation in patients with at least one other identified risk factor.49 Identification of patient and
operative or laboratory risks should prompt further investigation.
Cigarette smoking is directly toxic to respiratory epithelium and is associated with chronic lung
disease. A large systematic review concluded that cigarette smoking led to delayed healing and
complications through prolonged effect on inflammatory and reparative cell functions.109 A history of
502
cigarette smoking is associated with increased chance of major morbidity (surgical site infection,
pneumonia, shock, unplanned intubation) and mortality.110
Benefits of smoking cessation likely increase with increased interval between stopping and surgery.
Meta-analyses suggest that the effects of cigarette smoking on the tissue microenvironment and
inflammatory cellular functions may be reversed within 4 weeks109 and that smokers who quit more
than 4 weeks before surgery have lowered risk of perioperative respiratory and wound
complications.111 Reports of increased airway reactivity during these initial weeks following smoking
cessation raise concerns regarding proceeding with surgery during this period,112,113 although more
recent studies suggest no increase in complications for shorter intervals.111,114 A general
recommendation is that for maximum benefit, smoking should be discontinued 6 to 8 weeks
preoperatively, but that stopping for any duration before surgery is beneficial.
In addition, surgery may represent an opportunity for a teachable moment for the patient’s health. In
a longitudinal study, patients undergoing major surgery doubled the chances of quitting.115 A recent
Cochrane review suggested that brief and intensive interventions reduced perioperative smoking, and
that more intensive structured smoking cessation interventions, including weekly preoperative
counseling and nicotine replacement therapy, may be used to extend perioperative smoking cessation to
long-term success.116
Preoperative Evaluation Prior to Lung Cancer Resection

Considerations for patients undergoing surgical treatment of lung cancer balance the intent for curative
resection with concern for residual function and long-term disability following surgery. As conditions
promoting the development of lung cancer, that is, cigarette smoking and occupational exposures, are
also associated with intrinsic reductions in pulmonary function, the guidelines rely on physiologic
testing to estimate perioperative risk as well as the effect on postoperative lung function.
In 2007, the ACCP published recommendations for evaluation of patients with lung cancer being
considered for resection (Algorithm 15-3).117 Multidisciplinary evaluation was stressed as essential for
counseling, particularly in patients with borderline function. Age alone was felt to be insufficient
grounds to deny lung resection surgery. Cardiology evaluation was recommended for patients with
major factors for increased perioperative cardiac risk. Initial pulmonary function testing is
recommended for patients undergoing lung resection surgery and is to be performed with the patient on
optimal bronchodilator therapy. Significant hypoxemia (SaO2 <90%) but not hypercarbia (PaCO2 >45
mm Hg) was an independent risk factor for increased perioperative complications and, in its presence,
physiologic testing is recommended. Additional pulmonary function testing should be prompted if
forced expiratory volume in the first second of expiration (FEV1) is <80%, if absolute values on
spirometry are lower than generally accepted threshold for safe resection (1.5 L for lobectomy, 2.0 L
for pneumonectomy) or if dyspnea on exertion or interstitial lung disease is suspected. Further risk
stratification is based on measurement of DLCO, estimation of cardiopulmonary exercise tolerance and
calculation of the postoperative expected FEV1. In patients with borderline assessments, counseling
regarding nonstandard surgery and nonoperative treatment options was recommended.
Postoperative atrial fibrillation occurs in up to 19% of patients following lung cancer resection with
incidence peaking on the second postoperative day.118 Greater risk is present for men >55 years of age
and in the presence of a resting heart rate >72 beats per minute and close attention should be paid to
volume and electrolyte status.
503
Algorithm 15-3. Preoperative evaluation of patients with lung cancer for resection. (Adapted from Colice GL, Shafazand S, Griffin
JP, et al. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: ACCP evidenced-based
clinical practice guidelines. 2nd ed. Chest 2007;132(3) (suppl):161S–177S.)
Operative considerations include timing, site, duration, and choice of anesthetic. Emergency and
extended (duration greater than 3 to 4 hours) procedures are associated with increased risk of
pulmonary complications. In NSQIP, thoracic surgery, upper abdominal surgery, vascular surgery, and
head and neck surgery have also been associated with additional risk of pulmonary complications, with
thoracotomy and upper abdominal incisions associated with most marked changes in postoperative
functional residual capacity. Minimally invasive and robotic approaches balance potential advantages in
postoperative pain and early mobilization with the physiologic consequences of intracavitary
insufflation and any additional operative time and are not always accompanied by reductions in
pulmonary complications.119 Improving postoperative mobilization with minimally invasive approaches
or intraoperative epidural anesthesia may have benefit in patients with underlying chronic lung
disease.120 For vascular surgery, endovascular approaches reduce risk of pulmonary complications
compared with open surgery.121
General anesthesia-related reduction in functional residual capacity (FRC) may persist for up to 2
weeks postoperatively, with endotracheal intubation, inhalational anesthetic, and neuromuscular
blockade, all potentially contributing to pulmonary dysfunction. Shorter-acting neuromuscular blocking
agents may minimize periprocedural weakness and promote better recovery from general anesthesia.
Meta-analysis of 141 randomized controlled trials suggested that the incidence of postoperative
pneumonia and respiratory failure was decreased with the use of spinal or regional anesthesia.41
Epidural anesthesia combined with general anesthesia can reduce intraoperative shunting and
preemptively address postoperative pain.122
Intraoperative management is directed at minimizing overzealous volume administration. Use of lung-
protective tidal volume ventilation may reduce postoperative complications and intraoperative PEEP
strategies are being explored in high-risk populations. Selective use of nasogastric tubes may reduce
complications after abdominal surgery.123 Although low serum albumin is associated with increased
504
risk, studies demonstrating pulmonary benefits of nutritional support and specific immunonutrition
regimens are lacking.
Table 15-14 Modified Childs–Pugh–Turcotte Score
Pulmonary complications may be reduced by optimizing status of patients with preexisting lung disease,
lung expansion maneuvers, and smoking cessation.
Patients with chronic lung disease should be optimized prior to elective surgery with longer-acting
controller medications. Aerosolized β2-adrenergic receptor agonists, inhaled anticholinergics, and
inhaled and systemic corticosteroids may be used to improve pulmonary function.49 Preoperative
management of poorly controlled asthma includes eliminating wheezing, cough or dyspnea, and
targeting peak expiratory flows >80% of predicted or the patient’s personal best.124 Elective surgery
should be delayed for signs of acute infection, including increased secretions or change in character of
sputum.
Lung expansion maneuvers reduce postoperative reductions in FRC by augmenting alveolar
recruitment. Common modalities, including incentive spirometry, deep-breathing exercises, and
continuous positive airway pressure (CPAP), have been demonstrated to improve postoperative
pulmonary outcomes.49,125 In patients undergoing CABG, postoperative pneumonia was reduced by 2
weeks of preoperative inspiratory muscle conditioning.126 Concentrating education during preoperative
sessions may increase patient compliance and enhance improvements in high-risk patients.126,127
Patients with lobar collapse or high-volume secretions may benefit from additional postural drainage
and chest physiotherapy, but these maneuvers may also exacerbate bronchospasm.
Hepatic
Postoperative risk in liver disease is related to the severity of underlying liver disease and the extent of
the surgical procedure.128 Patients are living longer with chronic liver disease and they may present as
relatively asymptomatic with normal liver function tests even with substantial degrees of hepatic
dysfunction. In addition, occult chronic liver disease with silent cirrhosis may be present. Nonalcoholic
steatohepatitis affects 2% to 5% of Americans, primarily middle-aged, overweight, or obese patients. In
a series of patients undergoing bariatric surgery, 6% were found to have unsuspected cirrhosis in the
setting of fatty liver.129
The presence of cirrhosis is associated with high risk of complications and death; hepatic
decompensation can follow routine surgery. While the liver is usually protected from ischemia due to
dual portal and systemic blood flow, in disease states, alterations in splanchnic and autonomic vascular
regulation increase vulnerability to hypoperfusion and ischemic injury. Avoidance of shock states is
imperative for at-risk patients.
Risk Stratification
Overall surgical risk in cirrhotic patients appears to correlate with established scoring systems. Risk
stratification extrapolates scoring based on studies in cirrhotic patients undergoing portal decompression
(Modified Child–Pugh–Turcotte [CPT] score; Table 15-14)130,131 and survival models for patients with
end-stage liver disease (Model for End-Stage Liver Disease, MELD score; Table 15-15).132–134 Both
MELD and CPT scores may correlate with postoperative mortality and are useful to guide preoperative
505
counseling.135,136
Table 15-15 Model End-Stage Liver Disease Score
Historically, surgery in Child class A patients carries a mortality of 10%, Child class B, 30% and Child
class C, 76% to 82%.137,138 The rate of postoperative complications, including liver failure,
encephalopathy, bleeding infection, renal failure, hypoxia and intractable ascites, also increases with
class. Poorer outcomes are associated with anemia, ascites, the presence of encephalopathy,
hypoalbuminemia, hypoxia, malnutrition, concomitant infection, preoperative upper GI bleeding,
intraoperative hypotension, associated renal failure or COPD, and emergency, cardiac, hepatic
resection, or abdominal procedures.128,139 In general, mortality rates for patients undergoing emergency
surgery and patients with portal hypertension are higher.
History and physical examination may reveal unsuspected liver disease. History of prior hepatitis, prior
anesthetic toxicity, biliary disease, hereditary metabolic disorders, bleeding, or prior alcohol or
substance abuse should be sought. Physical examination may reveal stigmata of portal hypertension,
including hepatomegaly, splenomegaly, ascites, abdominal wall varices, asterixis, and palmar erythema.
Thrombocytopenia secondary to splenic sequestration may be an early sign of previously undiagnosed
portal hypertension. If liver disease is suspected during routine preoperative evaluation, elective
surgery should be deferred for further workup.140
Acute conditions for which elective surgery is contraindicated include acute liver failure, acute viral
hepatitis, alcoholic hepatitis, liver disease with associated acute renal failure, cardiomyopathy,
hypoxemia, or severe coagulopathy.128 Hepatic recovery may occur following an initial insult and
elective surgery should be deferred for a period of several weeks to optimize the patient’s condition.
For acute alcoholic hepatitis, abstinence from alcohol for 12 weeks before elective surgery has been
recommended.
For patients with known chronic liver disease and cirrhosis, surgical morbidity and mortality correlate
with the degree of hepatic dysfunction. Patients with compensated chronic liver disease generally
tolerate most surgery well; however, patients with decompensated cirrhosis may have substantial
perioperative risk proportional to the degree of hepatic dysfunction. A suggested preoperative
evaluation for hepatic disease is presented in Algorithm 15-4.141
Intra-abdominal surgery142,143 and cardiac surgery144 have been associated with high mortality rates in
cirrhotics. In one series, patients with cirrhosis undergoing surgery had a 30-day mortality of 11.6% and
an overall complication rate of 30%.139 The most frequent complication was pneumonia, with other
complications including bleeding, hepatic decompensation, sepsis, and renal failure. Umbilical hernia
may be aggravated in the presence of uncontrolled ascites and nonoperative management may be
506
warranted. Percutaneous interventions for drainage of biliary obstruction are preferred over surgical
approaches. Biliary surgery may be performed safely in Child Class A patients, following optimization in
Class B patients and preferably avoided in Class C patients.128 Formal hepatic resection in cirrhosis
carries a high mortality rate that is elevated in patients with postresectional liver failure.145
Perioperative management includes optimization of liver function, including management of portal
hypertension, cholestasis and coagulopathy, and avoidance of further hepatic injury secondary to
hypoperfusion and ischemia. Direct evidence that medical management affects subsequent outcomes is
lacking in randomized studies.
Anesthetic management is directed at preservation of hepatic perfusion. The choice of inhalational
agent depends on avoiding direct hepatotoxicity and depressed cardiac output; halothane is historically
associated with direct injury and isoflurane and sevoflurane may be the preferred agents. Perioperative
management also includes careful consideration of altered drug metabolism and toxicity. Sedative and
narcotic metabolism may be reduced and careful dose titration or use of propofol may reduce
oversedation.
A preoperative checklist for patients with portal hypertension has been published.146 Patients with
portal hypertension are at risk for bleeding from visceral and retroperitoneal varices; meticulous
hemostasis is necessary and may prolong expected operative times. Impaired aldosterone metabolism
leads to increased sodium conservation with subsequent volume overload. Peripheral shunting and
vasodilation complicate management of acute volume shifts and intraoperative invasive hemodynamic
monitoring or transesophageal echocardiography may permit goal-directed resuscitation. Surgical
procedures with anticipated right-sided heart failure may worsen hepatic congestion and thus may be
contraindicated. β-Blockade and octreotide may be of use in reducing splanchnic hypertension; the role
of preoperative TIPS is unclear and its use cannot be routinely recommended.
Coagulopathy may exist from decreased synthetic function and may be monitored with PT and
measurement and replacement of individual coagulation factors. In the presence of biliary obstruction
or poor nutrition, deficiencies of vitamin K-dependent clotting factors may be reduced with oral or
intravenous supplementation or factor transfusion with fresh frozen plasma or concentrated factor
replacement. Enthusiasm for off-label use of Factor rVIIa to treat coagulopathy has waned in the wake
of reports of adverse thrombotic events.147 Thrombocytopenia from splenic sequestration may
aggravate surgical bleeding and response to platelet transfusion may be blunted. Increased fibrinolysis
may be present secondary to low-grade disseminated intravascular coagulation (DIC). Monitoring with
thromboelastography may appropriately direct factor replacement with fresh frozen plasma,
prothrombin complex concentrate or Factor rVIIa, or administration of antifibrinolytics.
Wound healing and surgical wound infection are associated with malnutrition, malignancy, and sepsis.
Protein calorie malnutrition, hypomagnesemia, and hypophosphatemia may aggravate this. Empiric
thiamine, folate, and multivitamin replacement should be administered. Perioperative nutritional
support may be limited by intolerance of enteral protein loading and cholestatic changes from
parenteral nutrition. Uncontrolled ascites can be managed with volume restriction, active diuresis once
acute resuscitation is complete, and paracentesis to minimize abdominal hypertension and local wound
disruption.
The development of postoperative liver dysfunction may manifest days to weeks following surgery.
Encephalopathy may initially manifest as subtle cognitive changes and progress to substantial changes
in mental status. Serum ammonia levels are not correlated with extent of cognitive disturbance. The
European Association for the Study of the Liver (EASL) has published guidelines regarding diagnosis and
management of hepatic encephalopathy.148 Medical management consists of careful oversight of volume
shifts, judicious sedation use, enteral lactulose titrated to 2 to 3 loose stools daily and oral antibiotics,
such as rifaximin, to minimize colonic bacterial amine transformation and reduce bacterial translocation.
Patients with a history of alcohol abuse may undergo acute withdrawal following surgery. Classic
delirium tremens (DTs) is seen 72 hours after cessation of alcohol use but may be seen at any time.
Symptoms of autonomic instability, agitation, and delirium should be managed symptomatically with β-
blockade, clonidine, and benzodiazepines. Protocolized symptom-triggered regimens are associated with
lower total medication dose compared to standing regimens.149 DT prophylaxis with round-the-clock
medication is not indicated outside of high-risk cases or a history of prior DTs.
507
Algorithm 15-4. Proposed algorithm for preoperative evaluation of patients with liver disease. (Adapted from Hanje AJ, Patel T.
Preoperative evaluation of patients with liver disease. Nat Clin Pract Gastroenterol Hepatol 2007;4(5):266–276.)
Renal
Surgery may worsen preexisting renal dysfunction. There is increasing recognition that new renal
failure manifested by even small, transient increases in serum creatinine during the postoperative period
is associated with later mortality.150 Therefore, preoperative evaluation should be based not only on
determining current status of chronic or acute renal disease but also on the potential for further
deterioration.
Risk Stratification
The strongest risk factor for development of postoperative acute kidney injury is the presence of
preexisting chronic renal disease.151 The development of postoperative renal failure is in turn strongly
associated with increased mortality.150,152,153 A single episode of acute kidney injury (AKI) as defined by
RIFLE criteria is associated with long-term mortality in proportion with the severity of injury. In a large
noncardiac surgery series,154 anemia (hemoglobin < 12.0 g/dL) and a decrease in postoperative
hemoglobin greater than 1.1 g/dL were associated with higher risk for renal failure. Using a large
intraoperative data set, risk factors for the development of acute kidney injury in noncardiac surgical
patients were identified and used to model an Acute Kidney Index scoring system (Table 15-16).153
The presence of underlying renal disease should be suspected on the basis of history. Chronic renal
disease in the adult population is not uncommon, with an estimated prevalence at 13%.155 Common
systemic conditions such as hypertension, diabetes mellitus, and arteriosclerosis may lead to end organ
damage. Renal impairment must be considered in the context of the presence of associated systemic
disease.
Determination of renal function is based on the glomerular filtration rate (GFR), estimated by
equations such as the Cockcroft–Gault equation.156 As the GFR is reduced to <30% of baseline,
electrolyte, volume, and red cell homeostasis are altered. Medication excretion will be decreased and
drug dosing should be titrated by levels to minimize toxicity.
Defining Acute Kidney Injury

In a noncardiac general surgical population, the incidence of postoperative renal failure may be as high
as 1%.153 The majority of perioperative studies have used differing definitions of postoperative renal
failure and direct comparisons are difficult. Small increases in creatinine, as little as 0.3 mg/kg, may
increase risk.157 The search for a consistent definition continues. Criteria utilized in the ICU setting are
being validated as predictors of renal outcomes in cardiac, general, and vascular surgery
outcomes.150,158 In 2004, the Acute Dialysis Quality Initiative group developed the RIFLE (Risk, Injury,
Failure, Loss, End-Stage) consensus definition of renal failure (Table 15-17).159 Subsequent refinements
508
(the Acute Kidney Injury Network and Kidney Disease Improving Global Outcomes) have been proposed
as an attempt to further incorporate oliguria, as well as relative and absolute changes in serum
creatinine to the RIFLE framework. Promising biomarkers for predicting and measuring acute renal
failure have been identified and it is likely that future definitions will incorporate these.
Prevention of Acute Kidney Injury

Strategies for prevention of postoperative renal failure include stabilization of homeostatic imbalances,
maintenance of adequate renal perfusion, avoidance of intraoperative hypotension, and judicious use of
nephrotoxic agents, including aminoglycosides, ace-inhibitors, intravenous contrast agents, and NSAIDs.
In patients with known chronic renal disease, careful evaluation of electrolyte abnormalities, anemia,
and intravascular volume should be performed.
The mainstay of prevention strategies is to ensure adequate renal perfusion by avoiding hypotension
from hypovolemia. In diabetic patients receiving IV contrast dye, preemptive saline hydration reduced
the risk of renal failure; the addition of prophylactic sodium bicarbonate was not demonstrably superior
to saline hydration alone.160
Despite extensive clinical testing, no pharmacologic intervention has been found to successfully
improve postoperative renal outcomes. Preoperative statin,161 prophylactic or therapeutic
acetylcysteine,162 ANP,163 insulin-like growth factor164 tight glycemic control, and antiplatelet drugs
have all failed to show efficacy. In the POISE-2 trial, neither aspirin nor clonidine reduced the risk of
renal failure in noncardiac surgery, although each drug had increased rates of complications (bleeding,
hypotension) associated with higher rates of renal failure.157 Calcium channel blockers have been
associated with renoprotection in transplant surgery165 but have been associated with increased renal
failure rates after cardiac surgery.166 Forced diuresis with low-dose dopamine and furosemide can
maintain urinary flow but do not improve intrinsic renal function.167 A recent randomized trial of
fenoldopam in cardiac surgery demonstrated no reduction in need for renal replacement therapy or 30-
day mortality but did show a higher incidence of hypotension.168
Table 15-16 General Surgery Acute Kidney Injury Risk Index Classification
System
Preoperative hyperkalemia may exist in up to 38% of patients with chronic renal failure.169 Acute ECG
changes should be immediately stabilized with administration of intravenous calcium and intracellular
shifts with sodium bicarbonate or insulin and glucose. Removal of excess potassium may be
accomplished with exchange resins or acute dialysis.
509
Anemia is well tolerated in patients with chronic renal failure. Erythropoietin-stimulating agents are
recommended for patients on and approaching dialysis; black box warnings have been issued for use in
oncologic patients and advise against high hemoglobin targets. Associated coagulopathy related to
uremic platelet dysfunction may be managed with desmopressin acetate, platelet transfusion, or
dialysis.
Volume overload may accompany acute and chronic oliguric renal failure. Following surgery, volume
resuscitation should be goal directed and hydroxyethyl starch170 and hyperchloremic solutions should be
avoided.171 Hyperresuscitation may result in development of abdominal compartment syndrome; if
prerenal oliguria persists despite medical management, decompressive laparotomy may be required to
restore renal perfusion.172
Table 15-17 The RIFLE Classification for Acute Renal Failure
Once renal failure occurs, substantial alterations in drug metabolism and excretion must be
considered. From an anesthetic standpoint, sedative and narcotic dosing must be adjusted for elevated
half-life and prolonged neuromuscular blockade may occur with agents acting at the neuromuscular
junction. Succinylcholine is contraindicated in the presence of hyperkalemia. Agents undergoing
peripheral Hoffman degradation may be used preferentially in the face of renal dysfunction. Meta-
analysis in cardiac surgery has suggested that the use of volatile anesthetics may also be associated with
lower absolute increases in serum creatinine.173
Renal replacement therapy is indicated emergently for correction of acidosis, symptomatic
hyperkalemia, severe volume overload, or uremic pericarditis. Dialysis may be undertaken
preoperatively to optimize volume and electrolyte status prior to surgery. Once GFR falls below 5 to 10
mL/min, hemodialysis is usually indicated for clearance. Continuous venovenous hemodialysis may
permit volume removal in the hemodynamically unstable patient. Consideration should be given to the
location of temporary dialysis access; subclavian and upper extremity access should be avoided in
patients who may eventually go on to require permanent dialysis access.
ADDITIONAL CONSIDERATIONS, FUTURE DIRECTIONS

Considerable progress has been made in refining preoperative risk assessment; however, the majority of
the risk factors identified to date have been nonmodifiable (i.e., age, need for emergent surgery, and
type of surgery required). As electronic health data collection becomes more prevalent and facile, new
predictors of surgical risk that permit targeted interventions may be uncovered and present
opportunities for study.
In the meantime, the preoperative visit should continue to function as an opportunity to initiate care
for patients identified as high-risk. Process of care practices with broad proven benefit can be
protocolized as part of routine presurgical orders; an example would be compliance with the Surgical
Care Initiative Project (SCIP) performance measures in the domains of infection prophylaxis and deep
venous thrombosis (DVT) prophylaxis. Studies evaluating early “prehabilitation” or “training for
surgery” for patients with functional deficits are in progress. Advance in preoperative assessment will
continue to contribute to the best outcomes for surgical patients.
References
1. Goldman L, Caldera DL, Nussbaum SR, et al. Multifactorial index of cardiac risk in noncardiac
surgical procedures. N Engl J Med 1977;297(16):845–850.
510
2. Chassin MR. Is health care ready for Six Sigma quality? Milbank Q 1998;76(4):565–591, 510.
3. Finlayson EV, Birkmeyer JD. Operative mortality with elective surgery in older adults. Eff Clin Pract
2001;4(4):172–177.
4. Semel ME, Lipsitz SR, Funk LM, et al. Rates and patterns of death after surgery in the United States,
1996 and 2006. Surgery 2012;151(2):171–182.
5. Khuri SF, Henderson WG, Daley J, et al. Successful implementation of the Department of Veterans
Affairs’ National Surgical Quality Improvement Program in the private sector: the Patient Safety in
Surgery study. Ann Surg 2008;248(2):329–336.
6. Pearse RM, Moreno RP, Bauer P, et al. Mortality after surgery in Europe: a 7 day cohort study.
Lancet 2012;380(9847):1059–1065.
7. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a Safer Health System.
Washington, DC: the National Academies Press; 2000.
8. Silber JH, Rosenbaum PR, Trudeau ME, et al. Changes in prognosis after the first postoperative
complication. Med Care 2005;43(2):122–131.
9. Glance LG, Osler TM, Mukamel DB, et al. Effect of complications on mortality after coronary artery
bypass grafting surgery: evidence from New York State. J Thorac Cardiovasc Surg 2007;134(1):53–
58.
10. Khuri SF, Henderson WG, DePalma RG, et al. Determinants of long-term survival after major
surgery and the adverse effect of postoperative complications. Ann Surg 2005;242(3):326–341;
11. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpatient
surgery. N Engl J Med 2009;361(14):1368–1375.
12. Dimick JB, Weeks WB, Karia RJ, et al. Who pays for poor surgical quality? Building a business case
for quality improvement. J Am Coll Surg 2006; 202(6):933–937.
13. Eappen S, Lane BH, Rosenberg B, et al. Relationship between occurrence of surgical complications
and hospital finances. JAMA 2013;309(15):1599–1606.
14. Joynt KE, Gawande AA, Orav EJ, et al. Contribution of preventable acute care spending to total
spending for high-cost Medicare patients. JAMA 2013;309(24):2572–2578.
15. Kassin MT, Owen RM, Perez SD, et al. Risk factors for 30-day hospital readmission among general
surgery patients. J Am Coll Surg 2012;215(3):322–330.
16. Morris MS, Deierhoi RJ, Richman JS, et al. The relationship between timing of surgical
complications and hospital readmission. JAMA Surg 2014;149(4):348–354.
17. Wick EC, Shore AD, Hirose K, et al. Readmission rates and cost following colorectal surgery. Dis
Colon Rectum 2011;54(12):1475–1479.
18. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with
evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240(2):205–213.
19. Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical
complications: Five-year experience. Ann Surg 2009;250(2):187–196.
20. Kwok AC, Semel ME, Lipsitz SR, et al. The intensity and variation of surgical care at the end of life:
a retrospective cohort study. Lancet 2011;378(9800):1408–1413.
21. Rowell KS, Turrentine FE, Hutter MM, et al. Use of national surgical quality improvement program
data as a catalyst for quality improvement. J Am Coll Surg 2007;204(6):1293–1300.
22. Hall BL, Hamilton BH, Richards K, et al. Does surgical quality improve in the American College of
Surgeons National Surgical Quality Improvement Program: an evaluation of all participating
hospitals. Ann Surg 2009;250(3):363–376.
23. Cohen ME, Liu Y, Ko CY, et al. Improved surgical outcomes for ACS NSQIP hospitals over time:
evaluation of hospital cohorts with up to 8 years of participation. Ann Surg 2016;263(2):267–273.
24. Osborne NH, Nicholas LH, Ryan AM, et al. Association of hospital participation in a quality
reporting program with surgical outcomes and expenditures for Medicare beneficiaries. JAMA
2015;313(5):496–504.
25. Etzioni DA, Wasif N, Dueck AC, et al. Association of hospital participation in a surgical outcomes
monitoring program with inpatient complications and mortality. JAMA 2015;313(5):505–511.
26. Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for
511
prediction of cardiac risk after surgery. Circulation 2011;124(4):381–387.
27. Bilimoria KY, Liu Y, Paruch JL, et al. Development and evaluation of the universal ACS NSQIP
surgical risk calculator: a decision aid and informed consent tool for patients and surgeons. J Am
Coll Surg 2013;217(5):833–842; e831–e833.
28. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guideline on Perioperative
Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery: Executive
Summary: a report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines. Circulation 2014;130(24):2215–2245.
29. Halaszynski TM, Juda R, Silverman DG. Optimizing postoperative outcomes with efficient
preoperative assessment and management. Crit Care Med 2004;32(4) (suppl):S76–S86.
30. Brumfield VC, Kee CC, Johnson JY. Preoperative patient teaching in ambulatory surgery settings.
AORN J 1996;64(6):941–946, 948, 951–952.
31. Smetana GW, Macpherson DS. The case against routine preoperative laboratory testing. Med Clin
North Am 2003;87(1):7–40.
32. Kaplan EB, Sheiner LB, Boeckmann AJ, et al. The usefulness of preoperative laboratory screening.
JAMA 1985;253(24):3576–3581.
33. Benarroch-Gampel J, Sheffield KM, Duncan CB, et al. Preoperative laboratory testing in patients
undergoing elective, low-risk ambulatory surgery. Ann Surg 2012;256(3):518–528.
34. Kachalia A, Berg A, Fagerlin A, et al. Overuse of testing in preoperative evaluation and syncope: a
survey of hospitalists. Ann Intern Med 2015; 162(2):100–108.
35. Roberts S, Spain B, Hicks C, et al. Telemedicine in the Northern Territory: an assessment of patient
perceptions in the preoperative anaesthetic clinic. Aust J Rural Health 2015;23:136–141.
36. Amrock LG, Neuman MD, Lin HM, et al. Can routine preoperative data predict adverse outcomes in
the elderly? Development and validation of a simple risk model incorporating a chart-derived
frailty score. J Am Coll Surg 2014;219(4):684–694.
37. Hilditch WG, Asbury AJ, Jack E, et al. Validation of a pre-anaesthetic screening questionnaire.
Anaesthesia 2003;58(9):874–877.
38. Hilditch WG, Asbury AJ, Crawford JM. Pre-operative screening: criteria for referring to
anaesthetists. Anaesthesia 2003;58(2):117–124.
39. Davenport DL, Bowe EA, Henderson WG, et al. National Surgical Quality Improvement Program
(NSQIP) risk factors can be used to validate American Society of Anesthesiologists Physical Status
Classification (ASA PS) levels. Ann Surg 2006;243(5):636–641; discussion 641–644.
40. Smetana GW, Lawrence VA, Cornell JE. Preoperative pulmonary risk stratification for
noncardiothoracic surgery: systematic review for the American College of Physicians. Ann Intern
Med 2006;144(8):581–595.
41. Rodgers A, Walker N, Schug S, et al. Reduction of postoperative mortality and morbidity with
epidural or spinal anaesthesia: results from overview of randomised trials. BMJ
2000;321(7275):1493.
42. Khuri SF, Daley J, Henderson W, et al. Risk adjustment of the postoperative mortality rate for the
comparative assessment of the quality of surgical care: results of the National Veterans Affairs
Surgical Risk Study. J Am Coll Surg 1997;185(4):315–327.
43. Daley J, Khuri SF, Henderson W, et al. Risk adjustment of the postoperative morbidity rate for the
Surgical Risk Study. J Am Coll Surg 1997;185(4):328–340.
44. Russo CA, Andrews RM, Barrett ML. Racial and Ethnic Disparities in Hospital Patient Safety Events,
2005.HCUP Statistical Brief #53. Rockville, MD: Agency for Healthcare Research and Quality; June
2008.
45. Sukumar S, Ravi P, Sood A, et al. Racial disparities in operative outcomes after major cancer
surgery in the United States. World J Surg 2015;39(3):634–643.
46. World Health Organization. 10 facts on ageing and the life course.
http://www.who.int/features/factfiles/ageing/en/. Published 2015.
47. Chow WB, Rosenthal RA, Merkow RP, et al. Optimal preoperative assessment of the geriatric
surgical patient: a best practices guideline from the American College of Surgeons National Surgical
Quality Improvement Program and the American Geriatrics Society. J Am Coll Surg
512
2012;215(4):453–466.
48. Nicholas JA. Preoperative optimization and risk assessment. Clin Geriatr Med 2014;30(2):207–218.
49. Qaseem A, Snow V, Fitterman N, et al. Risk assessment for and strategies to reduce perioperative
pulmonary complications for patients undergoing noncardiothoracic surgery: a guideline from the
American College of Physicians. Ann Intern Med 2006;144(8):575–580.
50. Sheetz KH, Krell RW, Englesbe MJ, et al. The importance of the first complication: Understanding
failure to rescue after emergent surgery in the elderly. J Am Coll Surg 2014;219(3):365–370.
51. Bettelli G. Preoperative evaluation in geriatric surgery: comorbidity, functional status and
pharmacological history. Minerva Anestesiol 2011;77(6):637–646.
52. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple
index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100(10):1043–
1049.
53. Welten GM, Schouten O, van Domburg RT, et al. The influence of aging on the prognostic value of
the revised cardiac risk index for postoperative cardiac complications in vascular surgery patients.
Eur J Vasc Endovasc Surg 2007;34(6):632–638.
54. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of obesity in the United States, 2009–2010 NCHS
Data Brief 2012;(82):1–8.
55. Mullen JT, Moorman DW, Davenport DL. The obesity paradox: Body mass index and outcomes in
patients undergoing nonbariatric general surgery. Ann Surg 2009;250(1):166–172.
56. American Society of Anesthesiologists Task Force on Perioperative Management of patients with
obstructive sleep apnea. Practice guidelines for the perioperative management of patients with
obstructive sleep apnea: an updated report by the American Society of Anesthesiologists Task Force
on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology
2014;120(2):268–286.
57. Gross JB, Bachenberg KL, Benumof JL, et al. Practice guidelines for the perioperative management
of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task
Force on Perioperative Management of patients with obstructive sleep apnea. Anesthesiology
2006;104(5):1081–1093; quiz 1117–1118.
58. Beattie WS, Karkouti K, Wijeysundera DN, et al. Risk associated with preoperative anemia in
noncardiac surgery: a single-center cohort study. Anesthesiology 2009;110(3):574–581.
59. Hebert PC. Transfusion requirements in critical care (TRICC): a multicentre, randomized, controlled
clinical study. Transfusion Requirements in Critical Care Investigators and the Canadian Critical
care Trials Group. Br J Anaesth 1998;81(suppl 1):25–33.
60. Murphy GJ, Pike K, Rogers CA, et al. Liberal or restrictive transfusion after cardiac surgery. N Engl
J Med 2015;372(11):997–1008.
61. Carson JL, Terrin ML, Noveck H, et al. Liberal or restrictive transfusion in high-risk patients after
hip surgery. N Engl J Med 2011;365(26):2453–2462.
62. Lin DM, Lin ES, Tran MH. Efficacy and safety of erythropoietin and intravenous iron in
perioperative blood management: a systematic review. Transfus Med Rev 2013;27(4):221–234.
63. Hirst C, Williamson L. Preoperative blood transfusions for sickle cell disease. Cochrane Database
Syst Rev. 2012;1:CD003149.
64. Lacroix J, Hebert PC, Fergusson DA, et al. Age of transfused blood in critically ill adults. N Engl J
Med 2015;372(15):1410–1418.
65. Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac
surgery. N Engl J Med 2008;358(12):1229–1239.
66. Reilly DF, McNeely MJ, Doerner D, et al. Self-reported exercise tolerance and the risk of serious
perioperative complications. Arch Intern Med 1999;159(18):2185–2192.
67. Jette M, Sidney K, Blumchen G. Metabolic equivalents (METs) in exercise testing, exercise
prescription, and evaluation of functional capacity. Clin Cardiol 1990;13(8):555–565.
68. Lachs MS, Feinstein AR, Cooney LM Jr, et al. A simple procedure for general screening for
functional disability in elderly patients. Ann Intern Med 1990;112(9):699–706.
69. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol
A Biol Sci Med Sci 2001;56(3):M146–M156.
70. Oresanya LB, Lyons WL, Finlayson E. Preoperative assessment of the older patient: a narrative
513
review. JAMA 2014;311(20):2110–2120.
71. Mortensen K, Nilsson M, Slim K, et al. Consensus guidelines for enhanced recovery after
gastrectomy: enhanced Recovery After Surgery (ERAS(R)) Society recommendations. Br J Surg
2014;101(10):1209–1229.
72. Uppal S, Igwe E, Rice LW, et al. Frailty index predicts severe complications in gynecologic
oncology patients. Gynecol Oncol 2015;137(1):98–101.
73. Sepehri A, Beggs T, Hassan A, et al. The impact of frailty on outcomes after cardiac surgery: a
systematic review. J Thorac Cardiovasc Surg 2014;148(6):3110–3117.
74. Miller AL, Min LC, Diehl KM, et al. Analytic morphomics corresponds to functional status in older
patients. J Surg Res 2014;192(1):19–26.
75. Waits SA, Kim EK, Terjimanian MN, et al. Morphometric age and mortality after liver transplant.
JAMA Surg 2014;149(4):335–340.
76. Lee JS, He K, Harbaugh CM, et al. Frailty, core muscle size, and mortality in patients undergoing
open abdominal aortic aneurysm repair. J Vasc Surg 2011;53(4):912–917.
77. Makary MA, Segev DL, Pronovost PJ, et al. Frailty as a predictor of surgical outcomes in older
patients. J Am Coll Surg 2010;210(6):901–908.
78. Quill TE, Holloway R. Time-limited trials near the end of life. JAMA 2011;306(13):1483–1484.
79. Neuman MD, Allen S, Schwarze ML, Uy J. Using time-limited trials to improve surgical care for
frail older adults. Ann Surg 2015;261(4):639–641.
80. Ang-Lee MK, Moss J, Yuan CS. Herbal medicines and perioperative care. JAMA 2001;286(2):208–
216.
81. Kaye AD, Clarke RC, Sabar R, et al. Herbal medicines: current trends in anesthesiology practice—a
hospital survey. J Clin Anesth 2000;12(6):468–471.
82. Cui J, Garle M, Eneroth P, Bjorkhem I. What do commercial ginseng preparations contain? Lancet
1994;344(8915):134.
83. Whinney C. Perioperative medication management: general principles and practical applications.
Cleve Clin J Med 2009;76(suppl 4):S126–S132.
84. Rosenman DJ, McDonald FS, Ebbert JO, et al. Clinical consequences of withholding versus
administering renin-angiotensin-aldosterone system antagonists in the preoperative period. J Hosp
Med 2008;3(4):319–325.
85. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic Therapy and Prevention
of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012;141(2) (suppl):7S–47S.
86. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists:
American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition).
Chest 2008;133(6) (suppl):160S–198S.
87. Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in patients undergoing noncardiac surgery. N
Engl J Med 2014;370(16):1494–1503.
88. O’Riordan JM, Margey RJ, Blake G, et al. Antiplatelet agents in the perioperative period. Arch Surg
2009;144(1):69–76; discussion 76.
89. Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin
infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract
2004;10(suppl 2):21–33.
90. Papadopoulos S, Cook AM. You can withdraw from that? The effects of abrupt discontinuation of
medications. Orthopedics 2006;29(5):413–417.
91. Subramanian V, Pollok RC, Kang JY, et al. Systematic review of postoperative complications in
patients with inflammatory bowel disease treated with immunomodulators. Br J Surg
2006;93(7):793–799.
92. Subramanian V, Saxena S, Kang JY, et al. Preoperative steroid use and risk of postoperative
complications in patients with inflammatory bowel disease undergoing abdominal surgery. Am J
Gastroenterol 2008;103(9):2373–2381.
93. Marik PE, Varon J. Requirement of perioperative stress doses of corticosteroids: a systematic
review of the literature. Arch Surg 2008;143(12):1222–1226.
514
94. Mashour GA, Shanks AM, Kheterpal S. Perioperative stroke and associated mortality after
noncardiac, nonneurologic surgery. Anesthesiology 2011;114(6):1289–1296.
95. Healy KO, Waksmonski CA, Altman RK, et al. Perioperative outcome and long-term mortality for
heart failure patients undergoing intermediate- and high-risk noncardiac surgery: impact of left
ventricular ejection fraction. Congestive Heart Fail 2010;16(2):45–49.
96. Kazmers A, Cerqueira MD, Zierler RE. Perioperative and late outcome in patients with left
ventricular ejection fraction of 35% or less who require major vascular surgery. J Vasc Surg
1988;8(3):307–315.
97. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of
Patients With Valvular Heart Disease: Executive summary: a report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;
129(23):2440–2492.
98. Minai OA, Yared JP, Kaw R, et al. Perioperative risk and management in patients with pulmonary
hypertension. Chest 2013;144(1):329–340.
99. Ramakrishna G, Sprung J, Ravi BS, et al. Impact of pulmonary hypertension on the outcomes of
noncardiac surgery: predictors of perioperative morbidity and mortality. J Am Coll Cardiol
2005;45(10):1691–1699.
100. Warnes CA, Williams RG, Bashore TM, et al. ACC/AHA 2008 Guidelines for the Management of
Adults with Congenital Heart Disease: executive Summary: A report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to
develop guidelines for the management of adults with congenital heart disease). Circulation
2008;118(23):2395–2451.
101. Bouri S, Shun-Shin MJ, Cole GD, et al. Meta-analysis of secure randomised controlled trials of beta-
blockade to prevent perioperative death in non-cardiac surgery. Heart 2014;100(6):456–464.
102. Durazzo AE, Machado FS, Ikeoka DT, et al. Reduction in cardiovascular events after vascular
surgery with atorvastatin: a randomized trial. J Vasc Surg 2004;39(5):967–975; discussion 975–976.
103. Devereaux PJ, Sessler DI, Leslie K, et al. Clonidine in patients undergoing noncardiac surgery. N
Engl J Med 2014;370(16):1504–1513.
104. Manku K, Bacchetti P, Leung JM. Prognostic significance of postoperative in-hospital complications
in elderly patients. I. Long-term survival. Anesth Analg 2003;96(2):583–589, table of contents.
105. Arozullah AM, Daley J, Henderson WG, et al. Multifactorial risk index for predicting postoperative
respiratory failure in men after major noncardiac surgery. The National Veterans Administration
Surgical Quality Improvement Program. Ann Surg 2000;232(2):242–253.
106. Canet J, Gallart L, Gomar C, et al. Prediction of postoperative pulmonary complications in a
population-based surgical cohort. Anesthesiology 2010;113(6):1338–1350.
107. Jeong BH, Shin B, Eom JS, et al. Development of a prediction rule for estimating postoperative
pulmonary complications. PloS One 2014;9(12):e113656.
108. Warner DO, Warner MA, Barnes RD, et al. Perioperative respiratory complications in patients with
asthma. Anesthesiology 1996;85(3):460–467.
109. Sorensen LT. Wound healing and infection in surgery: the pathophysiological impact of smoking,
smoking cessation, and nicotine replacement therapy: a systematic review. Ann Surg
2012;255(6):1069–1079.
110. Turan A, Mascha EJ, Roberman D, et al. Smoking and perioperative outcomes. Anesthesiology
2011;114(4):837–846.
111. Wong J, Lam DP, Abrishami A, et al. Short-term preoperative smoking cessation and postoperative
complications: a systematic review and meta-analysis. Can J Anaesth 2012;59(3):268–279.
112. Barrera R, Shi W, Amar D, et al. Smoking and timing of cessation: Impact on pulmonary
complications after thoracotomy. Chest 2005;127(6):1977–1983.
113. Nakagawa M, Tanaka H, Tsukuma H, et al. Relationship between the duration of the preoperative
smoke-free period and the incidence of postoperative pulmonary complications after pulmonary
surgery. Chest 2001;120(3):705–710.
114. Shi Y, Warner DO. Brief preoperative smoking abstinence: is there a dilemma? Anesth Analg
2011;113(6):1348–1351.
115. Shi Y, Warner DO. Surgery as a teachable moment for smoking cessation. Anesthesiology
515
2010;112(1):102–107.
116. Thomsen T, Villebro N, Moller AM. Interventions for preoperative smoking cessation. Cochrane
Database Syst Rev 2014;3:CD002294.
117. Colice GL, Shafazand S, Griffin JP, et al. Physiologic evaluation of the patient with lung cancer
being considered for resectional surgery: ACCP evidenced-based clinical practice guidelines (2nd
edition). Chest 2007; 132(3) (suppl):161S–177S.
118. IRoselli EE, Murthy SC, Rice TW, et al. Atrial fibrillation complicating lung cancer resection. J
Thorac Cardiovasc Surg 2005;130(2):438–444.
119. Lawrence VA, Cornell JE, Smetana GW. Strategies to reduce postoperative pulmonary
complications after noncardiothoracic surgery: systematic review for the American College of
Physicians. Ann Intern Med 2006;144(8):596–608.
120. Licker MJ, Widikker I, Robert J, et al. Operative mortality and respiratory complications after lung
resection for cancer: impact of chronic obstructive pulmonary disease and time trends. Ann Thorac
Surg 2006;81(5):1830–1837.
121. Elkouri S, Gloviczki P, McKusick MA, et al. Perioperative complications and early outcome after
endovascular and open surgical repair of abdominal aortic aneurysms. J Vasc Surg 2004;39(3):497–
505.
122. Von Dossow V, Welte M, Zaune U, et al. Thoracic epidural anesthesia combined with general
anesthesia: the preferred anesthetic technique for thoracic surgery. Anesth Analg 2001;92(4):848–
854.
123. Nelson R, Tse B, Edwards S. Systematic review of prophylactic nasogastric decompression after
abdominal operations. Br J Surg 2005;92(6):673–680.
124. Sweitzer BJ, Smetana GW. Identification and evaluation of the patient with lung disease. Med Clin
North Am 2009;93(5):1017–1030.
125. Zarbock A, Mueller E, Netzer S, et al. Prophylactic nasal continuous positive airway pressure
following cardiac surgery protects from postoperative pulmonary complications: a prospective,
randomized, controlled trial in 500 patients. Chest 2009;135(5):1252–1259.
126. Hulzebos EH, Helders PJ, Favie NJ, et al. Preoperative intensive inspiratory muscle training to
prevent postoperative pulmonary complications in high-risk patients undergoing CABG surgery: a
randomized clinical trial. JAMA 2006;296(15):1851–1857.
127. Torrington KG, Henderson CJ. Perioperative respiratory therapy (PORT). A program of
preoperative risk assessment and individualized postoperative care. Chest 1988;93(5):946–951.
128. Friedman LS. Surgery in the patient with liver disease. Trans Am Clin Climatol Assoc 2010;121:192–
204; discussion 205.
129. Brolin RE, Bradley LJ, Taliwal RV. Unsuspected cirrhosis discovered during elective obesity
operations. Arch Surg 1998;133(1):84–88.
130. Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg 1964;1:1–85.
131. Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding
oesophageal varices. Br J Surg 1973;60(8):646–649.
132. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage
liver disease. Hepatology 2001;33(2):464–470.
133. Northup PG, Wanamaker RC, Lee VD, et al. Model for end-stage liver disease (MELD) predicts
nontransplant surgical mortality in patients with cirrhosis. Ann Surg 2005;242(2):244–251.
134. Farnsworth N, Fagan SP, Berger DH, et al. Child-Turcotte-Pugh versus MELD score as a predictor of
outcome after elective and emergent surgery in cirrhotic patients. Am J Surg 2004;188(5):580–583.
135. Schroeder RA, Marroquin CE, Bute BP, et al. Predictive indices of morbidity and mortality after
liver resection. Ann Surg 2006;243(3):373–379.
136. Cucchetti A, Ercolani G, Vivarelli M, et al. Impact of model for end-stage liver disease (MELD)
score on prognosis after hepatectomy for hepatocellular carcinoma on cirrhosis. Liver Transplant
2006;12(6):966–971.
137. Garrison RN, Cryer HM, Howard DA, et al. Clarification of risk factors for abdominal operations in
patients with hepatic cirrhosis. Ann Surg 1984;199(6):648–655.
138. Mansour A, Watson W, Shayani V, et al. Abdominal operations in patients with cirrhosis: still a
major surgical challenge. Surgery 1997;122(4):730–735; discussion 735–736.
516
139. Ziser A, Plevak DJ, Wiesner RH, et al. Morbidity and mortality in cirrhotic patients undergoing
anesthesia and surgery. Anesthesiology 1999; 90(1):42–53.
140. O’Leary JG, Yachimski PS, Friedman LS. Surgery in the patient with liver disease. Clin Liver Dis
2009;13(2):211–231.
141. Hanje AJ, Patel T. Preoperative evaluation of patients with liver disease. Nat Clin Pract
Gastroenterol Hepatol 2007;4(5):266–276.
142. Meunier K, Mucci S, Quentin V, et al. Colorectal surgery in cirrhotic patients: assessment of
operative morbidity and mortality. Dis Colon Rectum 2008;51(8):1225–1231.
143. Lehnert T, Herfarth C. Peptic ulcer surgery in patients with liver cirrhosis. Ann Surg
1993;217(4):338–346.
144. Suman A, Barnes DS, Zein NN, et al. Predicting outcome after cardiac surgery in patients with
cirrhosis: a comparison of Child-Pugh and MELD scores. Clin Gastroenterol Hepatol 2004;2(8):719–
723.
145. van den Broek MA, Olde Damink SW, Dejong CH, et al. Liver failure after partial hepatic resection:
Definition, pathophysiology, risk factors and treatment. Liver Int 2008;28(6):767–780.
146. Im GY, Lubezky N, Facciuto ME, et al. Surgery in patients with portal hypertension: A preoperative
checklist and strategies for attenuating risk. Clin Liver Dis 2014;18(2):477–505.
147. O’Connell KA, Wood JJ, Wise RP, et al. Thromboembolic adverse events after use of recombinant
human coagulation factor VIIa. JAMA 2006;295(3):293–298.
148. American Association for the Study of Liver Diseases; European Association for the Study of the
Liver. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the European
Association for the Study of the Liver and the American Association for the Study of Liver Diseases.
J Hepatol 2014;61(3):642–659.
149. Jaeger TM, Lohr RH, Pankratz VS. Symptom-triggered therapy for alcohol withdrawal syndrome in
medical inpatients. Mayo Clin Proc 2001;76(7):695–701.
150. Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kidney injury during
hospitalization after major surgery. Ann Surg 2009;249(5):851–858.
151. Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury.
Clin J Am Soc Nephrol 2008;3(3):844–861.
152. Chertow GM, Levy EM, Hammermeister KE, et al. Independent association between acute renal
failure and mortality following cardiac surgery. Am J Med 1998;104(4):343–348.
153. Kheterpal S, Tremper KK, Heung M, et al. Development and validation of an acute kidney injury
risk index for patients undergoing general surgery: results from a national data set. Anesthesiology
2009;110(3):505–515.
154. Walsh M, Garg AX, Devereaux PJ, et al. The association between perioperative hemoglobin and
acute kidney injury in patients having noncardiac surgery. Anesth Analg 2013;117(4):924–931.
155. Coresh J, Selvin E, Stevens LA, et al. Prevalence of chronic kidney disease in the United States.
JAMA 2007;298(17):2038–2047.
156. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron
1976;16(1):31–41.
157. Garg AX, Kurz A, Sessler DI, et al. Perioperative aspirin and clonidine and risk of acute kidney
injury: a randomized clinical trial. JAMA 2014;312(21):2254–2264.
158. Kuitunen A, Vento A, Suojaranta-Ylinen R, et al. Acute renal failure after cardiac surgery:
evaluation of the RIFLE classification. Ann Thorac Surg 2006;81(2):542–546.
159. Bellomo R, Ronco C, Kellum JA, et al. Acute renal failure—definition, outcome measures, animal
models, fluid therapy and information technology needs: the Second International Consensus
Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8(4):R204–R212.
160. Brar SS, Shen AY, Jorgensen MB, et al. Sodium bicarbonate vs sodium chloride for the prevention
of contrast medium-induced nephropathy in patients undergoing coronary angiography: a
randomized trial. JAMA 2008;300(9):1038–1046.
161. Argalious MY, Dalton JE, Sreenivasalu T, et al. The association of preoperative statin use and acute
kidney injury after noncardiac surgery. Anesth Analg 2013;117(4):916–923.
162. Fishbane S. N-acetylcysteine in the prevention of contrast-induced nephropathy. Clin J Am Soc
Nephrol 2008;3(1):281–287.
517
163. Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. Auriculin Anaritide
Acute Renal Failure Study Group. N Engl J Med 1997;336(12):828–834.
164. Hirschberg R, Kopple J, Lipsett P, et al. Multicenter clinical trial of recombinant human insulin-like
growth factor I in patients with acute renal failure. Kidney Int 1999;55(6):2423–2432.
165. Wagner K, Albrecht S, Neumayer HH. Prevention of posttransplant acute tubular necrosis by the
calcium antagonist diltiazem: A prospective randomized study. Am J Nephrol 1987;7(4):287–291.
166. Young EW, Diab A, Kirsh MM. Intravenous diltiazem and acute renal failure after cardiac
operations. Ann Thorac Surg 1998;65(5):1316–1319.
167. Mahesh B, Yim B, Robson D, et al. Does furosemide prevent renal dysfunction in high-risk cardiac
surgical patients? Results of a double-blinded prospective randomised trial. Eur J Cardiothorac Surg
2008;33(3):370–376.
168. Bove T, Zangrillo A, Guarracino F, et al. Effect of fenoldopam on use of renal replacement therapy
among patients with acute kidney injury after cardiac surgery: a randomized clinical trial. JAMA
2014;312(21):2244–2253.
169. Krishnan M. Preoperative care of patients with kidney disease. Am Fam Physician 2002;66(8):1471–
1476, 1379.
170. Bagshaw SM, Chawla LS. Hydroxyethyl starch for fluid resuscitation in critically ill patients. Can J
Anaesth 2013;60(7):709–713.
171. Yunos NM, Bellomo R, Hegarty C, et al. Association between a chloride-liberal vs chloride-
restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA
2012;308(15):1566–1572.
172. Cheatham ML, Malbrain ML, Kirkpatrick A, et al. Results from the International Conference of
Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. II.
Recommendations. Intensive Care Med 2007;33(6):951–962.
173. Cai J, Xu R, Yu X, et al. Volatile anesthetics in preventing acute kidney injury after cardiac surgery:
a systematic review and meta-analysis. J Thorac Cardiovasc Surg 2014;148(6):3127–3136.
518
Chapter 16
Measuring the Quality of Surgical Care

Justin B. Dimick and John D. Birkmeyer
Key Points
1 Quality measures fall into three categories: structure, process, and outcomes. Healthcare structure
refers to fixed attributes of the system in which patients receive care. Process of care measures are
the clinical details of care provided to patients. Outcome measures reflect the end result of care,
from a clinical perspective or as judged by the patient.
2 Composite measures, created by combining multiple individual quality indicators, are becoming
increasingly used in the assessment of surgical quality. Most existing value-based purchasing
programs use composite measures of some type to assess the quality of care.
3 No quality measure is perfect. Clinical leaders, patient advocates, payers, and policy makers will
have to make decisions about when imperfect measures are good enough to act upon. A measure
should be implemented only with the expectation that acting on it will result in net improvement in
health quality.
4 It is important to ensure a good match between the performance measure and the primary goal of
measurement. The right measure depends on whether the underlying goal is (a) quality
improvement – raising the level of performance for all providers or (b) selective referral – directing
patients to higher-quality hospitals and/or providers.
5 For quality improvement purposes, a good performance measure must be actionable. Measurable
improvements in the given process should translate to clinically meaningful improvements in patient
outcomes.
6 With selective referral, a good measure will steer patients to better hospitals or physicians. As a
basic litmus test, a measure based on prior performance should reliably identify providers likely to
have superior performance now and in the future.
7 One of the biggest limitations of surgical quality measurement is the statistical “noise” from the
small sample sizes at most hospitals. This problem makes it difficult to isolate the quality signal from
the background statistical noise. An emerging technique, reliability adjustment, directly addresses
this problem. This technique, based on hierarchical modeling, quantifies and subtracts statistical
noise from the measurement process.
8 Another significant limitation of existing approaches to surgical quality assessment is a lack of good
measures of global quality. As payers and purchasers of health care move forward with value-based
purchasing, there is a growing need for better composite scores. In this chapter, we discuss an
emerging technique for creating empirically weighted composite measures of surgical performance.
9 An emerging technique for creating empirically weighted composite measures of surgical
performance is improving the quality and efficiency of surgical care. Quality measures are only
useful if they inform improvement efforts. Future refinements in measurement should therefore aim
to meet the diverse needs of the improvement efforts of patients, payers, and providers.
With growing recognition that the quality of surgical care varies widely, good measures of performance
are in high demand. Patients and their families need accurate information to help them choose the safest
hospitals for surgery.1 Employers and payers need reliable measures for their value-based purchasing
programs.2 Motivated in part by these external pressures, clinical leaders need better measures to guide
their quality improvement efforts.3
Despite a broadening array of measures, there remains considerable uncertainty about which
measures are most useful.4,5 Current measures are remarkably heterogeneous, encompassing different
elements of healthcare structure, process, and outcomes. With the proliferation of value-based
purchasing, which requires a global assessment of quality, there has been a rapid growth in the use of
519
booksmedicos.org
composite measures.6 Although each of these types of performance measures has strengths, each is also
associated with conceptual, methodological, and/or practical problems (Table 16-1).
This chapter provides an overview of existing quality indicators followed by a review of the main
strengths and limitations of each type of measure: structure, process, outcomes, and composites. The
chapter then closes with recommendations for selecting the right measure and a description of emerging
techniques that address some of the limitations of existing quality measures.
OVERVIEW OF CURRENT MEASURES

An ever-broadening array of performance measures has been developed for assessing surgical quality.
Over the past few years, the National Quality Forum (NQF) has emerged as the leading organization
endorsing quality measures. While the NQF is the central organization for evaluating candidate
measures, many other organizations continue to create their own quality indicators. For example, the
Center for Medicare and Medicaid Services (CMS) Surgical Care Improvement Program (SCIP), which
includes process measures related to prevention of surgical site infections, postoperative cardiac events,
venous thromboembolism, and respiratory complications, are routinely collected and publicly reported
on the Hospital Compare website for most US hospitals.
The Agency for Healthcare Research and Quality (AHRQ) has focused on quality measures that can be
used with administrative data. For example, the AHRQ maintains and distributes state and national
administrative data as part of their Healthcare Cost and Utilization Project (HCUP). Processes of care
are generally not available in these datasets, so the AHRQ measures focus mainly on structure (e.g.,
hospital volume) and outcomes (e.g., mortality rates).
Table 16-1 Examples, Strengths, and Limitations of Different Approaches to

Measuring Surgical Performance
The Leapfrog Group, a coalition of large employers and healthcare purchasers, has issued perhaps the
most visible set of surgical quality indicators for its value-based purchasing initiative. Although
originally focused exclusively on structural measures, including volume standards, their current
standards also include selected processes and risk-adjusted outcomes. More recently, the Leapfrog Group
began publicly reporting a composite measure of operative mortality and hospital volume as the
primary measure for their evidence-based hospital referral initiative on their website.7 We will discuss
composite measures in detail later in this chapter.
INDIVIDUAL QUALITY MEASURES

1 Quality measures fall into three categories: structure, process, and outcomes.
Structure
Healthcare structure refers to fixed attributes of the system in which patients receive care. Many
structural measures describe hospital-level attributes, such as the resources or staff coordination and
organization (e.g., nurse-to-patient ratios, hospital teaching status). Other structural measures reflect
520
booksmedicos.org
attributes of individual physicians (e.g., subspecialty board certification, procedure volume).
Strengths
Structural measures of quality have several attractive features. First, they are strongly related to patient
outcomes. For example, with esophagectomy and pancreatic resection, operative mortality rates at high-
volume hospitals are often 10% lower, in absolute terms, than low-volume centers.8,9 In some instances,
structural measures such as procedure volume are more predictive of subsequent hospital performance
than any known processes of care or even direct mortality measures (Fig. 16-1).
Perhaps the most important advantage of structural variables is the ease with which they can be
assessed. Many can be determined using readily available sources, such as administrative billing data.
Although some structural measures require surveying hospitals or providers, such data are much less
expensive to collect than measures requiring detailed patient-level information.
Figure 16-1. Ability of hospital rankings based on 2003–2004 mortality rates and hospital volume to predict risk-adjusted
mortality in 2005–2006. Data shown for abdominal aortic aneurysm repair (A) and pancreatic cancer resection (B). Source:
National Medicare data.
Limitations
Perhaps the greatest limitation of structural measures is that they are not readily actionable. For
example, a small hospital cannot readily make itself a high-volume center. Thus, while selected
structural measures may be useful for selective referral initiatives, they have limited value for quality
improvement purposes. Structural measures are also limited in their ability to discriminate the
performance of individual providers. For example, in aggregate, high-volume hospitals have much
lower mortality rates than lower-volume centers for pancreatic resection.8,9 However, some individual
high-volume hospitals may have high mortality rates, and some low-volume hospitals may have low
mortality rates.10 Although the true performance of individual hospitals is difficult to confirm
empirically (for sample size reasons), this lack of discrimination is one reason structural measures are
often viewed as “unfair” by many providers.
Process of Care
Process of care measures are the clinical details of care provided to patients. Although long the
predominant quality indicators for medical care, their popularity in surgery is growing rapidly. Perhaps
521
booksmedicos.org
the best example of the trend toward using process measures is the CMS’s SCIP. As previously
mentioned, this quality measurement initiative focuses exclusively on processes related to prevention of
surgical site infections, postoperative cardiac events, venous thromboembolism, and respiratory
complications.
Strengths
Since processes of care reflect the care actually delivered by physicians, they have face validity and
enjoy greater buy-in from providers. They are also directly actionable and provide good substrate for
quality improvement activities. Although risk adjustment may be important for outcomes, it is not
required for many process measures. For example, the appropriate prophylaxis against postoperative
venous thromboembolism is a widely used process measure. Since virtually all patients undergoing open
abdominal surgery should be offered some form of prophylaxis, there is little need to collect detailed
clinical data for risk adjustment.
Limitations
The biggest limitation of process measures is the lack of correlation between processes of care and
important outcomes.4 There is a growing body of empirical data showing very little correlation between
processes of care and important outcomes.11–13 Most data come from literature on medical diagnoses,
such as acute myocardial infarction. For example, the Joint Commission and CMS process measures for
acute myocardial infarction explained only 6% of the observed variation in risk-adjusted mortality for
acute myocardial infarction.12
Emerging evidence demonstrates a similar relationship for surgical process measures, especially for
SCIP measures, with no measurable relationship between these widely collected process measures and
important outcomes.13
There are several reasons why existing process measures explain very little of the variation in
important surgical outcomes. First, most process measures currently used in surgery relate to secondary
outcomes. While none would dismiss the value of prophylactic antibiotics in reducing risks of superficial
wound infection, this process is not related to the most important adverse events of major surgery,
including death.
Second, process measures in surgery often relate to complications that are very rare. For example,
there is consensus that venous thromboembolism prophylaxis is necessary and important. The SCIP
measures, endorsed by the NQF, include the use of appropriate venous thrombosis prophylaxis.
However, pulmonary embolism is very uncommon, and improving adherence to these processes will,
therefore, not avert many deaths. Until we understand which processes of care account for those
adverse events leading to death, process measures will have limited usefulness in surgical quality
measurement.4,11–14
Outcomes
Outcome measures reflect the end result of care, from a clinical perspective or as judged by the patient.
Although mortality is by far the most commonly used measure in surgery, other outcomes that could be
used as quality indicators include complications, hospital readmission, and a variety of patient-centered
measures of quality of life or satisfaction. The best example of this type of measurement is found in the
American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).15 The
ACS-NSQIP is a surgeon-led clinical registry for feeding back risk-adjusted morbidity and mortality rates
to participating hospitals. After its successful implementation in Veterans Affairs (VA) hospitals, it was
introduced into the private sector with good results.16 Under the guidance of the American College of
Surgeons, hospital participation in the NSQIP continues to grow, with more than 400 hospitals currently
participating. Several innovations to the ACS-NSQIP measurement platform in the past few years will no
doubt help make the program less expensive and more useful.3
Strengths
There are at least two key advantages of outcome measures. First, outcome measures have obvious face
validity, and thus are likely to get the greatest “buy-in” from hospitals and surgeons. Surgeon
enthusiasm for the ACS-NSQIP and the continued dissemination of the program clearly underline this
point. Second, the act of simply measuring outcomes may lead to better performance – the so-called
Hawthorne effect. For example, surgical morbidity and mortality rates in VA hospitals have fallen
dramatically since implementation of the NSQIP two decades ago.15 No doubt many surgical leaders at
522
booksmedicos.org
individual hospitals made specific organizational or process improvements after they began receiving
feedback on their hospitals’ performance. However, it is very unlikely that even a full inventory of
these specific changes would explain such broad-based and substantial improvements in morbidity and
mortality rates.
Limitations
Hospital- or surgeon-specific outcome measures are severely constrained by small sample sizes. For the
large majority of surgical procedures, very few hospitals (or surgeons) have sufficient adverse events
(numerators) and cases (denominators) for meaningful, procedure-specific measures of morbidity or
mortality. For example, Dimick et al.17 used data from the Nationwide Inpatient Sample to study seven
procedures for which mortality rates have been advocated as quality indicators by the AHRQ. For six of
the seven procedures, a very small proportion of US hospitals had adequate caseloads to rule out a
mortality rate twice the national average (Fig. 16-2). Although identifying poor-quality outliers is an
important function of outcome measurement, focusing on this goal alone significantly underestimates
problems with small sample sizes. Discriminating among individual hospitals with intermediate levels of
performance is even more difficult.
Another significant limitation of outcome assessment is the expense of data collection. Reporting
outcomes requires the costly collection of detailed clinical data for risk adjustment. For example, it costs
over $100,000 annually for a private sector hospital to participate in the ACS-NSQIP. Because of the
expense of data collection, the ACS-NSQIP currently collects data on only a sample of patients
undergoing surgery at each hospital. Although this sampling strategy decreases the cost of data
collection, it exacerbates the problem of small sample size with individual procedures.
COMPOSITE MEASURES
2 Composite measures, created by combining multiple individual quality indicators, are becoming
increasingly used in the assessment of surgical quality.6,7,18 Most existing pay-for-performance efforts,
including the CMS pilot, use composite measures to assess the quality of medical and surgical diagnoses.
The Society of Thoracic Surgeons (STS) Measurement Taskforce has created a new composite score that
combines elements of outcomes and processes of care into a single measure.18 With growing enthusiasm
for this approach, the AHRQ recently published a technical review of composite measures.19
Figure 16-2. Big problems with small samples: the proportion of hospitals in the United States with sufficient caseloads (sample
size) to reliably use mortality rates to measure quality.
Strengths
Composite measures have two main advantages over individual quality indicators. First, pooling
multiple measures overcomes the problem with small sample sizes described earlier. Second, this
approach deals with the problem of multiple conflicting measures, and simplifies quality measurement
by providing a single, summary measure of performance. For example, the STS measure for cardiac
surgery combines several measures of process and outcomes to create a single score with three
categories: one star, two stars, and three stars.18
Limitations
Composite measures have both technical and practical limitations. Perhaps the biggest technical
523
booksmedicos.org
challenge is weighting the input measures. Most existing composite measures are created using equal
weighting, expert opinion, or the “all or none” approach. For example, the STS cardiac surgery
composite score calculates a domain-specific score for morbidity, mortality, process of care, and
perioperative medications, and then places equal weight on each domain.18 Unfortunately, these
simplistic weighting schemes do not take into account the simple fact that some measures are more
important than others. Ideally, input measures would be weighted empirically, based on how strongly
they are related to important outcomes.19 An emerging technique for creating such empirically
weighted composite measures of surgical performance will be discussed at the end of the chapter.20,21
Composite measures also have a practical limitation. By design, composite measures reflect global
performance with a procedure or specialty. It is hard to know exactly where improvement is needed
with this global assessment. Thus, it is important to deconstruct the composite measures into the
individual process and outcome measures. Actionable targets for improvement (e.g., high complication
rates or failure to adhere to specific processes) can then be addressed.
CHOOSING THE RIGHT MEASURE

3 No quality measure is perfect. Clinical leaders, patient advocates, payers, and policy makers will have
to make decisions about when imperfect measures are good enough to act upon. A measure should be
implemented only with the expectation that acting on it will result in net improvement in health
quality. Thus, the direct benefits of implementing a particular measure cannot be outweighed by the
indirect harms. Unfortunately, these benefits and harms are often difficult to measure and heavily
influenced by the specific context and who – patients, payers, or providers – is doing the accounting.
For this reason, there is no simple answer for where to “set the bar.”
4 It is important to ensure a good match between the performance measure and the primary goal of
measurement. The right measure depends on whether the underlying goal is (a) quality improvement –
raising the performance of all providers or (b) selective referral – directing patients to higher-quality
hospitals and/or providers. Although many pay-for-performance initiatives have both goals, one often
predominates. For example, the ultimate objective of the CMS’s pay-for-performance initiative with
prophylactic antibiotics is improving quality at all hospitals (quality improvement). Conversely, the
Leapfrog Group’s efforts in surgery are primarily aimed at getting patients to hospitals likely to have
the best outcomes (selective referral).
5 For quality improvement purposes, a good performance measure must be actionable. Measurable
improvements in the given process should translate to clinically meaningful improvements in patient
outcomes. Although quality improvement activities are rarely “harmful,” their major downsides relate
to their opportunity cost. Initiatives hinged on bad measures divert resources (e.g., time and focus of
physicians and other staff) away from more productive activities.
6 With selective referral, a good measure will steer patients to better hospitals or physicians. As a
basic litmus test, a measure based on prior performance should reliably identify providers likely to have
superior performance now and in the future. At the same time, an ideal measure would not incentivize
perverse behaviors (e.g., surgeons doing unnecessary procedures to meet a specific volume standard) or
negatively affect other domains of quality (e.g., patient autonomy, access, and satisfaction).
Many believe that a good performance measure must discriminate performance at the individual
level. From the provider perspective in particular, a “fair” measure must reliably reflect the
performance of individual hospitals or physicians. Unfortunately, as described earlier, small caseloads
(and sometimes case mix variation) conspire against this objective for most procedures. Patients,
however, should value information that improves their odds of good outcomes on average. Many
measures meet this latter interest while failing on the former (e.g., hospital volume standards). There
may be no simple solution to resolving the basic tension implied by performance measures that are
unfair to providers yet informative for patients. However, it underscores the importance of being clear
about both the primary purpose (quality improvement or selective referral) and whose interests are
receiving top priority (provider or patient).
524
booksmedicos.org
Figure 16-3. Variation in hospital mortality rates before and after adjusting for reliability. Twenty randomly sampled hospitals are
shown. Source: National Medicare data, 2005–2006.
DEVELOPING BETTER MEASURES

7 Although great progress has been made, the science of quality measurement is in its infancy. In fact,
there are solutions on the horizon for many of the limitations discussed earlier. One of the biggest
limitations of surgical quality measurement is the statistical “noise” from the small sample sizes at most
hospitals. This problem makes it difficult to isolate the quality signal from the background statistical
noise. In other words, it is often hard to know whether hospitals or surgeons have poor performance
because they provide low-quality care or because they were unlucky. For obvious reasons, labeling
surgeons and hospitals correctly is extremely important.
An emerging technique, reliability adjustment, directly addresses the problem of statistical noise.22,23
This technique, based on hierarchical modeling, quantifies and subtracts statistical noise from the
measurement process. Essentially, it “shrinks” providers’ performance back toward average unless they
deviate to such an extreme that it is safe to assume they are truly different. In this way, it gives
providers the benefit of doubt. Figure 16-3 shows the risk-adjusted mortality rates for pancreatic
resection in Medicare patients before and after reliability adjustment. Prior to reliability adjustment, the
mortality rates varied from 0% to 100%. After reliability adjustment, the mortality rates only vary from
2% to 22%, yielding a range of performance that is clinically more realistic. Reliability adjustment is
gaining popularity outside surgery (e.g., ambulatory care) and is becoming widely recognized as a valid
tool for improving the accuracy of quality measurement.22,23
Despite wide use in other fields, reliability adjustment is only beginning to find application in
surgery. Perhaps the most prominent example is the Massachusetts state cardiac surgery report card,
which publishes “smoothed” mortality rates for each hospital.24 These are obtained with reliability
adjustment using hierarchical modeling techniques, as described earlier. This approach was also recently
applied to the morbidity and mortality rates in the ACS’s NSQIP, as described with other changes in a
recent “Blueprint” for a new ACS NSQIP.3 As the advantages of this technique become more widely
known, there is no doubt it will become the standard technique for reporting risk-adjusted outcomes.
8, 9 Another significant limitation of existing approaches to surgical quality assessment is a lack of
good measures of global quality. As payers and purchasers of health care move forward with value-
based purchasing, there is a growing need for better composite scores. Unfortunately, as discussed
earlier, most approaches are not thoughtful about how they weight input measures. However, there is
an emerging technique for creating empirically weighted composite measures of surgical
performance.20,21 To create these measures, a “gold standard” quality measure is first identified (e.g.,
risk-adjusted mortality). The relationships between all input measures and this “gold standard” measure
are then determined. A composite is then created that weights the input measures based on how reliable
they are (a measure of precision) and how closely they are related to the “gold standard” outcome.
Dimick et al.20,21 recently published the methods for creating these measures using a range of surgical
procedures. They found that a composite measure of risk-adjusted mortality and hospital volume,
combined with risk-adjusted mortality for other, related procedures explained a large proportion of
hospital-level variation in mortality and was better at predicting future performance than any individual
measure (Fig. 16-4).
Although both of these emerging techniques will enhance our ability to profile hospitals on technical
525
booksmedicos.org
quality, we also need to develop better measures of surgical decision making. Wide geographic
variations in the use of surgical procedures imply substantial underuse, misuse, and overuse. Escalating
healthcare costs are at least in part due to overuse and misuse of surgical interventions. Measures of
appropriateness or utilization will need to become part of our armamentarium if meaningful attempts at
reducing these variations are to be made. Although appropriateness criteria have been extensively
studied, there is growing consensus that they are impractical on a large scale.25 The task of tabulating
all of the potential scenarios in which a procedure is “appropriate” or “inappropriate” is daunting. Even
when these exhaustive lists are created, reasonable clinicians may still disagree in a large proportion of
cases.25 Appropriateness criteria should be limited to “low-hanging fruit,” those procedures with a few,
well-agreed-upon indications for operation.
Figure 16-4. Ability of various historical (2000–2001) quality indicators to forecast subsequent (2002–2003) risk-adjusted
mortality with aortic valve replacement (AVR). Hospitals sorted into quintiles according to hospital volume alone, risk-adjusted
mortality alone, and composite measure based on AVR mortality, AVR hospital volume, and mortality and volume with other
cardiac procedures.
For the majority of procedures, however, another approach is needed. One potential approach is the
measurement of utilization at the level of the Accountable Care Organization (ACO). ACOs are
organization of physicians and/or hospitals that assume care for a group of patients. ACOs are felt by
some health policy experts to be the right level of accountability for measuring the quality of the
extended healthcare system.26,27 Most current ACO models fall far short of full capitation, which would
undoubtedly lower rates of discretionary procedures, but there are many other ways these organizations
could approach overutilization. For example, rates of surgery for each ACO could be used for public
reporting, value-based purchasing, or tiered health plans. This approach would allow patients to choose
hospitals based on how “aggressive” they are. Public disclosure of surgery rates would also put
downward pressure on hospitals with high rates of surgery, potentially discouraging expanding capacity
when it may not be necessary.
The near future will no doubt bring other major advances in the science of quality measurement. The
accelerating pace of technology will surely play a role. As electronic medical records become more
widely adopted, clinical data will be more easily abstracted from the patient record. Such improvements
in technology will provide cost-efficient risk adjustment and more practicable approaches for assessing
the adherence to important processes of care. While improvements in technology and infrastructure are
of great benefit, involvement of surgeons in health services research will also be important. Studies
using tools of clinical epidemiology are needed to generate evidence linking high-leverage processes of
care to important outcomes. These processes of care could then be applied to existing quality
measurement platforms. Surgeon-scientists with scholarship in quality improvement will be
instrumental in providing these insights and leading this high-impact academic field forward.
When measuring quality, it is important to keep in mind the ultimate goal: improving the quality and
efficiency of surgical care. Quality measures are only useful if they inform improvement efforts. Future
refinements in measurement should therefore aim to meet the diverse needs of the improvement efforts
of patients, payers, and providers. In the previous chapter, the three dominant approaches for
improving surgical quality were discussed: selective referral, process compliance, and outcome
measurement. These three policy approaches roughly mirror the three types of quality measures
(structure, process, and outcomes), providing real-world examples of how various stakeholders weigh
the pros and cons of quality indicators, and ultimately choose an assessment approach by matching the
measure to the purpose.
526
booksmedicos.org
References
1. Lee TH, Meyer GS, Brennan TA. A middle ground on public accountability. N Engl J Med
2004;350:2409–2412.
2. Galvin R, Milstein A. Large employers’ new strategies in health care. N Engl J Med 2002;347:939–
942.
3. Birkmeyer JD, Shahian DM, Dimick JB, et al. Blueprint for a new American College of Surgeons:
National Surgical Quality Improvement Program. J Am Coll Surg 2008;207:777–782.
4. Birkmeyer JD, Dimick JB, Birkmeyer NJ. Measuring the quality of surgical care: structure, process,
or outcomes? J Am Coll Surg 2004;198: 626–632.
5. Landon BE, Normand SL, Blumenthal D, et al. Physician clinical performance assessment: prospects
and barriers. JAMA 2003;290(9):1183–1189.
6. O’Brien SM, DeLong ER, Dokholyan RS, et al. Exploring the behavior of hospital composite
performance measures: an example from coronary artery bypass surgery. Circulation
2007;116:2969–2975.
7. Dimick JB, Staiger DO, Baser O, et al. Composite measures for predicting surgical mortality in the
hospital. Health Aff 2009;28:1189–1198.
8. Halm EA, Lee C, Chassin MR. Is volume related to outcome in health care? A systematic review and
methodologic critique of the literature. Ann Intern Med 2002;137:511–520.
9. Dudley RA, Johansen KL, Brand R, et al. Selective referral to high volume hospitals: estimating
potentially avoidable deaths. JAMA 2000;283:1159–1166.
10. Rathore SS, Epstein AJ, Volpp KG, et al. Hospital coronary artery bypass graft surgery volume and
patient mortality, 1998–2000. Ann Surg 2004;239:110–117.
11. Fonarow GC, Abraham WT, Albert NM, et al. Association between performance measures and
clinical outcomes for patients hospitalized with heart failure. JAMA 2007;297:61–70.
12. Bradley EH, Herrin J, Elbel B, et al. Hospital quality for acute myocardial infarction: correlation
among process measures and relationship with short-term mortality. JAMA2006;296:72–78.
13. Stulberg JJ, Delaney CP, Neuhauser DV, et al. Adherence to surgical care improvement project
measures and the association with postoperative infections. JAMA 2010;303:2479–2485.
14. Hawn MT, Itani KM, Gray SH, et al. Association of timely administration of prophylactic antibiotics
for major surgical procedures and surgical site infection. J Am Coll Surg 2008;206:814–819.
15. Khuri SF, Daley J, Henderson W, et al. The Department of Veterans Affairs’ NSQIP: the first
national, validated, outcome-based, risk-adjusted, and peer-controlled program for the
measurement and enhancement of the quality of surgical care. National VA Surgical Quality
Improvement Program. Ann Surg 1998;228:491–507.
16. Fink AS, Campbell DA Jr, Mentzer RM Jr, et al. The National Surgical Quality Improvement
Program in non-Veterans Administration hospitals: initial demonstration of feasibility. Ann Surg
2002;236:344–353.
17. Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of hospital quality: the
problem with small sample size. JAMA 2004;292:847–851.
18. O’Brien SM, Shahian DM, DeLong ER, et al. Quality measurement in adult cardiac surgery: part 2 –
statistical considerations in composite measure scoring and provider rating. Ann Thorac Surg
2007;83(suppl 4):S13–S26.
19. AHRQ Inpatient Quality Indicators Composite Measure. Draft technical report. Available at:
http://qualityindicators.ahrq.gov/news/AHRQ_IQI_Composite_Draft.pdf. Accessed June 27, 2007.
20. Dimick JB, Staiger DO, Osborne NH, et al. Composite measures for rating hospital quality with
major surgery. Health Serv Res 2012;47:1861–1679.
21. Dimick JB, Staiger DO, Hall BL, et al. Composite measures for profiling hospitals on surgical
morbidity. Ann Surg 2013;257:67–72.
22. Dimick JB, Staiger DO, Birkmeyer JD. Ranking hospitals on surgical mortality: the importance of
reliability adjustment. Health Serv Res 2010;45:1614–1629.
23. Dimick JB, Ghaferi AA, Osborne NH, et al. Reliability adjustment for reporting hospital outcomes
with surgery. Ann Surg 2012;255:703–707.
24. Adult Coronary Artery Bypass Graft Surgery in the Commonwealth of Massachusetts. Fiscal Year
527
booksmedicos.org
2006 Report, October 1, 2005–September 30, 2006. Available at:
http://www.massdac.org/reports/CS%20FY2006.pdf. Accessed June 17, 2010.
25. Casparie AF. The ambiguous relationship between practice variation and appropriateness of care: an
agenda for further research. Health Policy 1996; 35:247–265.
26. Bynum JP, Bernal-Delgado E, Gottlieb D, et al. Assigning ambulatory patients and their physicians
to hospitals: a method for obtaining population-based provider performance measurements. Health
Serv Res 2007;42:45–62.
27. Fisher ES, Staiger DO, Bynum JP, et al. Creating accountable care organizations: the extended
hospital medical staff. Health Aff (Millwood) 2007; 26:w44–w57.
528
booksmedicos.org
Chapter 17
Policy Approaches to Improving Surgical Quality

John D. Birkmeyer and Justin B. Dimick
Key Points
1 Center of excellence programs implemented by private payers and CMS have failed to identify
hospitals with superior outcomes because they rely on weak process of care measures or inaccurate,
self-reported data.
2 Pay-for-performance programs in surgery have been successful in increasing hospital compliance
with evidence-based practice in perioperative care. It is not clear that they have improved patient
outcomes, however.
3 Focusing on a few discrete steps in the care of surgical patients underestimates the complexity of
surgical care. Higher leverage measures, including those that reflect important aspects of surgical
decision making or technical skill, are needed.
4 Outcome measurement and feedback may provide early benefits by capitalizing on the surgical
“Hawthorne effect,” but their impact may be limited if they are tied to coordinated efforts aimed at
changing practice.
5 With Qualified Clinical Data Registries, surgeons may be eligible for CMS pay-for-performance
incentive payments by participating in ACS-NSQIP and other society-led registries.
6 Although prophylactic strategies aimed at avoiding complications in the first place are obviously
important, “rescuing” patients once a complication has occurred may be even more critical in
reducing current variations in hospital mortality rates.
INTRODUCTION
Improving the quality of surgical care is a public health imperative. As many as 100,000 patients die
every year undergoing surgery in the United States; an order of magnitude more experience serious
complications.1 Despite recent studies suggesting that surgery is becoming safer over time,2 a large
body of literature suggests that a large proportion of surgical morbidity and mortality may be
avoidable. In its seminal 1999 report To Err is Human, the Institute of Medicine estimated that between
44,000 and 98,000 Americans die every year as a result of medical errors, at least half of whom are
surgical patients.3,4 Evidence that morbidity and mortality vary widely across hospitals and surgeons
further implies opportunities for improvement. In addition to variation among individual providers, 5–7
surgical outcomes differ according to a number of provider attributes, including procedure volume,
surgeon subspecialty training, and other factors.8–10
In response, payers, policy makers, and professional organizations have launched a broad array of
strategies aimed at improving surgical quality.11 Some of these efforts, including the so-called Centers
of Excellence (COE) programs, aim to direct surgical patients to hospitals or surgeons with the best
results.12 With pay-for-performance programs, payers are instead aiming to incentivize improvements at
all hospitals, providing financial rewards (and penalties) to hospitals and/or surgeons meeting
performance targets on both outcomes and process of care measures.13 And finally, surgical professional
societies and state organizations are hoping to improve surgical quality through clinical outcome
registries, performance feedback, and collaborative quality improvement activities.14–16
Although hospitals and surgeons also engage in improvement activities at the local level, these three
strategies – COE programs, pay for performance, and outcome feedback – represent the major, policy-
level approaches to improving surgical quality at the present time. In this chapter, we review the
relative strengths and weaknesses of each approach (Table 17-1). We close by reviewing new research
on mechanisms underlying variation in surgical outcomes across hospitals and surgeons, and its
implications for quality improvement in the future.
529
booksmedicos.org
CENTERS OF EXCELLENCE
COE programs hope to identify hospitals and/or surgeons with the best results with selected procedures
and direct as many patients as possible to these settings. In some instances, payers restrict insurance
approval to narrow networks of approved providers. In others, they implement tiered health plans and
benefits packages that give patients financial incentives (e.g., lower copays) to select higher-quality
providers. Such programs generally make public comparative information about hospital and surgeon
performance, hoping to further motivate patients to “shop for quality.”
Among the most prominent examples of active COE programs, Blue Cross Blue Shield Association
identifies the so-called “Blue Distinction” centers for cancer care, cardiovascular surgery, organ
transplantation, and bariatric surgery, based on periodic surveys of hospital performance on multiple
different measures with each specialty area. The CMS until recently restricted bariatric surgery to
hospitals designated as COE by either the American College of Surgeons (ACS) or the American Society
of Metabolic and Bariatric Surgeons. Although led by employers and purchasers rather than payers, the
Leapfrog Group is promoting “evidence-based hospital referral” for aortic valve replacement and
complex cancer surgery, based on both procedure volume criteria and hospital mortality rates.17
Such strategies reflect the natural response of payers (and many patients) to data indicating variation
in provider performance with surgery. Among other advantages, selective referral can often be
implemented expediently and inexpensively, particularly when based on simple structural measures of
quality (e.g., procedure volume). For many procedures, commonly used quality indicators can reliably
identify groups of hospitals and surgeons with superior outcomes. For example, data readily obtained
from administrative sources, including procedure volume and hospital mortality, not only describe past
performance, but also forecast future performance with many procedures.18 A recent national study
suggests the potential benefits of concentrating complex procedures in COEs. Based on national
Medicare data, mortality with high-risk cancer surgery fell almost 20% between 1999 and 2008.2
Approximately half of that mortality decline could be attributed to market concentration – more
procedures being done in high-volume hospitals.
Table 17-1 Characteristics of Three Different Models for Reducing Variation and
Improving Surgical Quality
1 Despite their conceptual appeal and potential benefits, the results of many COE initiatives have
been largely disappointing. For example, analyses by Mehrotra et al.19 found no evidence that the Blue
Distinction Centers had better outcomes than nondesignated hospitals with spine surgery and total joint
replacement. In another study examining the effects of CMS’ 2006 policy restricting bariatric surgery to
COEs, Dimick et al.20 found no evidence that COEs had better performance than non-COEs, or that the
CMS policy had improved outcomes overall. As a result of that study and others reaching similar
conclusions,12,21 CMS decided to rescind its policy restricting bariatric surgery to COEs in 2013. These
examples highlight problems with current approaches to assessing the comparative quality of hospitals
and surgeons for COE purposes. These challenges include using administrative data to assess outcomes
other than mortality, putting too much weight on hospital attributes and processes of care not tightly
530
booksmedicos.org
linked to outcomes, and relying on self-reported data.22
Measurement challenges aside, COE programs have other downsides. Strategies that displace patients
from their usual site of care and regular physicians may interfere with coordination of care. They tend
to be highly polarizing, dividing hospitals and surgeons into winners and losers. In alienating the latter,
a price of COE programs may be lost opportunities for engaging physicians in other types of quality
improvement efforts. And finally, such programs improve outcomes exclusively to the extent that they
steer care away from poor performers. It provides no mechanism for helping non-COE hospitals and
surgeons improve their outcomes.
PAY FOR PERFORMANCE

Another approach to improving surgical outcomes is to encourage hospitals and surgeons to provide
higher-quality care with financial incentives. Both public and private payers have active pay-for-
performance programs involving surgery. CMS has both a Value-Based Purchasing program aimed at
hospitals and a more recent effort targeting physicians – the so-called Physician Value-Based Payment
Modifier program.23 Although such programs are moving toward specialty-specific outcome-based
measures (as described later), pay-for-performance programs have until now focused on adherence to
evidence-based practices related to perioperative care. For example, many private payers link hospital
reimbursement to process measures established by the Surgical Care Improvement Project (SCIP),24
including practices aimed at reducing rates of surgical site infection, postoperative cardiac events,
venous thromboembolism, and ventilator-associated pneumonia.
Among their strengths, pay-for-performance initiatives aimed at improving compliance with specific
processes of care are considerably less polarizing than selective referral. In theory, anyone can “win.”
To the extent that surgeons can “play to the quiz,” process-based pay-for-performance programs have
the potential to achieve rapid and significant improvements in many aspects in perioperative care.
Studies in primary care suggest that pay-for-performance programs may be particularly effective in
improving process compliance among poor performers and thus reducing overall variation.13,25 In
surgery, evidence to date suggests similar improvements in compliance with SCIP measures.26
2 Nonetheless, the extent to which improvements in evidence-based practice compliance translate to
improvements in surgical outcomes remains uncertain. Studies to date have generally failed to
demonstrate a strong correlation between provider performance with specific process measures and
patient outcomes. For example, hospitals successful in examining at least 12 lymph nodes from the
surgical specimens of patients undergoing colectomy for colon cancer, one popular measure, did not
have better 5-year survival rates than those scoring worse on this quality indicator.27 Even when
hospital performance is measured across multiple, evidence-based practices related to a specific
postoperative complication, process compliance is not well correlated with patient outcomes. In
examining national data compiled by CMS’ Hospital Compare program, for example, Nicholas et al.28
found that hospital compliance with the “bundles” of SCIP process measures related to surgical site
infection and venous thromboembolism varied widely. Moreover, hospital compliance rates were not
related to the incidence of those two postoperative complications.
A more recent study by Shih et al.29 provides the most direct evaluation of the overall effects of
surgical pay-for-performance programs. Focusing on coronary bypass surgery and total joint
replacement, Medicare’s Premier Hospital Quality Incentive Demonstration (HQID) was intended to
incentivize quality and quality improvement by increasing reimbursements to both top performing
hospitals and those demonstrating the greatest degree of improvement over time.30 While mortality and
complication rates for cardiac and orthopedic patients decreased significantly over time in premier
hospitals, improvements of similar magnitude were observed in nonparticipating hospitals.29
3 Together, these studies do not invalidate the importance of timely antibiotics and other well-tested
prophylactic measures against surgical complications. Rather, they underscore the complexity of
surgical care and the limitations of focusing exclusively on a small number of discrete steps in managing
a surgical patient. As we describe later, these studies also highlight that surgical outcomes also depend
on aspects of care not traditionally addressed in pay-for-performance programs, like surgeons’ technical
skill and their proficiency in managing complications after they have occurred.
OUTCOME FEEDBACK
531
booksmedicos.org
In contrast to strategies led by payers and policy makers, surgeons and their professional organizations
are focusing primarily on registry-based quality improvement programs.14,15,31 Their goal is to provide
hospitals and surgeons with rigorous feedback about their outcomes relative to those of their peers.
Some of these programs have centralized approaches to coordinating quality improvement activities,
while others focus primarily on performance feedback, leaving improvement work at the local level.
The Scientific Registry of Transplant Recipients and the Adult Cardiac Surgery Database of the Society
of Thoracic Surgeons were among the earliest and most recognized surgical outcome registries. The
large majority of US hospitals involved in those two specialties now contribute to those databases.32,33
Originally developed by the Department of Veterans Affairs, the American College of Surgeons-National
Surgical Quality Improvement Program (ACS-NSQIP) has become the largest outcome measurement
platform for noncardiac surgery.14,34 Often supported by payers, state and regional collaborative
improvement programs – based on either society-developed or “home-grown” outcome registries – have
become increasingly popular.
This model of performance feedback and data-driven quality improvement has particular appeal
among surgeons. As they represent the “bottom line” of success, outcome measures tend to be more
meaningful to surgeons than process measures. When coupled with coordinated programs aimed at
effecting practice change, registry-based improvement programs in surgery can be highly effective. In
Michigan, for example, Blue Cross Blue Shield of Michigan has supported collaborative improvement
programs across numerous surgical specialties.35 Though not every initiative supported by the Michigan
collaborative has been well studied, Michigan hospitals have substantially outperformed national
benchmarks in cardiac, general, and bariatric surgery.16
4 Whether performance feedback alone improves outcomes remains less clear, however. Early studies
support the existence of a surgical “Hawthorne effect” – that the process of measurement spurs
improvement. For example, surgical morbidity rates at VA hospitals fell over 40% almost immediately
after implementation of NSQIP in the early 1990s,6 before any systematic attempt to change practice
across that system. Mortality rates with cardiac surgery have fallen dramatically over the past 20 years,
coincident with national dissemination of the STS registry.36 The extent to which secular trends toward
declining surgical mortality can be attributed to society-led registries and reporting systems is
uncertain, however. Using national Medicare data, we compared hospitals participating in ACS-NSQIP to
a matched group of nonparticipating hospitals. Though hospitals in the former group had lower
mortality rates at the time they enrolled in ACS-NSQIP, both groups improved at the same rate between
2006 and 2012.
Surgeon-led outcome registries and improvement programs have other limitations. Though this issue
may fade in the future as electronic medical record data become more accessible, current programs rely
on extensive and expensive manual data collection, which has limited their dissemination in most
specialties. Outcome measures, particularly when assessed at the level of specific procedures, are often
hindered by small sample sizes and can be too “noisy” to inform hospitals and surgeons of their true
performance.37 And finally, as currently implemented, most registry-based improvement programs have
several important “blind spots,” such as addressing the appropriateness of surgical procedures, variation
in surgeon technical skill, and management of patients with postoperative complications.
SUMMARY
5 Although this chapter has laid out some of the distinct features, advantages and disadvantages with
each strategy, the field is fast evolving and the lines between COE programs, pay for performance, and
outcome feedback are blurring over time. Connecting the first and third strategy, for example, the STS
recently decided to allow hospitals participating in its registry program to publicly report their
outcomes for COE programs and other purposes. In another example, CMS is expanding measurement
options for physicians participating in its physician-based P4P program, allowing them to submit
specialty-specific outcome data through the so-called Qualified Clinical Data Registries, including those
administered by surgical societies.
Each of the three strategies would benefit from advances in quality measurement and improvement.
COE programs in particular would benefit from measures that more reliably discriminate performance
among individual hospitals and surgeons. As described elsewhere, individual measures of structure
(including procedure volume), process of care, and outcomes have major limitations in reflecting
provider-specific quality.38 Composite quality measures, which empirically combine information from
532
booksmedicos.org
several quality domains, appear very promising.39,40 As described by Dimick et al.41 such measures far
surpass existing quality indicators in capturing true variation in provider performance. More
importantly, empirically derived composite measures perform extremely well in forecasting a hospital’s
future outcomes, a key litmus test given the underlying goals of COE programs.
6 Although better statistical methods for assessing postoperative morbidity and mortality will help, it
may be even more important that future initiatives target a broader range of performance domains.
First, given that the use of surgical procedures varies as much as outcomes, practical measures of
appropriateness – and the quality of surgeons’ decisions to operate in the first place – are essential.
Second, rather than focusing exclusively on aspects of perioperative care, quality measurement and
improvement initiatives should target surgeons’ operative proficiency. Recent research suggests that, at
least for some procedures, the technical skill of the operating surgeon varies widely and may be the
single most important predictor of patient outcomes after surgery.42 And finally, improving surgical
quality will require reducing rates of the so-called “failure to rescue.” A growing body of research
suggests that hospital mortality rates are explained less by their complication rates than by their case-
fatality rates among patients with serious complications.43,44 Thus, ensuring timely recognition and
effective management of complications once they have occurred may be even more important to the
success of strategies aimed at reducing surgical mortality.
References
1. Goodney PP, Siewers AE, Stukel TA, et al. Is surgery getting safer? National trends in operative
mortality. J Am Coll Surg 2002;195:219–227.
2. Finks JF, Osborne MH, Birkmeyer JD. Trends in hospital volume and operative mortality for high-
risk surgery. N Engl J Med 2011;364:2128–2137.
3. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System.
Washington, DC: National Academy Press; 1999.
4. Gawande AA, Thomas EJ, Zinner MJ, et al. The incidence and nature of surgical adverse events in
Colorado and Utah in 1992. Surgery 1999;126(1):66–75.
5. Hannan EL, Kilburn H Jr, O’Donnell JF, et al. Adult open heart surgery in New York State. An
analysis of risk factors and hospital mortality rates. JAMA 1990;264(21):2768–2774.
6. Khuri SF, Daley J, Henderson WG. The comparative assessment and improvement of quality of
surgical care in the Department of Veterans Affairs. Arch Surg 2002;137(1):20–27.
7. O’Connor GT, Plume SK, Olmstead EM, et al. A regional prospective study of in-hospital mortality
associated with coronary artery bypass grafting. JAMA 1991;266:803–809.
8. Dudley RA, Johansen KL, Brand R, et al. Selective referral to high volume hospitals: estimating
potentially avoidable deaths. JAMA 2000;283:1159–1166.
9. Halm EA, Lee C, Chassin MR. Is volume related to outcome in health care? A systematic review and
methodologic critique of the literature. Ann Int Med 2002;137:511–520.
10. Houghton A. Variation in outcome of surgical procedures. Br J Surg 1994; 81:653–660.
11. Birkmeyer NJ, Birkmeyer JD. Strategies for improving surgical quality–should payers reward
excellence or effort? N Engl J Med 2006;354(8):864–870.
12. Livingston EH. Bariatric surgery outcomes at designated centers of excellence vs nondesignated
programs. Arch Surg 2009;144(4):319–325; discussion 325.
13. Rosenthal MB, Frank RG, Li Z, et al. Early experience with pay-for-performance: from concept to
practice. JAMA 2005;294(14):1788–1793.
14. Fink A, Campbell DJ, Mentzer RJ, et al. The National Surgical Quality Improvement Program in
non-veterans administration hospitals: initial demonstration of feasibility. Ann Surg 2002;236:344–
353.
15. Rowell KS, Turrentine FE, Hutter MM, et al. Use of national surgical quality improvement program
data as a catalyst for quality improvement. J Am Coll Surg 2007;204:1293–1300.
16. Share DA, Campbell DA, Birkmeyer NJ, et al. How a regional collaborative of hospitals and
physicians in Michigan cut costs and improved the quality of care. Health Aff 2011;30(4):636–645.
17. http://www.leapfroggroup.org/about_us/leapfrog-factsheet. Last accessed September 1, 2014.
18. Birkmeyer JD, Dimick JB, Staiger DO. Operative mortality and procedure volume as predictors of
533
booksmedicos.org
future hospital performance. Ann Surg 2006;243:411–417.
19. Mehrotra A, Sloss, EM, Hussey PS, et al. Evaluation of centers of excellence programs for knee and
hip replacement. Med Care 2013;51(1):28–36.
20. Dimick JB, Nicholas LH, Ryan AM, et al. Bariatric surgery complications before vs after
implementation of a national policy restricting coverage to centers of excellence. JAMA
2013;309(8):792–799.
21. Birkmeyer NJ, Dimick JB, Share D, et al. Hospital complication rates with bariatric surgery in
Michigan. JAMA 2010;304(4):435–442.
22. Dimick JB, Birkmeyer NJ. Rethinking eligibility criteria for bariatric surgery. JAMA
2014;312(9):953–954.
23. Chien AT, Rosenthal MB. Medicare’s physician value-based payment modifier – will the tectonic
shift create waves. N Engl J Med 2013;369:2076–2078.
24. Gold JA, Gold JA. The surgical care improvement project. WMJ 2005; 104(1):73–74.
25. Rosenthal MB, Dudley RA. Pay-for-performance: will the latest payment trend improve care? JAMA
2007;297(7):740–744.
26. Ingraham AM, Cohen ME, Bilimoria KY, et al. Association of surgical care improvement project
infection-related process measure compliance with risk-adjusted outcomes: implications for quality
measurement. J Am Coll Surg 2010;211(6):705–714.
27. Wong SL, Ji H, Hollenbeck BK, et al. Hospital lymph node examination rates and survival after
resection for colon cancer. JAMA 2007;298(18):2149–2154.
28. Nicholas LH, Osborne NH, Birkmeyer JD, et al. Hospital process compliance and surgical outcomes
in medicare beneficiaries. Arch Surg 2010; 145(10):999–1004.
29. Shih T. Nicholas LH, Thumma JR, et al. Does pay-for-performance improve surgical outcomes? Ann
Surg 2014;259(4):677–681.
30. Centers for Medicare & Medicaid Services. Premier Hospital Quality Incentive Demonstration
Rewarding Superior Quality Care Fact Sheet December 2011. Available at
http://www.cms.gov/Medicare/Quality-Initiatives-Patient-Assessment-
Instruments/HospitalQualityInits/Downloads/HospitalPremierPressRelease-FactSheet.pdf. Accessed
September 1, 2014.
31. Birkmeyer JD, Shahian DM, Dimick JB, et al. Blueprint for a new American College of Surgeons:
National Surgical Quality Improvement Program. J Am Coll Surg 2008;207:777–782.
32. Massie AB, Kuricka LM, Segev DL. Big data in organ transplantation: registries and administrative
claims. Am J Transplant 2014;14(8):1723–1730
33. Shahian DM, Edwards FH, Ferraris VA, et al. Quality measurement in adult cardiac surgery: part 1–
Conceptual framework and measure selection. Ann Thorac Surg 2007;83(4 Suppl):S3–S12.
34. Khuri SF, Daley J, Henderson W, et al. Risk adjustment of the postoperative mortality rate for the
Surgical Risk Study. J Am Coll Surg 1997;185:315–327.
35. Birkmeyer NJ, Share D, Campbell DA Jr, et al. Partnering with payers to improve surgical quality:
the Michigan plan. Surgery 2005;138(5):815–820
36. O’Connor GT, Plume SK, Morton JR, et al. Results of a regional prospective study to improve the
in-hospital mortality associated with coronary artery bypass grafting. JAMA 1996;275:841–846.
37. Dimick JB, Welch HG, Birkmeyer JD. Surgical mortality as an indicator of hospital quality: the
problem with small sample size. JAMA 2004;292(7):847–851.
38. Birkmeyer JD, Birkmeyer NJ, Dimick JB. Measuring the quality of surgical care: structure, process,
or outcomes? J Am Coll Surg 2004;198:626–632.
39. O’Brien SM, Shahian DM, DeLong ER, et al. Quality measurement in adult cardiac surgery: part 2–
Statistical considerations in composite measure scoring and provider rating. Ann Thorac Surg
2007;83:S13–S26.
40. Staiger DO, Dimick JB, Baser O, et al. Empirically derived composite measures of surgical
performance. Med Care 2009;47(2):226–233.
41. Dimick JB, Staiger DO, Osborne NH, et al. Composite measures for rating hospital quality with
major surgery. Health Serv Res 2012;47(5):1861–1879.
534
booksmedicos.org
42. Birkmeyer JD, Finks JF, O’Reilly A, et al. Surgical skill and complication rates after bariatric
surgery. N Engl J Med 2013;369:1434–1442.
43. Ghaferi AA, Birkmeyer JD, Dimick JB. Variation in hospital mortality associated with inpatient
surgery. N Engl J Med 2009;361:1368–1375.
44. Ghaferi AA, Birkmeyer JD, Dimick JB. Complications, failure to rescue, and mortality with major
inpatient surgery in medicare patients. Ann Surg 2009;250(6):1029–1034.
535
booksmedicos.org
Chapter 18
Patient Safety
Darrell A. Campbell, Jr.
Key Points
1 Safety means “freedom from harm”; in the context of patient care, safety means freedom from harm
associated with any medical action or treatment.
2 Even though the system should be constructed to back up human fallibilities, it is instructive to
recognize these fallibilities. This subject is hard to quantify, but a good list, developed in a family
practice environment, reads as follows: hurry, distraction, lack of knowledge, premature closure of
the diagnostic process, and inadequate aggressiveness in patient management.
3 In the acute hospital setting, as opposed to the outpatient environment in family practice, safety
problems typically involve poor handoffs, failures of teamwork, excess workload, and fatigue.
4 Another approach to the implementation of safe practices is to educate and train physicians and
nurses within the context of a team.
5 The future of the patient safety movement depends on the development of an effective safety
reporting mechanism.
IMPORTANT DEFINITIONS: SAFETY VERSUS QUALITY

1 The terms quality and safety have important bearings on any discussion of patient care. These are
related subjects but have different meanings, and these differences should be underscored before any
dialog about patient safety begins. Safety means “freedom from harm”; in the context of patient care,
safety means freedom from harm associated with any medical action or treatment. Quality is a more
global term referring to a “degree of excellence.” It is theoretically possible for a hospital to be safe, but
for quality to be average or poor. It is not possible for a hospital to be of high quality and unsafe. In
this chapter, we focus primarily on the subject of patient safety, but admit that some aspects of the
subject drift into the area of quality as well.
THE PROBLEM
By now, all are familiar with the report issued by the Institute of Medicine (IOM) in 2000 entitled To
Err Is Human.1 The report was an exhaustive review of the status of safety in our nation’s hospitals. The
bottom line – which served as a “burning platform” for the patient safety movement – was the
astonishing calculation that between 44,000 and 98,000 Americans died annually in hospitals as the
result of preventable medical error. The report produced a flurry of outrage from consumer groups and
denials and refutations from medical groups, but when the dust settled, what was left was the
recognition, by all groups, that something was seriously wrong in our medical care delivery system.
Comparisons are often made between the safety of airline travel and medical care. One airline
disaster every 2 or 3 years produces calls for new regulation, better airports, more frequent mechanical
checks, and earlier retirement for pilots. But consider medical care. If even the lower number of
preventable deaths extrapolated by the IOM report (44,000 annually) were seen as accurate, and one
accepted that an average of 350 passengers were on board every major commercial aircraft flight,
deaths from medical error would be equivalent to 63 separate midair collisions per year in the airline
industry, or 5 per month. Imagine the public outcry this would produce, the laws that would be quickly
passed, and the boon to train travel that would result. With these staggering numbers as a backdrop, the
IOM asserted that “it would be irresponsible to expect anything less than a 50% reduction in errors over
5 years.” Sadly, 15 years later, only a modest improvement has been seen, and this is evident only in
the most recent 3 years.2 Why the tepid response? It is safe to say that the government and the medical
536
booksmedicos.org
community have been slow to acknowledge, and even slower to respond to the safety imperative.
CULTURE
Fundamental improvements in patient safety rest on establishing a robust safety culture, in which
caregivers view the safety of patients as their most important mission. Culture is defined as “how we do
things around here.” That is, there is a certain level of acceptance, or complacency, for what goes on in
a given hospital. Complacency is the result of two assumptions, which in the past have not been
challenged. One assumption is that medical errors exist because “humans will always make mistakes.”
While superficially true, this statement fails to acknowledge that modern human factors engineering
strategies can militate against commonly encountered errors. A concrete example of how human factors
engineering can be brought into play involves something as simple as a connector for medical tubing. If
the connector is designed such that it is not physically possible to connect an O2 line to a CO2 valve, a
potentially catastrophic mistake becomes impossible. More globally, work hour restrictions for medical
trainees, which reduce fatigue, could be expected to result in fewer errors by exhausted and stressed
doctors. To date, human factors engineering has not been brought into the delivery of medical care
effectively. While humans will always be capable of making mistakes, the number of mistakes will be
reduced if design is targeted to what we know about human fallibilities.
The second assumption accounting for complacency is the notion that a medical error is the result of
poor individual performance rather than an imperfect system of care. If an individual made the error, in
isolation, the only thing to do about it would be to fire the hapless caregiver, or immerse him or her in
intensive remedial education. The problem with this approach is that it does not apply to the next
hapless caregiver faced with the same situation. And so, since there is a high turnover in most medical
environments, mistakes continue to happen, caregivers continue to be fired, and nothing really changes.
This sequence has been ingrained in the medical culture, and is an important reason why the medical
community has been slow to respond to the safety crisis.
SWISS CHEESE AND MEDICAL ERRORS

A popular paradigm in the medical safety area is the “Swiss cheese” model, introduced by James Reason
(Fig. 18-1).3 This model is a visual representation of the multiple system layers that could prevent a
medical error from occurring. A beam of light, representing a latent medical error, passes through a
hole in the cheese, which represents system vulnerability. The latent error passing through the system
via vulnerability will result in a medical error. If enough systems are set up with vulnerabilities, but in
different locations, it becomes progressively harder for the latent error to get all the way through, and
to become manifest clinically. The point here is that, while we recognize that both humans and systems
of care have vulnerabilities, the prevention of error lies at the door of hospital leadership. Positive
results come from the establishment of a strong safety culture, and the establishment of effectively
redundant systems of error prevention. This concept is a major paradigm shift in the patient safety
movement.
2 Even though the system should be constructed to back up human fallibilities, it is instructive to
recognize these fallibilities because systems do not always work. This subject is hard to quantify, but a
good list, developed in a family practice environment, reads as follows: hurry, distraction, lack of
knowledge, premature closure of the diagnostic process, and inadequate aggressiveness in patient
management.4 The first three issues are probably obvious, but premature closure of the diagnostic
process is a problem needing emphasis. Humans often fall into this trap. We see issues as black and
white in an attempt to make sense out of complex circumstances. Hurry, distraction, and lack of
knowledge contribute. Relevant pieces of Swiss cheese, which could counteract this tendency, include
electronic diagnosis and decision-making aids; an institutional policy fostering physician interactions,
teamwork, and second opinions; and setting and adhering to reasonable workload standards.
3 Depending on the environment, other fallibilities are exposed. In the acute hospital setting, as
opposed to the outpatient environment in family practice, safety problems typically involve poor
handoffs, failures of teamwork, excess workload, and fatigue.5
But what about the concept of individual responsibility? One cannot show up for work with a careless
attitude, engage in irresponsible actions, and expect to be held unaccountable for poor performance
because of the emphasis on systems. This is a delicate balance for any health care system. The
537
booksmedicos.org
underlying principle here is that most employees of a hospital wake up each morning wanting to do a
good job, and to avoid mistakes, and hence (with exceptions) the general philosophy should be that a
major improvement in safety will be at the level of system engineering rather than individual fallibility.
When the onus of individual fallibility is lessened (not removed entirely), there then emerges a new
sense of system responsibility, with increased willingness to identify system errors and to participate in
safety enhancement as a group. This collaborative participation does not occur when one is worried
about punitive consequences for reporting and the possibility of job loss.
LEADERSHIP AND POLICY

A robust safety culture is essential, but how does one change a culture? This is not done easily. There
are two crucial elements, which, if effective, can change the culture direction positively. The first
element is set by the example of hospital leadership. When the rank and file sees that the hospital CEO
places patient safety at the top of the list and backs this priority up with funding, a lot of good things
happen. When the CEO emphasizes a change in hospital policy, with an emphasis on safety, the change
is reinforced. We introduced two policies that serve as examples to make this point. The first, the “full
disclosure” policy, stipulated that employees were obligated (not just encouraged) to disclose fully to
patients important errors made in rendering their care. Remarkably, this policy resulted in fewer
malpractice claims against the system, but more importantly, it underscored for employees the
institutional emphasis on openness and honesty.6 The second policy change implemented was the “speak
up with safety concerns” policy, which stipulated that no caregiver could be punished for voicing a
concern involving patient safety, regardless of feelings hurt or hierarchy violated. Again, this written
policy clearly articulated a health system goal – that patient safety trumped all other considerations.
One manifestation of an improved safety culture is an increased error reporting rate. Clearly, the
error reporting rate will not go up if there exists widespread fear of retribution for reporting. What is
desired is an increased rate of error reporting, but a decreasing rate of events resulting in temporary or
permanent harm. This pattern suggests that caregivers are vigilant, care about safety, and are reporting
on “near misses.” The data from “near misses” represent a treasure chest of information that can be used
to prevent actual mistakes. We have seen increased reporting in association with the purchase of a new
electronic reporting format. Whether a change in culture or a change in reporting format is responsible
for the increased level of reports is hard to say, but we believe that it is some combination of both (Fig.
18-2).
ASSESSING THE CULTURE

If one places priority on “improving” a safety culture, it is necessary that the “culture” can be measured.
Validated culture surveys exist, which, if applied periodically in a hospital environment, give important
insight into the success of safety culture initiatives. We use the Agency for Healthcare Research and
Quality (AHRQ) safety culture instrument primarily and survey all caregivers at approximately 2-year
intervals. We use the resulting information in three ways. First, we use the aggregate response to
answer the question, “Are we improving the safety culture?” and, if not, “What are the areas that need
to be addressed institutionally?” On our last survey, a clear sore point at our institution was difficulty
with “handoffs,” that is, the transfer of information between caregivers and teams. We then developed a
taskforce focused on fixing the problem, over both the short and long term. The long-term solution is an
electronic one; the short-term solution is a paper-based handoff tool. This effort was a direct result of
information gained from the safety culture survey.
Figure 18-1. Systems failures.
538
booksmedicos.org
Figure 18-2. Overview of the reporting system.
A second way we use the safety culture survey data is to identify specific hospital units that are
struggling with a dispirited or complacent attitude toward the safety effort. Such problems often result
from poor nurse leadership, disruptive physicians, or a lack of perceived resources. Armed with
information about the safety culture (or lack of it), the institution can implement a focused strategy
customized to the problem. Figure 18-3 shows results from our survey arranged by individual nursing
unit, demonstrating certain units in need of help with error reporting and, conversely, units where the
culture is good and institutional resources are not needed. A third source of information derived from
the survey comes from narrative comments entered by individual caregivers. This is a very rich source
of information and, since it is anonymous, often draws a fine line under issues that are hard to talk
about in any other forum. Issues of suspected physician impairment, abusive behavior, or lack of
leadership skills are sometimes identified.
Two important questions regarding safety culture and our efforts to improve it remain. First, using
the AHRQ tool, have we seen an aggregate improvement over the past two survey intervals? Many
safety initiatives have been instituted over this period of time, and yet the aggregate culture data have
not shown much change. We interpret this information to mean that much more work needs to be done,
and that changing a culture is a hard thing to do, akin to changing direction of an aircraft carrier. Also,
over the period of time we have been studying our culture, our institutional activity has gone up
dramatically, the complexity of our patients has increased, and nursing turnover has been high. Under
these circumstances, no change in the safety culture data might be viewed more optimistically.
A second question is, “Are there individual strategies we have used that influence the safety culture
positively?” If so, we could use these strategies more broadly. The answer to this question is yes.
Patient safety rounds have been an important strategy that has improved the safety culture. Over the
course of the past several years, we have made safety rounds on over 200 occasions, at 2-week
intervals. Safety rounds are carried out by leadership (chief medical officer, chief of nursing, CEO, etc.)
and a pointed 45-minute discussion ensues with the unit caregivers, including nurses, aides, clerks, and
transporters. The culture effects of this endeavor are profound. When caregivers believe that the
leadership is willing to listen, takes safety very seriously, and will put resources behind the articulated
concerns, an overall feeling of confidence and support of the safety effort follows. Figure 18-4
demonstrates that caregivers having participated in patient safety rounds viewed the patient safety
environment much more positively than those who had not.7
But, is a positive safety culture actually associated with improved safety? The assumption is yes, but
data were hard to come by until recently. In Michigan, a multihospital collaborative was initiated (the
Keystone Project), the objective of which was to implement evidence-based practices known to decrease
the incidence of bloodstream infections (BSIs).8 A total of 107 hospitals were involved, and caregivers
responded to the Safety Attitudes Questionnaire (SAQ), similar to the AHRQ tool described previously.
Results (incidence of BSIs) were correlated with answers to the SAQ. The results are seen in Figure 18-5.
539
booksmedicos.org
There was an important association noted between the best results (percent reduction in BSIs) and the
most positive answers to SAQ questions. This is only an association (and subject to the usual caveats
about associations vs. cause and effect), but important nonetheless. These results support the underlying
hypothesis that when leadership prioritizes safety and implements actions to support safety, caregivers
reflect this in their answers to the SAQ and this is associated with improved patient safety.
Figure 18-3. Nonpunitive response to error.
THE EVIDENCE BASE FOR PATIENT SAFETY

As important as it is to lay a strong foundation in safety culture, the energy and enthusiasm of
caregivers to provide safe patient care must be rooted in activities that have been found to be effective.
Unfortunately, there does not exist at this point a large base of evidence in patient safety, largely
because the field is relatively young. The World Health Organization (WHO) convened a group to
carefully analyze existing studies and highlight effective strategies with an evidence base.9 These are
listed in Table 18-1. Comments about specific evidence-based actions follow.
With regard to the administration of perioperative beta-blockers to prevent postoperative myocardial
ischemia, it is very clear that patients already on such medications must be given them postoperatively.
However, an initial interest in beta-blocker administration for patients never having received them
previously evaporated as the result of the POISE trial.10 This was an international randomized
controlled trial focusing on this specific issue, and the result, after analyzing many thousands of
patients, was that giving beta-blockers perioperatively to naive patients caused more harm than good.
Specifically, treated patients developed more troublesome bradycardia and hypotension than controls,
and this resulted in a higher incidence of stroke, obviating the potential benefit of the drug in
preventing myocardial ischemia.
540
booksmedicos.org
Figure 18-4. Comparison of 2007 Agency for Healthcare Research and Quality (AHRQ) data participants versus nonparticipants in
patient safety rounds.
Figure 18-5. Teamwork climate across Michigan intensive care units.
Using maximum sterile barriers for central venous pressure (CVP) catheter insertion to prevent BSI
may seem obvious, and the implementation of this protocol has resulted, in many studies, in a dramatic
fall in the incidence of this complication. This strategy is complemented by the use of antibiotic-
impregnated CVP catheter lines and the use of chlorhexidine in the daily maintenance of the insertion
site. The use of ultrasound to help guide CVP catheter line insertion is clearly effective.
Prevention of the feared complication of ventilator-associated pneumonia is a very important
consideration, since this development has a high fatality rate and is very expensive to treat. There is
some evidence that the continuous aspiration of subglottic secretions is important. Our institution has
been successful in decreasing the ventilator-associated pneumonia rate dramatically (Fig. 18-6) using the
multipronged strategy described in Table 18-2.
Table 18-1 Evidence-based Interventions for Safe Patient Care
541
booksmedicos.org
DEVELOPING CONSENSUS
Given the paucity of real evidence to achieve what we think of as safe patient care, and because there is
an urgent need to act, another strategy has been to develop consensus guidelines. Although such
guidelines are not based on randomized trials, there is value in getting the best and most experienced
minds together to synthesize what all would agree to be best practices. Trials may come later to support
or refute consensus.
A very influential group that develops consensus guidelines is the National Quality Forum (NQF), an
organization of a wide variety of experts, consumers, government officials, and corporate directors. The
NQF several years ago published its list of “30 Safe Practices” recommended for implementation.
Because this chapter is oriented toward surgery, Table 18-3 lists a selection of the 30 Safe Practices
germane to the inpatient setting.
Consensus and Accreditation

The NQF works closely with the Joint Commission. When the NQF has reached consensus on a specific
safety practice, this is often translated into a Joint Commission requirement for hospital accreditation,
in this setting recognized as Joint Commission “patient safety goals.” These goals are more specific than
consensus guidelines and have more “bite” to them, in that all hospitals need to fulfill these
requirements in order to be accredited. For example, goal 7, “Reduce the risk of health care–associated
infections,” stipulates, among other things, that hospitals have specific strategies in place to prevent
surgical site infections (SSIs); that they provide regular feedback about SSI rates to caregivers, with
follow-up for 30 days; that they discontinue the use of shaving as a method of preoperative hair
removal; and so on. Goal 8, “Reduce the risk of patient harm resulting from falls,” stipulates that each
hospital implement a specific falls reduction program.
Table 18-2 University of Michigan Protocol for Prevention of Ventilator-

Associated Pneumonia (VAP)
542
booksmedicos.org
Figure 18-6. Ventilator-associated pneumonia – University Hospital intensive care units.
Consensus, Accreditation, and Payment

The Centers for Medicare and Medicaid Services (CMS) has a lot to say about implementation of safety
practices in that they pay a large fraction of the nation’s health care bill. As it regards safety in surgery
and hospital care, CMS has embarked on two important strategies. The first is the Surgical Care
Improvement Project (SCIP), initiated in 2006, whose stated goal was to reduce the incidence of
selected surgical complications by 25% by the year 2010. To do this, CMS produced several specific
process measures required to be met by hospitals before receiving full payment for services. Private
insurers soon followed suit. SCIP measures are listed in Table 18-4. In contrast to the more broadly
defined consensus guidelines, agreed-upon SCIP measures had a strong evidence base. Whether this
effort will be translated into national improvement in results remains to be determined. The Joint
Commission has also integrated certain SCIP measures into its evaluation requirements.
Table 18-3 National Quality Forum Safe Practices
Results have been mixed. In some cases, a statistically meaningful relationship between adherence to
selected measures (antibiotic timing, appropriate antibiotic) was associated with reduced rates of
SSI.11,12 In contrast, a very large study involving over 60,000 patients within the Veterans
Administration hospitals showed remarkable improvement in compliance with five SCIP measures, but
without appreciable effect in reducing SSI, casting doubt on the value of this effort in the overall CMS
strategy for improving patient safety.13
Another important strategy embarked upon by the CMS is known as “nonpayment for hospital-
acquired conditions,” otherwise referred to as the “never event” policy. In this strategy, the CMS has
determined that it will not reimburse for flagrant medical errors, such as wrong patient, wrong side, or
wrong site surgery. Administrators and surgeons do not object to this policy as far as it goes. But great
concern has been raised about other conditions on the “never event” list, such as venous
thromboembolism (VTE) or patient falls. The controversy arises because in these cases there does not
exist an evidence base that would allow a hospital to eliminate these events entirely. Perfectly
appropriate VTE prophylaxis, for example, only reduces the incidence of postoperative VTE by 50%.
This situation seems unfair, and the list of “never event” conditions is progressively growing longer.
Whether this strategy will really improve quality and make patients safer remains to be proven.
Table 18-4 Surgical Care Improvement Program (SCIP) Process and Outcome
543
booksmedicos.org
Measures
PATIENT SAFETY INDICATORS

The AHRQ is another national group, funded by the National Institutes of Health. Several years ago the
AHRQ developed 21 patient safety indicators (PSIs), which are thought to reflect on an institution’s
safety. These indicators are captured from a hospital’s coding system, using International Classification
of Diseases-9 (ICD-9) codes after patient discharge. The PSIs are listed in Table 18-5. While useful
information can be obtained from this system, a disadvantage is that the data are obtained from medical
billing coders, and may not accurately reflect whether a complication was actually preventable. An
example might be the PSI labeled “accidental puncture and laceration.” An enterotomy made during the
course of a difficult dissection in an irradiated and multiply operated abdomen would fit into this
category and be interpreted by nonsurgeons as an “accident.” The surgeon who was carefully dissecting
under these circumstances would definitely not agree. Despite such limitations, the AHRQ PSIs will be
publicly reported as a safety indicator by the government next year, and already form the basis of
certain proprietary safety indices, such as those put forth by HealthGrades.com or the University Health
System Consortium.
EFFORTS FROM THE WORLD HEALTH ORGANIZATION

Recognizing that patient safety should be a global imperative, the WHO, working with the Joint
Commission, has embarked on an ambitious project to reduce the incidence of medical errors
internationally. One effort, known as the “high 5’s” initiative, focuses on reducing five prevalent types
of medical errors, over a 5-year period, in at least seven countries. The identified problem areas are: (a)
managing concentrated injectable medicines, (b) ensuring medication accuracy at transitions of care, (c)
improved communication during patient care handovers, (d) improved hand hygiene, and (e)
performance of the correct procedure at the correct body site.
Table 18-5 Agency for Healthcare Research and Quality Patient Safety Indicators
544
booksmedicos.org
The WHO has focused on surgical care specifically through a separate effort referred to as the “Safe
Surgery Saves Lives” campaign. One very tangible result of this effort is the Surgical Safety Checklist,
shown in Table 18-6.14 Now being tested in eight countries, the vision is that a standardized forum for
intraoperative communication will be adopted internationally, much in the same way that the
international aviation community has endorsed standardized flight checklists.
IMPLEMENTATION STRATEGIES
Establishing a safe culture is important, and emphasizing an evidence base and consensus guidelines is
important, but ensuring implementation of what is known to be safe practice is critical and may be the
most difficult of all safety strategies to accomplish. Several strategies have been helpful in our
environment.
Adding Pharmacists to Rounds

Our medical center is a tertiary care referral center; the complexity of cases is high and always going
higher. Transplants, complex oncologic problems, extracorporeal membrane oxygenation (ECMO)
patients, and others with multisystem organ failure fill a large portion of our beds. The pharmacologic
aspects of these cases are complex. Adding to the difficulty of managing such patients is the educational
aspect of our enterprise, which guarantees a constant supply of new faces on rounds. To address these
issues and to prevent errors, we have implemented a policy of adding a clinical pharmacist to each of
our high-complexity services. The role of this individual is to suggest appropriate drugs, screen for
allergies and incompatibilities, and monitor for important side effects. The program has been invaluable
in improving patient safety at our institution and at others.15
Rapid Response Team

Mortality rates for in-hospital cardiac arrest have been high for decades, despite advances in
cardiopulmonary resuscitation (CPR) techniques and cardiotropic medications. This is true particularly
for “floor arrests,” those cases of arrest occurring outside of the intensive care unit (ICU). In our center,
and in many others, analysis of CPR cases has led to frustration that insufficient attention had been paid
to the patient’s condition in the hours prior to the arrest, at a time when interventions could
conceivably have been very helpful.
One approach to this problem has been to develop a rapid response team (RRT), which is activated
when certain physiologic parameters fall outside a specified range. Such parameters identified at our
center are heart rate (<40 or >140 with new symptoms), respiratory rate (<8 or >36), blood
545
booksmedicos.org
pressure (systolic <80 or >220, diastolic >110 with symptoms), and unexplained change in cognition
or neurologic status of adult inpatients. A key feature of the RRT activation is that it is seen as
mandatory for nursing; no judgment is required. If the parameters are exceeded, the RRT is activated.
This relieves some of the anxieties experienced by nurses in the past about communication with
physicians, particularly at odd hours. In our center, activation of the RRT results in the timely arrival of
an experienced surgical ICU nurse and a respiratory therapist. If the conditions are found to warrant it,
a hospitalist is called. This occurs in 15% of cases. There is controversy in the literature as to whether
the RRT effort actually is effective.16 However, the concept has so much face validity that most
hospitals have accepted it as an important strategy to improve a safety culture.
Table 18-6 World Health Organization Surgical Safety Checklist
An interesting, and entirely unexpected, offshoot of the RRT has been the process, by the RRT team,
of visiting nursing floors on a shift-by-shift basis prior to any RRT activation. This process lets the team
become more familiar with patients who might subsequently warrant RRT activation. Visits often foster
a discussion among caregivers and family as to whether any intervention is appropriate or warranted.
Crew Resource Management

4 Another approach to the implementation of safe practices is to educate and train physicians and nurses
within the context of a team. The team is defined, goals are set, and individual responsibilities are
assigned. The completion of tasks (or omission) is apparent to members of the team, which provides a
fail-safe structure. There has been considerable interest in crew resource management in the area of
medicine since it has been conclusively shown to add value to aviation cockpit training. Crew resource
management is probably best applied in small, well-defined areas, with relatively consistent staffing
patterns, such as an operating room. In one report, a perioperative crew resource management training
program consisted of an e-learning module, the development of laminated checklists and pocket-sized
cards, briefing scripts, a communication whiteboard, and a hands-on training program facilitated by
experienced personnel. Even with focused effort at crew resource management, perioperative safety
practice implementation was found to be less than perfect, but the field, at least in medicine, is in its
infancy, and it will probably be an important part of safety strategies in the years to come.17
Developing Collaborative Groups of Hospitals

Under conditions where motivated hospitals get together to discuss safety, the result is often a more
consistent implementation of safety practices and better results. The development of a collaborative
group directed at safety and/or quality allows for comparative evaluation of quality and safety, and
often results in a spirit of friendly competition, which improves the aggregate level of safety.
A prominent example of such collaboration was mentioned previously, the Michigan Hospital
Association–sponsored Keystone Initiative. Here, evidence-based practice for the care of patients in the
ICU was monitored and found to be low across the state. A protocol was adopted for over 100 ICU
546
booksmedicos.org
groups, which included elevation of the head of the bed 30 degrees, ulcer prophylaxis, regular
respiratory weaning trials, and a central line insertion protocol, with line maintenance involving
chlorhexidine patches. When the latter protocol was implemented, a profound drop in the incidence of
BSIs across the state was seen, and the estimated cost savings exceeded $160 million.8
In a different example, 64 Michigan hospitals formed the Michigan Surgical Quality Collaborative.
These hospitals convene at 3-month intervals and share information about identified “best practices” and
correlation with surgical results. Hospitals with the fewest complications in a specific area discuss why
they feel they have been successful. “Best practices” are then distributed in a network including through
the internet and a hardcopy newsletter. Each hospital implements strategies it feels are appropriate for
its situation. The result has been a sharp drop in the incidence of surgical complications. The results
suggest that a collaborative quality organization, with regular and intensive sharing of data and best
practices, is an essential vehicle for quality improvement.
PATIENT AND FAMILY INVOLVEMENT

One element of the patient safety movement that will become more important in the future is the
involvement of the patient in various hospital safety strategies. A valuable source of information, and
an important feedback mechanism, is lost when the patient, or family, is not a part of the care process.
Two examples of the value of patient involvement involve hand washing and urgent care.
For hand washing, an effective hospital strategy prompts patients to ask physicians, “Have you
washed your hands?” when they come into the patient’s room. Physicians frequently wear buttons in
this effort, which say, “Ask me if I’ve washed my hands.” While it may seem trivial and somewhat
demeaning to the physicians, the fact remains that the percentage of physicians and nurses washing
their hands prior to patient contact remains far below 100%, and the prevalence of patient infection
with Clostridium difficile, vancomycin-resistant Enterococcus, and other hospital-acquired infections
remains high. In this context, patient involvement could be seen as a very important piece of Swiss
cheese.
Another example of patient and family involvement in the care process is the concept of “family
activation” of the RRT. Family members are often more aware of changes in a patient’s condition than
nurses or doctors, for the obvious reason that they know the personality and traits of the patient in
detail. “He wouldn’t complain about this unless it was really bad” is an important source of information
from a wife. In the past, this clue to an evolving situation was sometimes lost on caregivers more
focused on vital signs and urine output. In “family activation” of the RRT, family members are allowed
to call a phone number activating the RRT if they feel that more attention is needed to a given
situation. While it might seem that this would let loose a flood of such calls, in actuality, this has not
been the case.
DEVELOPING A TAXONOMY FOR PATIENT SAFETY

Ultimately, comparative data on the safety of patient care in this country will be available to the public,
much in the same way that the safety of retail products, medications, and automobiles is currently
reported. For any reporting system to be valuable and fair, the definitions of safety events need to be
refined and agreed upon. It is not possible to compare the safety of different hospitals if definitions used
are not standardized. Many national organizations are working on this topic. The WHO has recently
developed an “International Classification for Patient Safety” designed to “define, harmonize, and group
patient safety concepts into an internationally agreed upon classification in a way that is conducive to
learning and improve patient safety across systems.” This work, while difficult, is essential for the
patient safety movement.18
PUBLIC REPORTING OF SAFETY DATA

5 We live in an age of transparency. The public wants – and deserves – information about the safety
record of a given hospital. And yet, such information is hard to find. The future of the patient safety
movement depends on the development of an effective safety reporting mechanism. This is because, in
the absence of a large-scale database, information is not disseminated effectively, and one hospital may
547
booksmedicos.org
easily make the same mistake as its sister hospital down the street. One major impediment to the
development of a national safety database is the lack of a standardized taxonomy of patient safety
events. This problem is being addressed, as was just described.
Public reporting has been initiated using both voluntary and mandatory designs. Two examples of
successful voluntary reporting systems are the National Nosocomial Infection Survey, a branch of the
Centers for Disease Control and Prevention, and the MEDMARX program of the U.S. Pharmacopeia.
Mandatory safety reporting systems are often state initiated and provide various sanctions for hospitals
known to be engaged in unsafe practices. This penalty provides a disincentive to report, however. Only
a few states have successful mandatory reporting systems.
One very successful example of a voluntary reporting system, albeit in the field of aviation, is the
Aviation Safety Reporting System. This system analyzes 30,000 reports annually. Its success has
depended on these factors: the system is simple, it is safe (for the reporting pilots), and it provides
value. The patient safety movement would do well to emulate this system. When it does, and the
taxonomy is standardized, doctors, nurses, and administrators will be considerably more willing to
make safety data available to the public.
References
1. Kohn LT, Corrigan JM, Donaldson M, eds. Committee on Quality of Health Care in America IoM. To
Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000.
2. http://www.ahrq.gov/professionals/quality/safety/pfp/interimhacrate2013.pdf
3. Reason J. Education and debate. Human errors: models and management. BMJ 2000;320:768–770.
4. Ely JW, Levinson W, Elder NC, et al. Perceived causes of family physicians’ errors. J Fam Pract
1995;40:337–344.
5. Singh H, Thomas E, Petersen L, et al. Medical errors involving trainees: a study of closed
malpractice claims from 5 insurers. Arch Intern Med 2007;167(19):2030–2036.
6. Boothman RC, Blackwell AC, Campbell DA Jr, et al. A better approach to medical malpractice
claims? The University of Michigan Experience. J Health Life Sci Law 2009;2(2):125–159.
7. Campbell DA., Thompson M, Patient safety rounds: description of an inexpensive but important
strategy to improve the safety culture. Am J Med Qual 2007;22:26–33.
8. Pronovost P, Needham D, Berenholtz S, et al. An intervention to decrease catheter-related
bloodstream infections in the ICU. N Engl J Med 2007; 356(25):2660.
9. Ovretveit J. Which interventions are effective for improving patient safety? A synthesis of research
and policy issues. WHO HEN Copenhagen and MMC. Stockholm, Sweden: Karolinska.
http://homepage.mac.com.
10. POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-
cardiac surgery (POISE trial): a randomized controlled trial. Lancet 2008;371:1839–1847.
11. Cataife G, Weinberg DA, Wong HH, et al. The Effect of Surgical Care Improvement Project (SCIP)
compliance on surgical site infections (SSI). Med Care 2014;52(2 Supp 1):S66–S73.
12. Munday GS, Deveaux P, Roberts H, et al. Impact of Implementation of the Surgical Care
Improvement Project and future strategies for improving quality in surgery. Am J Surg
2014;208:835–840.
13. Hawn MT, Vick CC, Richman J, et al. Surgical Site Infection Prevention : time to move beyond the
surgical care improvement program. Ann Surg 2011;254:494–499.
14. World Alliance for Patient Safety Progress Report 2006–2007. Geneva, Switzerland: World Health
Organization; 2008.
15. Kucukarslan SN, Peters MP, Mlynarek M, et al. Pharmacists on rounding teams reduce preventable
adverse drug events in hospital general medicine units. Arch Intern Med 2003;163:2014–2018.
16. Hillman K, Chen J, Cretikos M, et al.; MERIT Study Investigators. Introduction of the medical
emergency team (MET) system: a cluster-randomised controlled trial. Lancet 2005;365:2091–2097.
17. France D, Leming L, Jackson T. An observational analysis of surgical team compliance with
perioperative safety practices after crew resource management training. Am J Surg 2008;195:546–
553.
18. Leape L. Reporting of adverse events. N Engl J Med 2002;347(20): 1633–1638.
548
booksmedicos.org
Part Two Surgical Practice
549
booksmedicos.org
SECTION A: TRAUMA
550
booksmedicos.org
Chapter 19
Trauma and Trauma Care: General

Considerations
Hasan B. Alam
Key Points
1 Injuries are the leading cause of death in young Americans, and account for 1 out of every 10 deaths
in the world.
2 Deaths due to penetrating trauma and motor vehicle collisions are decreasing whereas fall-related
fatalities are rapidly rising reflecting the aging population.
3 Establishment of trauma systems that use evidence-based triage and treatment protocols saves lives.
4 Bleeding is the number 1 cause of preventable deaths.
5 The vast majority of trauma-related deaths are within the first few hours (<6 hours) after sustaining
injuries.
6 Early hemorrhage control is the major priority along with balanced resuscitation using an
appropriate ratio of blood products.
7 Recent military conflicts have rapidly advanced trauma care in many domains, and these
developments are now being transferred to the civilian trauma settings.
BURDEN OF DISEASE
1 Injuries and violence affect everyone, regardless of age, race, or economic status. More young
Americans (under 46 years of age) die of injuries than any other cause.1 According to the Centers for
Disease Control and Prevention, National Center for Injury Prevention and Control, about a quarter of
all the emergency department visits are due to injuries (27 million in 2013),2 resulting in 3 million
hospitalizations and nearly 193,000 deaths – 1 person every 3 minutes.3 As opposed to cancers,
cardiovascular diseases, and strokes, injuries disproportionally strike people in the prime of their lives.
In fact, 59% of all deaths among people of 1 to 44 years of age in the United States are due to injuries,
which is more than all noncommunicable diseases and infectious diseases combined. Figure 19-1 shows
the top 10 causes of death in different age groups in the United States, whereas Figure 19-2 highlights
the unintentional causes. Young males are the highest risk groups, not due to any specific physiologic
disposition, but due to the propensity to engage in high-risk activities. Similarly, factors that increase
risk taking and impair judgment (e.g., alcohol, drugs, crime, conflicts) further exaggerate the chances to
get injured.
Although striking, the death data do not tell the entire story. Millions of injured people survive, but
they face lifelong mental, physical, and financial problems that add to the societal burden. The resultant
economic toll on our society is staggering. In 2013, the total cost of injuries in the United States was
estimated to be $671 billion. The costs associated with fatal injuries was $214 billion while nonfatal
injuries accounted for over $457 billion.4 This problem also has global dimensions. According to the
World Health Organization, injuries kill more than 5 million people, which is nearly 1.7 times the
number of fatalities that result from malaria, tuberculosis, and human immunodeficiency virus,
combined.5
EVOLVING MECHANISMS OF INJURIES WITH CHANGING

POPULATION DEMOGRAPHICS
2 Motor vehicle collisions (MVC), firearms, falls, cutting/piercing instruments, poisoning, and burns are
551
booksmedicos.org
among the leading mechanisms (Table 19-1).6 Their relative positions on the list are evolving. Over the
last decade, better roads, safer cars, more frequent use of seatbelts, and so forth have resulted in a
decrease in MVC fatality despite a marked increase in the number of cars on the roads and overall miles
driven (Fig. 19-3).7 Drug overdose, suicide, and prescription medication abuse on the other hand are on
the rise. For example, the age-adjusted suicide rate in the United States was 24% higher in 2014 than in
1999, and increases were observed for both females and males in all age groups under 75 years of age.8
In fact, we are witnessing a 30-year peak in suicide rates in the United States. Falls are also rapidly
becoming a major health care issue due to increasing age of the population.9 Currently, in the United
States, 1 in 9 Americans is aged 65 or older, which by 2050 will increase to 1 in 5 (Fig. 19-4).10 The fall
rates are already climbing (Fig. 19-5) and are expected to jump up even more dramatically over the
next few decades. These patients also have many more co-morbid problems, and the various age-related
anatomic, physiologic, and immunologic changes makes it especially challenging to take care of these
patients.11,12 Violent crimes were near record high from the 1970s to 1990s, but have shown a steady
decline in the recent years (Fig. 19-6). When considering 5- and 10-year trends, the total 2013 estimated
violent crime rate was 12.3% below the 2009 level, and 14.5% below the 2004 level.13 Despite the
focus by the media on violent crimes, by most measures, we are now witnessing one of the safest eras
in the American history.
CHANGING PATTERNS OF DEATH

3, 4, 5 The classical trimodal distribution of trauma deaths was described by Trunkey14 in 1983, based
upon the patterns of post-traumatic deaths in several counties of Northern California. In that report,
nearly half of the deaths occurred within minutes after injury due to disruption of major blood vessels,
devastating central nervous system (CNS) injuries or combination. The only practical solution for this
group appears to be better prevention strategies, as these deaths often occurred before any medical care
could be delivered. A smaller second peak, lasting a few hours, followed that first major peak in
mortality (∼30% of the deaths) where depending upon the mechanism of trauma, ongoing hemorrhage
and CNS injuries played an almost equal role. This group has been the impetus for the development of
better trauma delivery systems (emergency medical services, rapid transport mechanisms, and dedicated
trauma centers) across the world. In fact, data strongly show that preventable mortality is significantly
lower in geographical areas that have well-established trauma systems.15,16 The third peak was noted
days to weeks after injury due to infections, multiple organ failure (MOF) and various late
complications. In more contemporary studies, the trimodal distribution has evolved into essentially a
bimodal distribution, where 61% of the deaths are immediate, 29% early, and only 10% are late.17
Compared with the classical description, the percentage of immediate deaths remained unchanged, and
early deaths occurred much earlier (median 52 vs. 120 minutes). However, unlike the classic trimodal
distribution, the late peak has markedly diminished, most likely due to significant improvements in
surgical intensive care. Mortality rates for many of the reasons for late death are rapidly dropping with
wider adoption of best care practices for managing critical care illnesses.18–20 For example, due to more
judicious resuscitation practices severe respiratory failure after trauma has become a fairly rare
occurrence.21 Clearly, critical care is resource intensive and adds significantly to our health care costs,
but it has “flattened” the third peak. In other words, not only the incidence of late complications has
dropped, but our ability to “rescue” patients even if they develop the complications has markedly
improved. Today, even in massively bleeding patients (without head injuries) mortality beyond the first
24 hours is only ∼10%.22 Unfortunately, the area where we have failed to alter the mortality remains
the period immediately following the injury, including the prehospital phase. The majority of these
deaths are due to hemorrhage and/or traumatic brain injury (TBI).23–26 Of these two conditions,
bleeding is clearly more treatable, which makes it the number one cause of preventable deaths. Despite
numerous advances in trauma care, a recent multinational trial of more than 20,000 patients 27 once
again demonstrated that the majority of deaths (even in developing and under developed countries)
occur within a few hours after injuries, with <2.5% of the injured succumbing to MOF.
552
booksmedicos.org
Figure 19-1. Ten leading causes of death by age group in the United States (2014). Source: Centers for Disease Control and
Prevention.
Figure 19-2. Ten leading causes of death by age group in the United States (2014), highlighting unintentional causes. Source:
Centers for Disease Control and Prevention.
Table 19-1 Death Rates by Mechanisms (United States 2013)a
553
booksmedicos.org
6 Despite obvious differences in the mechanisms of injuries, hemorrhage and TBI remain the leading
causes of death not only in civilian but also in combat trauma,28 and effective treatment strategies have
the potential to save many lives in the battlefield.29 Traditionally, management of a bleeding patient
focuses on the replacement of lost blood, along with standard cardiopulmonary resuscitative strategies.
The type of fluid used for resuscitation has evolved since it was introduced nearly a century ago.
Toward the end of World War I and during World War II, transfusion of whole blood was the primary
approach in the treatment of military traumatic hemorrhage. However, after World War II, the
separation of whole blood into its components became widely accepted and replaced the whole-blood
transfusion for logistical and financial reasons. During the Vietnam War era, use of salt-based solutions
(crystalloids) became popular. Over the next 3 decades we saw a major rise in the volume of salt-water
administration in trauma patients. Although it is cheap, easy to store and administer, from the very start
there were concerns about the suitability of crystalloid fluids as a substitute for the lost blood. Blood is
a complex fluid that contains thousands of proteins, cells that carry oxygen to the tissues (red blood
cells) and generate clot to stop bleeding (red blood cells and platelets), various clotting factors, buffers,
enzymes, and hormones. As crystalloids lack all of these, their administration results in rapid dilution of
cells, clotting factors, and proteins, which can worsen bleeding. Thus, aggressive crystalloid
resuscitation, especially in the absence of early hemorrhage control, is impractical, inadequate, and
potentially harmful in many circumstances.30–33 Not only it lacks any specific pro-survival properties,
large volume crystalloid infusion can exacerbate bleeding and worsens cellular injury.34 It should be
emphasized that survival in these patients requires definitive control of bleeding, and most deaths today
are caused by delays in controlling the source of bleeding, and not due to inadequate delivery of
resuscitation fluids. These challenges are compounded in austere circumstances such as a battlefield,
where 87% of deaths occur before patients reach a medical facility,28 yet nearly a quarter of these
injuries are considered potentially survivable (PS). Not surprisingly, the PS category is largely (91%)
made up of hemorrhage-related deaths, with most being truncal (67%).28 In the injured that live long
enough to reach a medical facility, the percentage of PS deaths increases to 51%, with hemorrhage
accounting for 80%.29 Thus, novel therapies that could improve hemorrhage control, and keep the
injured alive long enough to get to higher echelons of care, have the potential to make the biggest
difference.
554
booksmedicos.org
Figure 19-3. Motor vehicle-related fatalities over time in the United States. From US Department of Transportation. NHTSA. 2014
Motor Vehicle Crashes: Overview. http://www-nrd.nhtsa.dot.gov/Pubs/812246.pdf.
Figure 19-4. Age and sex distribution of the United Sates population: 2010, 2030, and 2050. From Vincent GK, Velkoff VA. The
next four decades, the older population in the United States: 2010 to 2050. Current Population Reports, pages 25–1138.
Washington, DC: US Census Bureau; 2010.
555
booksmedicos.org
Figure 19-5. Death rates from unintentional falls. The figure is a line chart showing that during 2000–2013, age-adjusted death
rates from unintentional falls increased steadily for both men and women aged ≥65 years, with consistently higher rates observed
among men. During this period, death rates from falls increased from 38.2 per 100,000 population in 2000 to 67.9 in 2013 among
men and from 24.6 to 49.1 among women. From National Vital Statistics System mortality data. Available at
http://www.cdc.gov/nchs/deaths.htm.
Figure 19-6. Death Rates for Three Selected Causes of Injury – National Vital Statistics System, United States, 1979–2012. In 2012,
a total of 41,502 drug poisoning deaths, 34,935 motor vehicle traffic deaths, and 33,563 firearm deaths occurred. The age-adjusted
death rate for drug poisoning more than quadrupled from 3 per 100,000 in 1979 to 13.1 in 2012. In contrast, the age-adjusted rate
dropped from 22.1 to 10.9 for motor vehicle traffic deaths and from 14.7 to 10.5 for firearm deaths during this period. The age-
adjusted drug poisoning death rate exceeded the motor vehicle traffic death rate beginning in 2009. From CDC WONDER,
compressed mortality file, underlying cause-of-death, available at http://wonder.cdc.gov/mortsql.html.
BIOMECHANICS OF INJURY
It is important to realize that at its most basic level injuries result from deformation of tissues that
results in damage. In general, injuries can be categorized as penetrating (sharp objects or firearms) or
blunt. There are clearly differences between these mechanisms that must be kept in mind while
evaluating the patient. Penetrating trauma causes injury to the objects that are in the path of the foreign
body, whereas blunt trauma causes damage either through crush or shear forces. The diagnostic and
management approach is therefore very different.
Blunt trauma is best understood by applying the rules of kinetic energy transfer: KE = (M × V)/2,
where KE is kinetic energy, M is mass of the object, and V is velocity. Thus, a head on collision between
two large sport utility vehicles (∼6,000 lb each) traveling at 65 mph can generate enormous amounts
of forces. Various safety mechanisms in the modern vehicles direct this force away from the occupants
of the vehicle, but the clinicians have a tendency to underappreciate the forces and the vectors involved
in the collision. With frontal impact, the vehicle stops abruptly and the occupants continue to move
556
booksmedicos.org
forward (if not belted) and either hit the steering wheel or slide under to hit their knees against the
dashboard resulting in classic injury patterns (Fig. 19-7). In a rear impact, the kinetic injury generated
depends upon the differences between the velocities of the two vehicles, and the occupant of the front
vehicle abruptly accelerates forward resulting in cervical spine hyperextension (“whiplash”). Lateral
impact imparts rotational forces and often results in significant protrusion of the passenger
compartment. In addition to limb trauma, this can result in major torso (chest, abdomen, and pelvis)
injuries. The rotational forces are also more likely to cause torsion injury where the mobile areas join
relatively fixed structures (e.g., aortic laceration, cervical spinal ligamentous injuries). Rollover crashes
are especially dangerous as the vehicle is impacted from various angles repeatedly during the process.
The occupants of the vehicle are thrown around and may even be ejected from the vehicle. Ejection
increases the chances of death by ∼10 fold. Similarly, death of another occupant is considered a high-
risk event, as it is a surrogate for the severity of impact or the complexity of the forces involved. The
clinician also must specifically look for clinical evidence of energy transfer. For example, a “seat belt”
sign across the abdomen must raise suspicion for energy transfer across the bowel, mesentery, pancreas,
and the lumbar spine. Similarly, wedge fracture of L1 vertebra in this setting mandates ruling out a
pancreatic injury as the pancreatic body drapes across the anterior aspect of L1. In fact, orthopedic
injuries should be considered markers of kinetic energy transfer and make the clinicians proactively
look for injuries to adjacent organs, nerves, vessels, and tendons (Table 19-2).
Penetrating trauma should broadly be considered in two categories based upon the mechanism. Sharp
objects can cause lacerations or puncture wounds. Lacerations are relatively more straightforward as the
structures in the depth of the wound can be examined and injuries to critical organs ruled out by careful
inspection. Puncture wounds (or stabs), on the other hand, are challenging when it comes to ruling out
occult injury to deeper structures. For example, stab wound to the neck can cause injuries to the airway,
esophagus, blood vessels, thyroid gland, or intrathoracic organs. Similarly, stab wound to the abdomen,
chest, flank, and so forth must be evaluated for potential intracavity vascular, solid organ or hollow
viscus injuries. Historically, most of these patients used to get surgical explorations but now with better
imaging techniques, carefully selected stable patients are often evaluated with advanced imaging studies
and/or endoscopy, and managed nonoperatively.35–39 Clearly, there has been a recent increase in the
use of computerized tomography (CT) scans in the evaluation of trauma patients,40 and careful use of
CT scan can reveal additional findings that may not be otherwise apparent.41 This, however, does not
apply to stab wounds to the abdomen, where CT scan has been shown to add no value to the serial
physical examinations and close observation.42 In this prospective study of 249 patients with stab
wounds to the abdomen, the CT scan findings did not alter the clinical decision making. Forty-five
patients (18.1%) underwent immediate laparotomy, 27 (10.8%) had superficial injuries allowing
immediate discharge, and the remaining 177 (71.1%) underwent CT. Of these, 154 (87.0%) were
successfully observed, with 20 (11.3%) requiring laparotomy, 2 (1.1%) thoracotomy, and 1 (0.6%)
sternotomy. Of the 20 laparotomies, 16 (80.0%) were therapeutic. All patients who underwent
therapeutic laparotomy did so based on their physical examination alone. The sensitivity and specificity
of physical examination were 100% and 98.7%, respectively, while those of CT were 31.3% and 84.2%,
respectively. Thus, even in this era of ubiquitous radiographic imaging, the burden is on the clinician to
carefully evaluate the patient and make a clinical decision in the trauma bay. One reason CT scans can
be misleading in stab wounds is because unlike the gunshot wounds where the track is easier to
appreciate due to surrounding tissue injury and cavitation effect, the depth of stab wounds is
notoriously difficult to determine on the CT scan. Often, the tissues come back together when the knife
is withdrawn, making it difficult to determine the precise depth of penetration (often the knife has
penetrated much deeper than the track that is visible on the scan). Thus, in stable patients, nonoperative
management of penetrating abdominal trauma is not unreasonable, even if they have solid organ
injuries,43 but it is not a simple radiographic decision. In fact, it remains a clinical decision that should
be made by an experienced trauma surgeon. These patients also require close observation, serial
examinations, and monitoring of laboratory parameters for the next 12 to 24 hours. In settings where
this is not possible (e.g., lack of 24/7 clinician availability), the safer option would be to explore the
injured body cavity (either laparoscopic or open). Bullet wounds differ from stab wounds not only in
the fact that the bullets impart significant kinetic energy depending upon their velocity and weight
(Table 19-3) but can also cause “cavitation” effect. Cavitation occurs as tissues impacted by the bullet
recoil and transmit the kinetic energy outward, creating a cavity due to the rapid acceleration and
deceleration. This can injure organs/tissues that are adjacent to the bullet track even if not hit directly
by the projectile. In addition to the kinetic energy, the actual area of injury is influenced by factors such
557
booksmedicos.org
as profile of the bullet, tumble (spin and yaw), and fragmentation. A jacketed bullet does not deform
much whereas a hollow point bullet fragments, spreads, and deforms (increasing the area of damage).
Similarly, tumbling of the bullet increases the area of energy exchange and much larger zone of
damage. Generally, low-velocity (<1,200 ft/s) or medium velocity (1,200 to 2,000 ft/s) firearms are
more common in urban trauma, with high-velocity wounds seen typically in combat settings. The
cavitation effect is significantly more pronounced in high-velocity injuries, and the kinetic energy
differences translate into a much larger area of destruction, more devitalized tissues, and contamination
(cavitation can pull in debris, clothes etc. into the wound). Injuries to multiple organs and structures,
even in different body cavities, is possible with bullet wounds. In the operating room, it is important to
set clear priorities, and to approach the injuries in a logical fashion. The first priority should be to
control the hemorrhage quickly (clamps, catheters, packing, etc.), followed by a quick assessment to
identify and treat other life-threatening injuries (pneumothorax, cardiac tamponade, etc.). This should
be followed by control of contamination. Then the physiologic status of the patient should be assessed
to determine whether definitive repair of all the injuries is feasible versus a “damage control approach”
(Table 19-4) where only an abbreviated operation is done and patient brought back to the operating
room later for additional interventions (after full resuscitation). While looking for injured organs in
penetrating trauma, topography for anatomic proximity must be kept in mind. For example, penetrating
injury to the carotid mandates that we exclude injury to adjacent organs such as jugular, trachea,
esophagus, and the spine. Similarly, one hole in the bowel should prompt us to look for another hole
(through and through injury) that may not be obvious, as well as examining other adjacent organs. For
example, a bullet injury to the anterior wall of the stomach can easily pass through the posterior wall,
through the pancreas, duodenum, vena cava, and the kidney, depending upon the trajectory. While
trying to determine the trajectory, it is important to not assume that the subject was in a “normal”
anatomical position (standing straight front facing with arms by his side) when shot. Typically, victims
assume a variety of odd positions in an effort to avoid getting hit. In addition, bullets do not necessarily
travel in a linear track and can bend and bounce off in atypical directions. Thus, gunshot wound to the
chest can easily result in injuries not only in the chest (ipsilateral or contralateral), but also in the
abdomen, pelvis, or the neck depending upon the course of the projectile. It is also wrong to notice two
holes and assume that they represent a through and through gunshot wound. It is equally likely to be
two separate gunshot wounds with both bullets still inside the body. As a general rule, the number of
gunshot wounds and the number of retained bullets should add up to an even number; otherwise, you
are either missing a hole or a bullet. Even in critically ill patients, quick x-rays of the
chest/abdomen/pelvis, as a “bullet survey” can be very helpful before rushing to the operating room.
This information can be critically important in planning the surgical approach, and in deciding which
body cavity to tackle in what sequence.
558
booksmedicos.org
Figure 19-7. A, B: Frontal deceleration impact.
Table 19-2 Patterns of Injury to the Head, Neck, Trunk, and Extremities
Associated with Orthopedic Injuries
Table 19-3 Muzzle Velocity, Kinetic Weight of Projectile, and Approximate

Maximum Kinetic Energy of Frequently Used Firearms
559
booksmedicos.org
Table 19-4 List of Proposed Indications for Damage Control, Including Range of
Values Reported in Various Articles
FIELD TRIAGE DECISIONS AND EARLY PRIORITIES

Broadly speaking, the trauma patients can be divided into three categories: patients with (a) rapidly
fatal injuries, (b) potentially fatal injuries, and (3) all others. A key component of effective prehospital
triage is to properly place the injured into these categories based on the available data (mechanism of
injury, age of the patient, co-morbid diseases, physiologic status, and injury patters), and then make a
rapid decision about what type of facility is the most appropriate for the patient. Committee on Trauma
for the American College of Surgeons (ACS-COT) has developed detailed criteria for designating
hospitals into different levels depending upon the resource availability, from the highest (level I) to the
lowest (level IV). These criteria can easily be found in the Resources for Optimal Care of the Injured
Patient – 2014.44 Working with the Centers for Disease Control and Prevention, ACS-COT has also
developed a guideline for the prehospital triage of the injured patients (Algorithm 19-1).45 The
document also contains very detailed guidelines about which patients should be transferred from lower-
level to higher-level trauma centers (Table 19-5).44 The key priorities during the prehospital phase are
the ABCs of trauma care (airway, breathing, and circulation), with a major focus on hemorrhage control
(direct compression, advanced hemostatic dressings, and tourniquets etc.). In patients that are in
hemorrhagic shock but are breathing and maintaining adequate airway/oxygenation, intubation and
mechanical ventilation should be avoided (especially for short prehospital times) as administration of
sedating drugs and an increase in the intrathoracic pressure (due to positive pressure ventilation)
further decreases the preload, which could precipitate an arrest. Judicial administration of crystalloid
fluids is acceptable, but aggressive fluid resuscitation in the absence of hemorrhage control can worsen
the outcomes. The proof of this concept in humans was published in the New England Journal of
Medicine in 1994.33 In that study, hypotensive patients with penetrating injury to the torso were
randomized to routine fluid resuscitation, or resuscitation was delayed until bleeding had been
surgically controlled. The results showed a survival advantage in the delayed resuscitation group (70%
vs. 62%, p = 0.04). In fact, a systematic analysis of all the published data failed to find any support in
favor of (or against) large volume crystalloid resuscitation in bleeding trauma patients.46 As these
studies had focused on young patients with penetrating trauma, the question remains whether these
findings can be generalized to the blunt trauma population. The blunt trauma patients are typically
older, may have a higher incidence of coronary and carotid stenosis, and about 20% to 30% have
associated TBI (which can worsen due to hypotension). Furthermore, as opposed to penetrating trauma,
560
booksmedicos.org
the sources of bleeding can be multiple and not always surgically fixable in the blunt trauma victims.
Because of all these reasons, limited volume (“controlled”) resuscitation rather than no resuscitation is
logical in this population. This is also supported by an early pilot prospective randomized trial where
192 patients with an out-of-hospital systolic blood pressure (SBP) of 90 mm Hg or lower were
randomized to receive controlled resuscitation (CR) or standard resuscitation (SR).47 CR patients
received 250 mL of fluid if they had no radial pulse or an SBP of lower than 70 mm Hg, and additional
250-mL boluses were given only to maintain a radial pulse or an SBP of 70 mm Hg or greater. The SR
group patients received 2 L initially and additional fluid as needed to maintain an SBP of 110 mm Hg or
greater. This protocol was maintained until hemorrhage control or 2 hours after arrival in the hospital.
The results showed that among the cohort of patients with blunt trauma, 24-hour mortality was 3% and
18% in CR and SR groups, respectively, with an adjusted odds ratio of 0.17(0.03 to 0.92).47 At present,
published data only support careful small volume crystalloid resuscitation to keep the injured alive
during transport, and aggressive crystalloid resuscitation should be avoided. In the future, preserved
blood products or specialized life-saving drugs may become available, but for now rapid transport to a
specialized trauma center (“scoop and run”) is the most reasonable strategy in urban environments
where the transport times are relatively short. In fact, a prospective comparison between Advanced Life
Support (ALS) and Basic Life Support (BLS) transport48 showed that patients transported by ALS units
more often underwent prehospital interventions (97% vs. 17%; p <0.01), including endotracheal
intubation, needle thoracostomy, cervical collar, IV placement, and crystalloid resuscitation. While ALS
ambulance on-scene time was significantly longer than that of BLS (p <0.01), and had more prehospital
interventions (1.8 ± 1.0 per ALS patient vs. 0.2 ± 0.5 per BLS patient; p <0.01), 69.5% ALS patients
and 88.4% of BLS patients (p <0.01) survived to hospital discharge. The message is clear – less is more
in the prehospital arena, and time to definitive care is the most critical variable. Others studies also
support the argument that rapid transport to the trauma center is more important than prehospital
interventions in urban victims of penetrating trauma.49
Table 19-5 Criteria for Consideration of Transfer from Level III Centers to Level I
or II Centers
561
booksmedicos.org
Algorithm 19-1. 2011 Guidelines for the Field Triage of the Injured Patients. Source: Sasser SM, Hunt RC, Faul M, et al. Centers for
Disease Control and Prevention. Guidelines for field triage of injured patients: recommendations of the National Expert Panel on
Field Triage, 2011. MMWR Recomm Rep 2012;61(RR-1):1–20. Available at: https://stacks.cdc.gov/view/cdc/23038/Share.
EARLY HOSPITAL CARE AND PRIORITIES

The Advanced Trauma Life Support (ATLS) program has put together a systematic, concise approach to
the care of a trauma patient. ATLS was developed by the American College of Surgeons, Committee on
Trauma (COT) and was first introduced in 1980, and is now taught in 60 countries across the world. The
562
booksmedicos.org
ATLS program provides participants with a safe, reliable method for immediate management of the
injured patient and the basic knowledge necessary to:
1. Assess the patient’s condition rapidly and accurately
2. Resuscitate and stabilize the patient according to priority
3. Determine if the patient’s needs exceed a facility’s capacity
4. Arrange appropriately for the patient’s interhospital transfer (who, what, when, and how)
5. Assure that optimum care is provided and that the level of care does not deteriorate at any point
during the evaluation, resuscitation, or transfer process.
The basic concepts of ATLS include a primary survey focusing on the ABCDE (airway, breathing,
circulation, disability, and exposure) to identify and address the life-threating issues, followed by a
secondary survey to identify all the injuries. The specific treatments of various injuries have been
addressed in the different chapters that follow. However, the key points to emphasize are that the two
main killers during the early hospital period (“golden hour”) are the same as the prehospital setting –
bleeding and TBI. As treatments for TBI remain mostly supportive, bleeding remains the number 1 cause
of preventable deaths during the first 6 hours following trauma. In a bleeding patient, the priorities are
to identify and control the source of bleeding in the shortest possible period of time. Sometimes the
bleeding source is obvious and can be controlled by direct compression (e.g., stab wound to the femoral
artery in the groin), tourniquets (e.g., mangled extremity), or sutures (e.g., scalp laceration), but often
it is inside a body cavity. Localization of the hemorrhage source is relatively easy for penetrating
trauma that is limited to a specific body region, but is notoriously difficult in the blunt polytrauma
patients. In these patients, it helps to remember that a person can only lose significant volumes of blood
in five locations: (1) pleural space, (2) intra-abdominal, (3) pelvis/retroperitoneal space, (4) soft tissues
at the site of long bone fractures/sheer injuries, and (5) externally. With a quick examination and a
chest x-ray, three of these possibilities can be easily ruled out, and the choice typically comes down to
deciding between the abdomen and the pelvis. If the pelvic x-ray shows a significant pelvic fracture then
the possibility of pelvic bleeding source is significant, and a pelvic binder should be applied promptly
(or pelvis wrapped tightly with a sheet) for appropriate fracture patterns (e.g., suitable for open book
fracture but potentially harmful for severe lateral compression). Focused assessment with sonography
for trauma (FAST) can also be helpful in determining the source of hemorrhage. If it shows free fluid in
the abdomen in a hypotensive patient then emergent laparotomy for hemorrhage control is justified.
However, FAST has been reported to have a significant false negative rate even in experienced hands.50
Although diagnostic peritoneal lavage has largely been abandoned, a bedside diagnostic peritoneal
aspiration (DPA) can be very helpful in these patients. Percutaneous DPA can be performed in 1 minute,
and it has been shown to be accurate, safe, and superior to FAST for the diagnosis of abdominal blood as
the source of hemodynamic instability in multitrauma patients.51 In addition to hemorrhage control,
massive transfusion protocol (MTP) should be activated in patients that are actively bleeding to avoid
development of trauma associated coagulopathy (TAC). Normal coagulation homeostasis depends on a
delicate balance between clot formation and breakdown. Normally, trauma tilts the balance in favor of
clot formation at the site of injuries to stop the bleeding. However, major injuries, excessive blood loss,
prolonged tissue hypoperfusion, and TBI with disruption of the blood–brain barrier have all been shown
to upset the normal coagulation homeostasis, resulting in TAC.52,53 This can manifest as abnormal clot
formation and/or excessive or rapid clot breakdown (fibrinolysis). Unless treated promptly, this
coagulopathy leads to further bleeding, which sets up a vicious cycle resulting in the “lethal triad” of
coagulopathy, acidosis, and hypothermia that is associated with an extremely high mortality.54 An
analysis of trauma-associated coagulopathy suggests that depletion coagulopathy results in
abnormalities of traditional coagulation parameters (international normalized ratio, partial
thromboplastin time) and predicts mortality, whereas fibrinolytic coagulopathy predicts infection, end-
organ failure, and mortality, without a detectable difference in international normalized ratio or partial
thromboplastin time.55
Damage Control Resuscitation (DCR) or Hemostatic Resuscitation has recently emerged as a potential
solution for the prevention and reversal of trauma-associated coagulopathy.30,56,57 This approach
advocates early hemorrhage control, permissive hypotension (until control of hemorrhage), avoidance
of crystalloids, and early use of blood components such as fresh frozen plasma (FFP) and platelets (in
1:1 or 1:2 ratios). A recent prospective randomized multi-institutional trial enrolled 680 patients with
severe trauma and major bleeding to test two different blood component ratios.22 In this study, early
administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did
563
booksmedicos.org
not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in
the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours.22
It must be emphasized, however, that high-ratio protocols do not improve survival in patients who do
not require massive transfusion (10 U of packed red blood cells [PRBCs] in 24 hours).58 In fact,
inappropriate infusion of plasma in patients who are not massively bleeding can worsen their
outcomes.59 So, while the exact ratio of PRBCs to FFP and platelets may be debatable, contemporary
resuscitation practices have moved to early delivery of component therapy in the setting of massive
bleeding, using standardized protocols (see below). Also, it should be emphasized that resuscitation is
an adjunct to early hemorrhage control and not a substitute. In a bleeding patient, initiating DCR is a
great idea, but the patient’s eventual survival depends on the ability (or inability) to obtain rapid and
reliable hemorrhage control. In addition, prevention and active reversal of hypothermia (e.g., use of
fluid warmers, body warming devices) and correction of acidosis and hypocalcemia are critically
important while resuscitation protocols are carried out.
We also know that development of a clot is just the initial part of the process, and rapid breakdown
of the clot may be equally detrimental. It has been shown that development of fibrinolysis is a highly
lethal event in severely injured patients,60,61 and treatment with blood products alone is incapable of
reversing this process. Despite ongoing debate about precise ratios of blood products,62 there is general
agreement that blood products should be administered in the form of a MTP to optimize the processes
of care and to improve outcomes. Cotton et al.63 tested the effectiveness of a trauma exsanguination
protocol by comparing patients treated with the protocol (n = 94 over 18 months) to a cohort of
similar patients admitted during the prior 18 months (n = 117). The study found that implementation
of the protocol reduced 30-day mortality (51% vs. 66%, P <0.03), decreased intraoperative crystalloid
administration (4.9 L vs. 6.7 L, P = 0.002), and reduced postoperative blood product use (2.8 U of
PRBCs vs. 8.7 U, P <0.001; 1.7 U of FFP vs. 7.9 U, P <0.001; 0.9 U of platelets vs. 5.7 U, P <0.001).
Dente et al.64 conducted a similar study of an MTP (1:1:1 ratio of platelets, FFP, and PRBCs) by
comparing matched patients during a 1-year period before and after implementation of protocol (73
patients in the protocol group and 84 matched controls). Implementation of the protocol was found to
reduce mortality in the first 24 hours (17% with MTP vs. 36% pre-MTP, P = 0.008) and at 30 days
(34% vs. 55%, P = 0.04), with a more pronounced impact in the patients with blunt trauma.64 This
study also showed that MTP patients required fewer overall transfusions of PRBCs and FFP after the
first 24 hours (2.7 vs. 9.3 U of PRBCs, P <0.0001; 3 vs. 7.5 U of FFP, P <0.05). The University of
Michigan MTP is provided for reference (Fig. 19-8).65 It should be emphasized that to be effective these
protocols should not only incorporate the best available evidence, which is constantly changing, but also
reflect the resources and realities of the individual institutions.
564
booksmedicos.org
Figure 19-8. Massive transfusion protocol (MTP). BB, blood bank; BUN, serum urea nitrogen; CBC, complete blood count; Cryo,
cryoprecipitate; FFP, fresh frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrates; Plts,
platelets; PRBCs, packed red blood cells; PT, prothrombin time; PTT, partial thromboplastin time; rFVIIa, recombinant factor VIIa.
T&S, type and screen; VS, vital signs; U/O, urine output; CVCOR, cardiovascular center operating room; DDAVP, Desmopressin (1-
desamino-8-D-arginine vasopressin); PRN, as needed (Pro re nata); ABG, arterial blood gas; D/C, discontinue. Reproduced with
permission from the University of Michigan Hospitals and Health Centers.65
LESSONS LEARNED FROM THE BATTLEFIELD

7 Every major war has catalyzed rapid advances in trauma care. As the medical systems grapple with
the challenges of taking care of massive numbers of injured people (military and civilian), often in very
austere settings, they quickly evolve, adapt, and improvise. Wars also prompt significant financial
investment by the governments in research and development, and attract some of the best minds to the
field. Many of the things (various operative interventions, drugs, fluids, dressings, rapid transport
systems, trauma teams, in-field care, and many more) that are taken for granted today in the civilian
trauma centers can be traced back to the wars of the past. Interestingly, as the war medicine improves
and evolves to take care of worse injuries, the war industry responds by developing more lethal
weaponry. Thus, the percentage of injured that die in the battlefield (Killed in action or KIA rate) has
remained relatively static during the 20th century, hovering around 25% (Table 19-6). The current
conflict is the first time in modern warfare that the KIA rate has dropped down to 10%.66,67 This
dramatic drop is clearly multifactorial in etiology, and reflects the focus on prevention strategies with
widespread use of superior protective body armor, and deployment of better-designed military vehicles.
In addition, the current ongoing conflicts have fundamentally altered how we take care of the injured,
which has resulted not only in improved survival rates but also markedly superior functional outcomes.
A brief list of the key advancements would include the following:
a. Prevention: Explosions (many due to improvised explosive devices or IEDs) have caused a greater
percentage of injuries in Iraq and Afghanistan than in any other large-scale conflict. Compared to
historical data, improvements in body armor have clearly changed the injury profile of the service
personnel.68 Kevlar helmets, protective eyewear, and body armor is now routinely used. Many direct
hits to the to the head and torso that used to be lethal in the previous wars are now potentially
survivable. TBI has become the “signature injury” of the current conflict, but increasingly large
numbers of individuals survive these injuries. An analysis of 4,623 combat explosion episodes in Iraq
565
booksmedicos.org
between March 2004 and December 2007 showed that the most frequent single injury type was a
mild TBI (10.8%).69 Other frequent injuries were open wounds in the lower extremity (8.8%) and
open wounds of the face (8.2%), which includes tympanic membrane rupture. The extremities were
the body regions most often injured (41.3%), followed by head and neck (37.4%) and torso (8.8%).
Majority of the explosions resulted in more than one injury, and the variety of injuries across nearly
every body region and injury type reflects the complex nature of explosion injuries. The fact that
large number of US military personnel involved in these explosions survive is a testament to the
sophisticated vehicle and personal body armor that is being used by the US and NATO forces, and to
superb medical care. For example, mortality from direct chest trauma has dropped down to 10% with
the most common injury pattern being pulmonary contusion rather than lethal injury to the critical
organs.70
b. Early hemorrhage control: This is another area where we have seen major improvements. At the start
of the conflict the battlefield dressings that were in the individual first aid kits were not a whole lot
different from the ones used by the Roman Legions centuries ago. Cotton-based compression
dressings and tourniquets had not changed much until the start of the conflict but then underwent a
very rapid evolution. A number of advanced hemostatic bandages were quickly developed, rigorously
tested, and expeditiously deployed by the military.71 These advanced hemostatic dressings were
widely used during the early years of the Iraq and Afghanistan wars and saved many lives. Since
then, second generation dressings have been developed and tested,72 and incorporated into the
Tactical Combat Casualty Care (TCCC) guidelines.73,74 Many of these dressings that were developed
for military use are now widely available, and are commonly used by the civilian emergency medical
response providers. When anatomically possible, even more secure hemorrhage control can be
obtained by placing a tourniquet. A review of 10 years of data from a military registry showed that
of 4,297 casualties with extremity trauma, 30% underwent application of tourniquets.75 Over this
period, tourniquet use increased by 10-fold, and survival rates improved markedly for casualties that
had injuries suitable for tourniquets. Typical tourniquets are not effective for really proximal
injuries,76 but in recent years, a number of junctional tourniquets have been developed, and two of
these [Combat Ready Clamp (CRoC; http://www.combatmedicalsystems.com) and SAM Junctional
Tourniquet (SJT; http://www.sammedical.com/products)] performed well when tested by military
medics.77 Development of advanced dressings and new military tourniquet (windlass devices that can
be self-applied and tightened using a single hand) has changed early battlefield care.78 However,
civilian trauma systems have been alarmingly slow in adopting these lessons and developing uniform
guidelines.79 This was at full display after the Boston Marathon bombing when most of the
tourniquets used were improvised (and inefficient) devices rather than the military versions.80 Our
experiences with mass casualties underline how important it is for all the emergency medical
personnel and physicians to learn the proper use of tourniquets and advanced hemostatic dressings.
Austere military settings with focus on damage control procedures have also generated interest in the
use of intraluminal occlusive balloons.81 A variety of balloons and catheters have historically been
used by trauma and vascular surgeons for the temporary control of bleeding. Recently, this concept
has been taken to the next level as a result of collaborative efforts between the civilian and military
surgeons, where the aorta (thoracic or abdominal) is controlled with the bedside application of a
resuscitative endovascular balloon occlusion of the aorta (REBOA) device.82 The balloon-carrying
catheter can be inserted using percutaneous techniques, typically via the femoral artery, advanced
(without need for fluoroscopy) into the aorta, and inflated to interrupt the aortic flow below the
balloon. In this way, REBOA functions essentially similar to an aortic cross-clamp that is applied
during resuscitative thoracotomy. Although these tools are not yet widely used, courses have been
developed to teach these new life-saving skills to the surgical community.83 While the strategy is
promising,84 and good results have been reported by the US trauma centers,85 data from Japan where
emergency medicine physicians typically use the REBOA technology have shown some concerning
outcomes.86 Wider use would require additional work to identify the best target population, the most
effective method for deployment, and optimal training requirement for the users.
Table 19-6 Lethality of War Wounds among US Soldiers
566
booksmedicos.org
c. DCR/Prevention and treatment of coagulopathy: Just like massive crystalloid resuscitation has been
associated with the Vietnam war, where “shock lung/Da Nang lung” (later termed acute respiratory
distress syndrome or ARDS) was first described in soldiers that received massive crystalloid
resuscitation, the current conflict would be remembered for advancing the concept of DCR. The
pendulum has clearly swung toward balanced resuscitation, in large parts based upon the battlefield
resuscitation practices. It is informative to briefly review how our clinical practices changed during
the war even in the absence of good class I/II clinical evidence. It should also be pointed out that
logistical issues (weight, volume, storage requirements etc.) are often a major driver of change in the
military. Historically, many DoD agencies, such as the Office of Naval Research (ONR), the US Army
Medical Research and Material Command (MRMC), and Defense Advanced Research Projects Agency
(DARPA) just to name a few, have been long-standing sponsors of resuscitation research. Primarily as
a result of leadership and funding by the ONR, three significant consensus conferences were held
where experts analyzed the available data on fluid resuscitation, and recommendations were made to
improve clinical practice and to guide future research. The first meeting was held under the
supervision of the Institute of Medicine (IOM) in 1998. The IOM report concluded that the current
resuscitation strategies were inadequate, potentially harmful, and needed radical changes. It
identified numerous areas of future research, and recommended that combat casualties should be
resuscitated with 250 mL bolus of 7.5% saline.87 Unfortunately, the US Food and Drug Administration
(FDA) had not approved this fluid for clinical use. In the follow-up meeting (June 2001, Uniformed
Services University, Bethesda, MD) a number of clinical recommendations were made including who
should (and should not) be resuscitated, appropriate end points of resuscitation, as well as the
optimal fluid for resuscitation.88 As the choice was deliberately limited to FDA-approved agents
(available in the United States), Hetastarch (hydroxyethyl starch) was narrowly recommended as the
fluid of choice for use in the battlefield. In the third meeting (October 2001, Toronto, Canada), the
scope was widened to include fluids that were available in the NATO countries (even if not available
in the United States).89 At that meeting a combination fluid (7.5% saline and 6% dextran-hypertonic
saline dextran) was recommended as the initial fluid of choice.90 At all of these meetings experts
agreed that aggressive resuscitation is deleterious, an “ideal” fluid is yet not available, and that low-
volume resuscitation (hypertonic, colloid, or combination) is the most logical choice for the military
needs. Proceedings of the last two meetings were published as a special supplement of the Journal of
Trauma (May 2003), including the recommendations for the initial fluid resuscitation of combat
casualties.91 Over the next decade, the concepts of DCR became more well established, and this
change is clearly reflected in the latest recommendations by the Tactical Combat Casualty Care
guidelines for Fluid Resuscitation for Hemorrhagic Shock92: “(1) dried plasma (DP) is added as an
option when other blood components or whole blood are not available; (2) the wording is clarified to
emphasize that Hextend is a less desirable option than whole blood, blood components, or DP and
should be used only when these preferred options are not available; (3) the use of blood products in
certain Tactical Field Care (TFC) settings where this option might be feasible (ships, mounted
patrols) is discussed; (4) 1:1:1 DCR is preferred to 1:1 DCR when platelets are available as well as
plasma and red cells; and (5) the 30-minute wait between increments of resuscitation fluid
administered to achieve clinical improvement or target blood pressure (BP) has been eliminated. Also
567
booksmedicos.org
included is an order of precedence for resuscitation fluid options. Maintained as recommendations are
an emphasis on hypotensive resuscitation in order to minimize (1) interference with the body’s
hemostatic response and (2) the risk of complications of over resuscitation. Hextend is retained as the
preferred option over crystalloids when blood products are not available because of its smaller
volume and the potential for long evacuations in the military setting.” It should be pointed out that
although these guidelines have been designed specifically for the battlefield environment, many of
these recommendations are now becoming an integral part of the civilian trauma care (e.g.,
avoidance of crystalloids, early blood product use, high ratios of plasma and platelets to red cells).
Many of the landmark studies such as PROMMTT57 and PROPPR,22 were also supported by the DoD
funds, and their findings have significantly changed our practices. Another area where military data
have advanced the field is in defining the appropriate use of antifibrinolytic agents. An organized
clot, histologically, is a clump of blood cells in a mesh of fibrin strands, which is the final product of
the coagulation cascades. Plasmin breaks down the fibrin strands to initiate clot resolution. Normally,
clot formation and breakdown are precisely balanced to prevent excessive thrombosis or
coagulopathy. Trauma-associated coagulopathy disrupts this balance and leads to poor clot formation
and rapid breakdown. Antifibrinolytic drugs such as aprotinin, tranexamic acid (TXA), and ε-
aminocaproic acid stabilize the blood clot, which can slow down the bleeding. Due to safety concerns,
aprotinin was withdrawn from world markets in May 2008, but TXA and ε-aminocaproic acid are in
fairly wide clinical use and appear to be free of serious adverse effects.93 TXA is a lysine analog that
binds with plasminogen to prevent its activation,94 and in higher concentrations is a noncompetitive
inhibitor of plasmin (actions similar to those of ε-aminocaproic acid but about 10 times more potent
in vitro). In the recent Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage
(CRASH-2) trial,27 which is one of the largest prospective randomized trials in trauma patients,
20,211 patients at 274 hospitals in 40 countries (mostly underdeveloped) were randomized to receive
either TXA or placebo within 8 hours of injury. All-cause mortality in TXA-treated patients was
significantly lower compared with placebo (14.5% and 16% in TXA and control groups, respectively;
P = 0.0035), as was the risk due to bleeding (4.9% and 5.7% in TXA and control groups,
respectively; P = 0.0077). Subgroup analysis showed that the benefit was found only in patients who
were given the drug early (within 3 hours of injury) and were severely hypotensive (SBP ≤75 mm
Hg). Skeptics point out that the overall survival improvement, although statistically significant, was
rather modest (1.5%). There were some other concerns, including the fact that only half the patients
in this study required any blood transfusion, suggesting that most were not severely injured. As this
study was conducted in developing countries where DCR is not in common use, it is unclear how the
results would be influenced by early use of blood component therapy. Critical data about the
physiological status of the patients, monitoring methods, blood loss, imaging studies, operative
interventions, and complications were not gathered. Also, the role of TXA in the setting of TBI was
not determined as only one-third of the patients had a Glasgow Coma Scale score of 12 or lower on
admission. Finally, this study was not designed to identify underlying protective mechanisms. These
limitations led some experts (military and civilian) to question the robustness and generalizability of
the findings, especially in the setting of massive bleeding.95 In this area of uncertainty, new data
from the battlefield have helped clarify the way forward. One important study was a retrospective
observational analysis of prospectively collected data in 896 battlefield casualties (377 civilian and
519 military patients) who received at least 1 U of PRBCs (within 24 hours of admission) at a
military hospital in Afghanistan.9 A third of the patients received massive transfusion (≥10 units of
PRBC). Unadjusted mortality rates were lower in TXA-treated patients (17.4% and 23.9% in TXA and
no-TXA groups, respectively; P = 0.03). The benefit was most pronounced in patients who received
massive transfusion (14.4% and 28.1% in TXA and no-TXA groups, respectively; P = 0.004). TXA
was also independently associated with higher odds of survival (odds ratio = 7.2) and less
coagulopathy (P = 0.003). A follow-up study (Military Application of Tranexamic Acid in Trauma
Emergency Resuscitation [MATTERs II]) showed that the addition of cryoprecipitate independently
added to the benefits of TXA in the seriously injured in the battlefield.97 A closer look at the data
from these studies raises some potential safety concerns. In CRASH-2, mortality due to bleeding
increased if TXA treatment was given after 3 hours (3.1% and 4.4%, in <3 hours and >3 hours,
respectively; P = 0.0049). In the MATTERs trial, a statistically significant increase was noted in
pulmonary embolism (TXA 2.7% vs. no TXA 0.3%, P = 0.001) and deep venous thrombosis (TXA
2.4% vs. no TXA 0.2%, P = 0.001). It is unclear whether this simply reflects sicker patients in the
TXA group or a real increase in the incidence of adverse events. Experts in the field have therefore
568
booksmedicos.org
developed evidence-based guidelines for the use of TXA98 that recommend the use of TXA in adult
trauma patients with severe hemorrhagic shock (SBP <75 mm Hg), with known predictors of
fibrinolysis, or with documented fibrinolysis on thromboelastography. In these patients, TXA should
be administered only if the time from injury is less than 3 hours, and the dose of TXA should be 1 g
over 10 minutes followed by another 1-g IV infusion over 8 hours. Although we are likely to see
ongoing debates about the concepts of DCR and whether and when to use adjunctive agents such as
TXA, cryoprecipitate, desmopressin, and prothrombin complex concentrates, the research supported
either directly or indirectly by the military over the last 10 to 15 years has clearly changed how we
treat the massively bleeding patients today (Fig. 19-8).
d. Rapid Evacuation and Long-distance Transport: Rapid air evacuation by specially trained teams was
popularized by the US military in the Korean War with great results. Although the war patterns have
changed to be more urban, nonlinear, and with a smaller foot-print, rapid evacuation is no less
important in the current era. In fact, after the US Secretary of Defense Robert M. Gates mandated in
2009 that the prehospital helicopter transport of critically injured combat casualties should be 60
minutes or less, the evacuation systems became even more efficient. An analysis of battlefield data
(21,089 US military casualties) before and after the mandate showed that for the total casualty
population, the percentage killed in action (16.0% [386 of 2411] vs. 9.9% [964 of 9755]; P < 0.001)
and the case fatality rate ([CFR] 13.7 [469 of 3429] vs. 7.6 [1344 of 17660]; P <0 .001) were higher
before versus after the mandate, while the percentage died of wounds (4.1% [83 of 2025] vs. 4.3%
[380 of 8791]; P = 0.71) remained unchanged.99 Decline in CFR after the mandate was associated
with an increasing percentage of casualties transported in 60 minutes or less (regression coefficient,
−0.141; P <0 .001), with projected versus actual CFR equating to 359 lives saved. Among 4,542
casualties (mean injury severity score, 17.3; mortality, 10.1% [457 of 4542]) with detailed data,
there was a decrease in median transport time after the mandate (90 min vs. 43 min; P <0.001) and
an increase in missions achieving prehospital helicopter transport in 60 minutes or less (24.8% [181
of 731] vs. 75.2% [2867 of 3811]; P <0 .001). Even more impressive are the results of long-distance
transport. One of the unique aspects of the military medical care system that emerged during
Operation Iraqi Freedom and Operation Enduring Freedom has been the opportunity to apply existing
civilian trauma system standards to the provision of combat casualty care across an evolving theater
of operations. Review of the Critical Care Air Transport Team (CCATT) and Joint Theater Trauma
Registry databases shows that for severely injured (mean ISS 23.7) that were evacuated to Landstuhl
Regional Medical Center in Germany, the en route mortality rate was less than 0.02%.100 This is a
huge testament to the superb skills, tools, training, and resources that the military has provided for
the care of the injured. It also proves that rapid movement of critically injured casualties within
hours of wounding appears to be effective, with a minimal mortality incurred during transport and
overall 30-day mortality of 2%.100 Many of these lessons will be translated into the general trauma
practice as these medics and physicians transition to civilian work.
e. Rehabilitation: Lower-extremity injuries continue to be the most common injuries in the current
conflict. In fact, they account for 60% of all injuries to the US troops in Iraq and Afghanistan, which
are to the lower extremities, mostly due to explosive devices.101 But unlike previous wars, the tools
and technologies available today are markedly different. Not only are temporary vascular shunts
being used widely,102,103 but also early vascular reconstruction is being performed more frequently
with excellent outcomes.104,105 Liberal use of temporary vascular shunts to control bleeding and
restore distal flow during transport to higher echelons of care is clearly a logical approach. It is also a
practical solution when dealing with combined vascular and orthopedic injuries, and when the
surgeon providing the initial care lacks the skills to perform the definitive vascular repairs.106
Development and implementation of comprehensive rehabilitation strategies,107 and cutting edge
technology in prosthetic limbs108 to treat the injured service members with complex lower-extremity
trauma from combat has resulted in some of the best functional outcomes in the history of warfare.
The civilian trauma system would clearly be the beneficiary of these developments in the future.
NEW DEVELOPMENTS IN INTRACAVITY HEMORRHAGE CONTROL

Current trauma training and equipment is sufficient to care for 53% of the potentially survivable deaths,
but novel methods of intravenous or intracavitary noncompressible hemostasis (combined with rapid
surgery) are required for the remaining 47% of the decedents.109 This is the next frontier in hemorrhage
569
booksmedicos.org
control, and many researchers are addressing the challenge of controlling intracavity bleeding especially
in the prehospital setting. There was some initial enthusiasm for using systemic therapies such as
recombinant clotting factors (factor VIIa), but randomized clinical trials have failed to show a benefit in
trauma patients.110 Recently, the focus has shifted to local/mechanical methods. In addition to devices
such as REBOA,86 approaches such as expanding foams,111,112 insufflation,113 and compression devices114
are being tested. If successful, these could be the game changers that we have been looking for decades.
FUTURE DIRECTIONS
Despite numerous advances, we have failed to make a significant impact on the early trauma deaths.
Many of these individuals have underlying injuries that are potentially survivable, but they die before
getting definitive care. While resuscitation restores tissue perfusion, it does not have any specific
prosurvival properties. By the time the injured gets to the hospital nothing can be done to reverse the
“irreversible shock.” A much more exciting approach would be to improve the survival by administering
specific pharmacological agents in the field that could immediately upregulate prosurvival genes and
proteins to create a prosurvival phenotype,115 or use strategies to induce a state of “suspended animation”
to keep the organs preserved until the source of hemorrhage can be controlled.116,117
In the not too distant future, early trauma resuscitation may be very different from what we currently
practice. In addition to early hemorrhage control and DCR, we are also likely to see:
a. Use of specific prosurvival drugs that can be given in the prehospital setting to keep the injured alive
long enough to get evacuated to higher levels of care (effective “bridge to definitive care”).
b. Early use of preserved plasma products, platelets, and red blood cells.
c. Availability of blood “farming” to eliminate the logistical barriers to supply.
d. Development of safe and effective nonblood oxygen carrying fluids that can be easily administered.
e. Ability to temporarily “suspend” life using hypothermia or hibernation strategies for patients that
have potentially survivable injuries, but need more time for surgery or transfer.
f. Individualized therapy with administration of specific pharmacological agents based upon the
individual’s cellular disturbances.
g. Monitoring of response to therapy that goes beyond measurement of physiology, and looks at the
reversal of cellular disturbances.
References
1. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg
2014;260(1):13–21.
2. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control.
Web-based Injury Statistics Query and Reporting System (WISQARS) Nonfatal Injury Data. (2015).
http://www.cdc.gov/injury/wisqars/nonfatal.html. Last accessed 4.25.16
3. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control.
Web-based Injury Statistics Query and Reporting System (WISQARS) Fatal Injury Data. (2015).
http://www.cdc.gov/injury/wisqars/fatal.html. Last accessed 4.25.16
4. Florence C, Simon T, Haegerich T, et al. Estimated lifetime medical and work loss costs of fatal
injury, United States 2013. MMWR 2015;64(38).
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6438a4.htm?s_cid=mm6438a4_w. Last
accessed 4.25.16
5. World Health Organization. Injuries and Violence: the Facts 2014.
http://www.who.int/violence_injury_prevention/media/news/2015/Injury_violence_facts_2014/en/.
Last accessed 4.25.16
6. Xu J, Murphy SL, Kochanek KD, et al. Deaths: final data for 2013. National Vital Statistics Reports.
2016;64(2):84–85.
7. US Department of Transportation. NHTSA. 2014 Motor Vehicle Crashes: Overview. http://www-
nrd.nhtsa.dot.gov/Pubs/812246.pdf. Last accessed 4.25.16.
8. Centers for Disease Control and Prevention, National Center for Health Statistics. Suicide Rates for
Females and Males by Race and Ethnicity: United States, 1999 and 2014.
570
booksmedicos.org
http://www.cdc.gov/nchs/data/hestat/suicide/rates_1999_2014.htm. Last accessed 4.25.16.
9. Halaweish I, Alam HB. Changing demographics of the American population. Surg Clin North Am
2015;95(1):1–10.
10. Vincent GK, Velkoff VA. The next four decades, the older population in the United States: 2010 to
2050. Current Population Reports, page 25–1138. Washington, DC: US Census Bureau; 2010.
https://www.census.gov/prod/2010pubs/p25–1138.pdf. Last accessed 4.25.16.
11. DeGrauw X, Annest JL, Stevens JA, et al. Unintentional injuries treated in hospital emergency
departments among persons aged 65 years and older, United States, 2006–2011. J Safety Res
2016;56:105–109.
12. Ramly E, Kaafarani HM, Velmahos GC. The effect of aging on pulmonary function. Implications for
monitoring and support of the surgical and trauma patients. Surg Clin N Am 2015;95(1):53–69.
13. Federal Bureau of Investigation. Uniform Crimes Reports. www.fbi.gov/about-us/cjis/ucr/crime-in-
the-u.s/2013/crime-in-the-u.s.-2013/violent-crime/violent-crime-topic-page/violentcrimemain_final.
Last accessed 4.25.16.
14. Trunkey DD. Trauma. Sci Am 1983;249:28–35.
15. Celso B, Tepas J, Langland-Orban B, et al. A systematic review and meta-analysis comparing
outcome of severely injured patients treated in trauma centers following the establishment of
trauma systems. J Trauma 2006;60(2):371–378.
16. MacKenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma-center
care on mortality. N Engl J Med 2006;354(4):366–378.
17. Gunst M, Ghaemmaghami V, Gruszecki A, et al. Changing epidemiology of trauma deaths leads to a
bimodal distribution. Proc (Bayl Univ Med Cent) 2010;23(4):349–354.
18. Dellinger RP, Levy MM, Rhodes A, et al; Surviving Sepsis Campaign Guidelines Committee
including the Pediatric Subgroup. Surviving sepsis campaign: international guidelines for
management of severe sepsis and septic shock: 2012. Crit Care Med 2013;41(2):580–637.
19. Levy MM, Rhodes A, Phillips GS, et al. Surviving Sepsis Campaign: association between
performance metrics and outcomes in a 7.5-year study. Crit Care Med 2015;43(1):3–12.
20. Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress
syndrome. Cochrane Database Syst Rev 2013;2:CD003844.
21. Plurad D, Martin M, Green D, et al. The decreasing incidence of late posttraumatic acute
respiratory distress syndrome: the potential role of lung protective ventilation and conservative
transfusion practice. J Trauma 2007;63(1):1–7.
22. Holcomb JB, Tilley BC, Baraniuk S, et al; PROPPR Study Group. Transfusion of plasma, platelets,
and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the
PROPPR randomized clinical trial. JAMA 2015;313(5):471–482.
23. Shackford SR, Mackersie RC, Holbrook TL, et al. The epidemiology of trauma death: a population
based analysis. Arch Surg 1993;128:571–575.
24. Sauaia A, Moore FA, Moore EE, et al. Epidemiology of trauma deaths: a reassessment. J Trauma.
1995;38:185–193.
25. Acosta JA, Yang JC, Winchell RJ, et al. Lethal injuries and time to death in a level I trauma center.
J Am Coll Surg 1998;186:528–533.
26. Demetriades D, Murray J, Charalambides K, et al. Trauma fatalities: time and location of hospital
deaths. J Am Coll Surg 2004;198:20–26.
27. CRASH-2 trial collaborators. Effects of tranexamic acid on death, vascular occlusive events, and
blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised,
placebo-controlled trial. Lancet 2010;376:23–32.
28. Eastridge BJ, Mabry RL, Seguin P, et al. Death on the battlefield (2001–2011): implications for the
future of combat casualty care. J Trauma Acute Care Surg 2012;73(6 suppl 5):S431–S437.
29. Eastridge BJ, Hardin M, Cantrell J, et al. Died of wounds on the battlefield: causation and
implications for improving combat casualty care. J Trauma 2011;71(1 suppl):S4–S8.
30. Alam HB, Velmahos GC. New trends in resuscitation. Curr Probl Surg 2011;48:531–564.
31. Mattox KL, Feliciano DV. Role of external cardiac compression in truncal trauma. J Trauma
1982;22:934–936.
571
booksmedicos.org
32. Liberman M, Mulder D, Sampalis J. Advanced or basic life support for trauma: meta-analysis and
critical review of the literature. J Trauma 2000;49:584–599.
33. Bickell WH, Wall MJ, Pepe PE, et al. Immediate versus delayed fluid resuscitation for hypotensive
patients with penetrating torso injuries. N Engl J Med 1994;331:1105–1109.
34. Santry H, Alam HB. Fluid resuscitation: past, present and the future. Shock 2010;33:229–241.
35. Kevric J, O’Reilly GM, Gocentas RA, et al. Management of haemodynamically stable patients with
penetrating abdominal stab injuries: review of practice at an Australian major trauma centre. Eur J
Trauma Emerg Surg 2015.
36. Peev MP, Chang Y, King DR, et al. Delayed laparotomy after selective non-operative management
of penetrating abdominal injuries. World J Surg 2015;39(2):380–386.
37. Lamb CM, Garner JP. Selective non-operative management of civilian gunshot wounds to the
abdomen: a systematic review of the evidence. Injury 2014;45(4):659–666.
38. Zafar SN, Rushing A, Haut ER, et al. Outcome of selective non-operative management of
penetrating abdominal injuries from the North American National Trauma Database. Br J Surg
2012;99 Suppl 1:155–164.
39. Burgess CA, Dale OT, Almeyda R, et al. An evidence based review of the assessment and
management of penetrating neck trauma. Clin Otolaryngol 2012;37(1):44–52.
40. Sierink JC, Saltzherr TP, Beenen LF, et al.; REACT-2 study group. A multicenter, randomized
controlled trial of immediate total-body CT scanning in trauma patients (REACT-2). BMC Emerg
Med 2012;12:4.
41. Salim A, Sangthong B, Martin M, et al. Whole body imaging in blunt multisystem trauma patients
without obvious signs of injury: results of a prospective study. Arch Surg 2006;141(5):468–473.
42. Inaba K, Okoye OT, Rosenheck R, et al. Prospective evaluation of the role of computed tomography
in the assessment of abdominal stab wounds. JAMA Surg 2013;148(9):810–816.
43. Demetriades D, Hadjizacharia P, Constantinou C, et al. Selective nonoperative management of
penetrating abdominal solid organ injuries. Ann Surg 2006;244(4):620–628.
44. American College of Surgeons, Committee on Trauma. Resources for Optimal Care of the Injured
Patient-2014. https://www.facs.org/
∼/media/files/quality%20programs/trauma/vrc%20resources/resources%20for%20optimal%20care%202014%
Last accessed 4.26.16.
45. Sasser SM, Hunt RC, Faul M, et al; Centers for Disease Control and Prevention. Guidelines for field
triage of injured patients: recommendations of the National Expert Panel on Field Triage, 2011.
MMWR Recomm Rep 2012;61(RR-1):1–20. Available at: www.facs.org/quality-
programs/trauma/vrc/resources
46. Kwan I, Bunn F, Roberts I. Timing and volume of fluid administration for patients with bleeding.
Cochrane Database of Systematic Reviews 2003;(3):Art. No.: CD002245.
47. Schreiber MA, Meier EN, Tisherman SA, et al.; ROC Investigators. A controlled resuscitation
strategy is feasible and safe in hypotensive trauma patients: results of a prospective randomized
pilot trial. J Trauma Acute Care Surg 2015;78(4):687–695.
48. Seamon MJ, Doane SM, Gaughan JP, et al. Prehospital interventions for penetrating trauma
victims: a prospective comparison between Advanced Life Support and Basic Life Support. Injury
2013;44(5):634–638.
49. Rappold JF, Hollenbach KA, Santora TA, et al. The evil of good is better: Making the case for basic
life support transport for penetrating trauma victims in an urban environment. J Trauma Acute Care
Surg 2015;79(3):343–348.
50. Miller MT, Pasquale MD, Bromberg WJ, et al. Not so FAST. J Trauma 2003;54(1):52–59.
51. Kuncir EJ, Velmahos GC. Diagnostic peritoneal aspiration—the foster child of DPL: a prospective
observational study. Int J Surg 2007;5(3):167–171.
52. Sixta SL, Hatch QM, Matijevic N, et al. Mechanistic determinates of the acute coagulopathy of
trauma (ACoT) in patients requiring emergency surgery. Int J Burns Trauma 2012;2:158–166.
53. Frith D, Brohi K. The pathophysiology of trauma-induced coagulopathy. Curr Opin Crit Care
2012;18:631–636.
54. Gerecht R. The lethal triad. Hypothermia, acidosis & coagulopathy create a deadly cycle for trauma
patients. JEMS 2014;39(4):56–60.
572
booksmedicos.org
55. Kutcher ME, Ferguson AR, Cohen MJ. A principal component analysis of coagulation after trauma.
J Trauma Acute Care Surg 2013;74:1223–1230.
56. Dutton RP. Haemostatic resuscitation. Br J Anaesth 2012;109(suppl 1):i39–i46.
57. Holcomb JB, del Junco DJ, Fox EE, et al.; PROMMTT Study Group. The prospective, observational,
multicenter, major trauma transfusion (PROMMTT) study: comparative effectiveness of a time-
varying treatment with competing risks. JAMA Surg 2013;148(2):127–136.
58. Sambasivan CN, Kunio NR, Nair PV, et al. High ratios of plasma and platelets to packed red blood
cells do not affect mortality in nonmassively transfused patients. J Trauma 2011;71(2 suppl
3):S329–S336.
59. Inaba K, Branco BC, Rhee P, et al. Impact of plasma transfusion in trauma patients who do not
require massive transfusion. J Am Coll Surg 2010;210:957–965.
60. Ives C, Inaba K, Branco BC, et al. Hyperfibrinolysis elicited via thromboelastography predicts
mortality in trauma. J Am Coll Surg 2012;215:496–502.
61. Cotton BA, Harvin JA, Kostousouv V, et al. Hyperfibrinolysis at admission is an uncommon but
highly lethal event associated with shock and prehospital fluid administration. J Trauma Acute Care
Surg 2012;73:365–370.
62. Gregory JA, Huitron SS, George AA, et al. Optimizing transfusion ratios in massive transfusion
protocols: An argument against the 1:1:1 dogma and approach to trauma resuscitation. Lab Med
2015 Spring;46(2):e46–e52.
63. Cotton BA, Gunter OL, Isbell J, et al. Damage control hematology: the impact of a trauma
exsanguination protocol on survival and blood product utilization. J Trauma 2008; 64:1177–1182.
64. Dente CJ, Shaz BH, Nicholas JM, et al. Improvements in early mortality and coagulopathy are
sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a
civilian level I trauma center. J Trauma 2009;66:1616–1624.
65. University of Michigan Hospitals and Health Centers. Massive transfusion protocol.
https://www.pathology.med.umich.edu/static/apps/cms/ckfinder/userfiles/238/files/Massive%20Transfusion%
Accessed 4.27.16
66. Gawande A. Casualties of war—military care for the wounded from Iraq and Afghanistan. N Engl J
Med 2004;351:2471–2475
67. U.S. casualty status. Washington, D.C.: Department of Defense; 2004. (Accessed April 27, 2016, at
http://www.defenselink.mil/news/casualty.pdf.)
68. Breeze J, Lewis EA, Fryer R, et al. Defining the essential anatomical coverage provided by military
body armour against high energy projectiles. J R Army Med Corps 2015. pii: jramc-2015–000431.
69. Eskridge SL, Macera CA, Galarneau MR, et al. Injuries from combat explosions in Iraq: injury type,
location, and severity. Injury 2012;43(10):1678–1682.
70. Keneally R, Szpisjak D. Thoracic trauma in Iraq and Afghanistan. J Trauma Acute Care Surg
2013;74(5):1292–1297.
71. Pusateri AE, Holcomb JB, Kheirabadi BS, et al. Making sense of the preclinical literature on
advanced hemostatic products. J Trauma 2006;60(3):674–682.
72. Kheirabadi BS, Scherer MR, Estep JS, et al. Determination of efficacy of new hemostatic dressings
in a model of extremity arterial hemorrhage in swine. J Trauma 2009;67(3):450–459.
73. Sims K, Montgomery HR, Dituro P, et al. Management of external hemorrhage in tactical combat
casualty care: The adjunctive use of XStat™ compressed hemostatic sponges: TCCC guidelines
change 15–03. J Spec Oper Med 2016 Spring;16(1):19–28.
74. Bennett BL, Littlejohn LF, Kheirabadi BS, et al. Management of external hemorrhage in tactical
combat casualty care: Chitosan-based hemostatic gauze dressings - TCCC guidelines-change 13–05. J
Spec Oper Med 2014 Fall;14(3):40–57.
75. Kragh JF Jr, Dubick MA, Aden JK, et al. U.S. Military use of tourniquets from 2001 to 2010.
Prehosp Emerg Care 2015;19(2):184–190.
76. Kragh JF Jr, Dubick MA, Aden JK 3rd, et al. U.S. Military experience with junctional wounds in
war from 2001 to 2010. J Spec Oper Med 2013;13(4):76–84.
77. Kragh JF Jr, Parsons DL, Kotwal RS, et al. Testing of junctional tourniquets by military medics to
control simulated groin hemorrhage. J Spec Oper Med 2014;14(3):58–63.
78. Butler FK. Military history of increasing survival: The U.S. military experience with tourniquets and
573
booksmedicos.org
hemostatic dressings in the Afghanistan and Iraq conflicts. Bull Am Coll Surg 2015;100(1 Suppl):60–
64.
79. Ramly E, Runyan G, King DR. The state of the union: Nationwide absence of uniform guidelines for
the prehospital use of tourniquets to control extremity exsanguination. J Trauma Acute Care Surg
2016;80(5):787–791.
80. King DR, Larentzakis A, Ramly EP; Boston Trauma Collaborative. Tourniquet use at the Boston
Marathon bombing: Lost in translation. J Trauma Acute Care Surg 2015;78(3):594–599.
81. Holcomb JB, Fox EE, Scalea TM, et al. Current opinion on catheter-based hemorrhage control in
trauma patients. J Trauma Acute Care Surg 2014; 76(3):888–893.
82. Brenner ML, Moore LJ, DuBose JJ, et al. A clinical series of resuscitative endovascular balloon
occlusion of the aorta for hemorrhage control and resuscitation. J Trauma Acute Care Surg
2013;75(3):506–511.
83. Villamaria CY, Eliason JL, Napolitano LM, et al. Endovascular Skills for Trauma and Resuscitative
Surgery (ESTARS) course: curriculum development, content validation, and program assessment. J
Trauma Acute Care Surg 2014;76(4):929–935.
84. Williams TK, Neff LP, Johnson MA, et al. Extending REBOA: Endovascular Variable Aortic Control
(EVAC) in a lethal model of hemorrhagic shock. J Trauma Acute Care Surg 2016. Apr 8. [Epub ahead
of print]
85. DuBose JJ, Scalea TM, Brenner M, et al; AAST AORTA Study Group. The AAST Prospective Aortic
Occlusion for Resuscitation in Trauma and Acute Care Surgery (AORTA) Registry: Data on
contemporary utilization and outcomes of aortic occlusion and resuscitative balloon occlusion of the
aorta (REBOA). J Trauma Acute Care Surg 2016 Apr 5. [Epub ahead of print]
86. Inoue J, Shiraishi A, Yoshiyuki A, et al. Resuscitative endovascular balloon occlusion of the aorta
might be dangerous in patients with severe torso trauma: A propensity score analysis. J Trauma
Acute Care Surg 2016 Apr;80(4):559–567.
87. Committee on fluid resuscitation for combat casualties. Fluid resuscitation: state of the science for
treating combat casualties and civilian trauma. Report of the Institute of Medicine. Washington,
DC: National Academy Press; 1999.
88. Uniformed Services University of the Health Sciences. Combat Fluid Resuscitation. Bethesda, MD:
Sponsored by US Office of Naval Research; US Army Medical Research and Material Command;
Department of Surgery; Department of Military and Emergency Medicine; 2001.
89. Defense and Civil Institute of Environmental Medicine. Fluid Resuscitation in Combat. Toronto,
Ontario: Sponsored by Defense R & D Canada, Defense and Civil Institute of Environmental
Medicine, Department of Surgery, University of Toronto; and the Office of Naval Research; —2001.
90. Champion HR. Combat fluid resuscitation: Introduction and overview of conferences. J Trauma
2003;54(supp):7–12.
91. Rhee P, Koustova E, Alam HB. Searching for the optimal resuscitation method: recommendations
for the initial fluid resuscitation of combat casualties. J Trauma 2003;54(supp):52–62.
92. Butler FK, Holcomb JB, Schreiber MA, et al. Fluid resuscitation for hemorrhagic shock in tactical
combat casualty care: TCCC guidelines change 14–01 - 2 June 2014. J Spec Oper Med 2014
Fall;14(3):13–38.
93. Henry DA, Carless PA, Moxey AJ, et al. Anti-fibrinolytic use for minimising perioperative
allogeneic blood transfusion. Cochrane Database Syst Rev 2011;(3):CD001886.
94. Silva MM, Thelwell C, Williams SC, et al. Regulation of fibrinolysis by C-terminal lysines operates
through plasminogen and plasmin but not tissue plasminogen activator (tPA). J Thromb Haemost
2012;10:2354–2360.
95. Pusateri AE, Weiskopf RB, Bebarta V, et al.; The US DoD Hemorrhage and Resuscitation Research
and Development Steering Committee. Tranexamic acid and trauma: current status and knowledge
gaps with recommended research priorities. Shock 2013;39:122–126.
96. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military application of tranexamic acid in trauma
emergency resuscitation (MATTERs) study. Arch Surg 2012;147:113–119.
97. Morrison JJ, Ross JD, Dubose JJ, et al. Association of cryoprecipitate and tranexamic acid with
improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg
2013;148:218–225.
574
booksmedicos.org
98. Napolitano LM, Cohen MJ, Cotton BA, et al. Tranexamic acid in trauma: how should we use it? J
Trauma Acute Care Surg 2013;74:1575–1586.
99. Kotwal RS, Howard JT, Orman JA, et al. The effect of a golden hour policy on the morbidity and
mortality of combat casualties. JAMA Surg 2016;151(1):15–24.
100. Ingalls N, Zonies D, Bailey JA, et al. A review of the first 10 years of critical care aeromedical
transport during operation Iraqi freedom and operation enduring freedom: the importance of
evacuation timing. JAMA Surg 2014;149(8):807–813.
101. Connolly M, Ibrahim ZR, Johnson ON 3rd. Changing paradigms in lower extremity reconstruction
in war-related injuries. Mil Med Res 2016;3:9.
102. Gifford SM, Aidinian G, Clouse WD, et al. Effect of temporary shunting on extremity vascular
injury: an outcome analysis from the Global War on Terror vascular injury initiative. J Vasc Surg
2009;50(3):549–555
103. Rasmussen TE, Clouse WD, Jenkins DH, et al. The use of temporary vascular shunts as a damage
control adjunct in the management of wartime vascular injury. J Trauma 2006;61(1):8–12.
104. Vertrees A, Fox CJ, Quan RW, et al. The use of prosthetic grafts in complex military vascular
trauma: a limb salvage strategy for patients with severely limited autologous conduit. J Trauma
2009;66(4):980–983.
105. Casey K, Sabino J, Weiss JS, et al. Limb salvage after vascular reconstruction followed by tissue
transfer during the Global War on Terror. J Vasc Surg 2015;61(3):734–740.
106. Alam HB, DiMusto PD. Management of lower extremity vascular trauma. Curr Trauma Rep
2015;1(1):61–68. Available at http://link.springer.com/article/10.1007/s40719–014–0007–2
107. Hoyt BW, Pavey GJ, Pasquina PF, et al. Rehabilitation of lower extremity trauma: A review of
principles and military perspective on future directions. Curr Trauma Rep 2015;1(1):50–60.
Available at http://link.springer.com/article/10.1007/s40719–014–0004–5
108. Fergason J, Keeling JJ, Bluman EM. Recent advances in lower extremity amputations and
prosthetics for the combat injured patient. Foot Ankle Clin 2010;15(1):151–174.
109. Holcomb J, Caruso J, McMullin N, et al. Causes of death in US special operations forces in the
global war on terrorism: 2001–2004. Ann Surg 2007;245(6):986–991.
110. Hauser CJ, Boffard K, Dutton R, et al. Results of the CONTROL trial: efficacy and safety of
recombinant activated factor VII in the management of refractory traumatic hemorrhage. J Trauma
2010;69:489–500.
111. Rago AP, Sharma U, Sims K, et al. Conceptualized use of self-expanding foam to rescue special
operators from abdominal exsanguination: Percutaneous damage control for the forward deployed.
J Spec Oper Med 2015 Fall;15(3):39–45.
112. Mesar T, Martin D, Lawless R, et al. Human dose confirmation for self-expanding intra-abdominal
foam: A translational, adaptive, multicenter trial in recently deceased human subjects. J Trauma
Acute Care Surg 2015;79(1):39–46.
113. Velmahos GC, Spaniolas K, Tabbara M, et al. Abdominal insufflation decreases blood loss without
worsening the inflammatory response: implications for prehospital control of internal bleeding. Am
Surg 2008;74(4):297–301.
114. Tiba MH, Draucker GT, McCracken BM, et al. Use of pelvic hemostasis belt to control lethal pelvic
arterial hemorrhage in a swine model. J Trauma Acute Care Surg 2015;78(3):524–529.
115. Halaweish I, Nikolian V, Georgoff P, et al. Creating a “prosurvival phenotype” through histone
deacetylase inhibition: Past, present, and future. Shock 2015;44 Suppl 1:6–16.
116. Alam HB, Pusateri AE, Kindzelski A, et al.; HYPOSTAT workshop participants. Hypothermia and
hemostasis in severe trauma: A new crossroads workshop report. J Trauma Acute Care Surg
2012;73(4):809–817.
117. Alam HB. Translational barriers and opportunities for emergency preservation and resuscitation in
severe injuries. Br J Surg 2012;99 Suppl 1:29–39.
575
booksmedicos.org
Chapter 20
Prehospital and New Advances in Resuscitation

John R. Taylor III, John B. Holcomb, and Bryan A. Cotton
Key Points
1 Prehospital care is an evolving field with more options to get early treatment to acutely injured
patients.
2 Prehospital care does not have to be done by EMS personnel only; the emphasis is now on care given
by other citizens on site.
3 Early and aggressive blood product resuscitation has transformed how we care for critically injured
patients.
4 Technologic advances to include end-tidal CO2 monitoring, ultrasound, tourniquets, and REBOA will
continue to advance the field.
5 Further research into optimal type, timing, and amount of resuscitative fluid will change how we
treat our patients in the field.
INTRODUCTION
Trauma continues to be the leading cause of death for 1 to 44 year olds and is the overall fifth leading
cause of death for all age groups.1 The care of the injured patient is a tightly integrated exercise
combining the expertise of the prehospital care team and the trauma team once they arrive at the
hospital. The likelihood of patient survival is vastly increased by timely transport and proper
intervention in the acutely injured patient. The care of the injured patient begins immediately following
injury. This may be rendered initially by nearby civilian bystanders or a variety of trained first
responders. The recently published Hartford Consensus III outlines that it is the shared responsibility of
the medical professionals as well as the noninjured, or minimally injured, patients at the scene to
provide care to those injured, specifically addressing cessation of ongoing hemorrhage.2 The main goal
of a prehospital system is to provide timely appropriate care for the sick or injured patient and get them
to the most appropriate hospital for definitive care as quickly and safely as possible. At times the most
appropriate hospital may be the closest and at others it may be more distant, but with the capabilities
more suitable to a particular patient. Most commonly, a phone call placed to a 9-1-1 dispatcher activates
the emergency medical system (EMS) and quickly allocates resources to the location where help is
needed.
PREHOSPITAL CARE
Personnel
Prehospital personnel are comprised of emergency medical technicians (EMTs), paramedics, firefighters,
police, nurses, and less commonly physicians. The recently released Hartford Consensus III places
nonmedical civilians on the forefront of hemorrhage control as a ready force of immediate responders.
There are multiple levels of EMTs. The EMT-B or basic level has training capable of providing basic life
support (BLS). BLS maneuvers include external hemorrhage control, spine immobilization, noninvasive
cardiopulmonary resuscitation, and administration of supplementary oxygen, and application of an
automated external defibrillator (AED). Paramedics require additional training, upward of 1200 hours,
and may administer advanced life support (ALS) techniques. Prehospital ALS was first employed as a
“mobile intensive care unit” in 1967.3 In addition to the maneuvers administered by BLS personnel an
ALS unit can provide cardiac drugs, pain control, blood pressure management, glucose control, needle
decompression of tension pneumothoraxes, and anticonvulsant medication. There is much debate as to
576
booksmedicos.org
whether ALS is superior to BLS in the prehospital setting. Recent meta-analysis concluded that ALS
provides a survival advantage only to nontrauma patients.4
In certain US cities a physician medical director of EMS is available at all times to respond to ground
crews and dispatch centers for advice. The physician may also respond in person to certain calls as
needed. Their role includes providing quality control, education, and approval of drug administration
outside of set protocols. Outside of the United States some countries have full time physicians riding
with ambulance crews at all time. While physician presence increases transport time there is evidence
which indicates an increase in survival in patients with acute myocardial infarction and respiratory
distress.5
Scoop and Run Versus Stay and Play

The two paradigms that dictate the amount and type of care that patients receive in the prehospital
setting are the “Scoop and Run” and the “Stay and Play.” The overarching premise of the Scoop and Run
technique is to get the injured patient to a facility that can provide definitive care in the shortest period
of time. The proponents of this system cite the increasing amount of evidence that prehospital
interventions are fraught with complications from both their intervention as well as the resultant delay
in arriving at a trauma facility.6 Stay and Play advocates feel that the early control of life-threatening
injuries is considered of critical importance in the management of the injured patient, and initiating
therapy for such injuries in the prehospital environment may improve patient survival.7 The true answer
to which paradigm is best for the patient most likely lies somewhere in the middle of the two. In an
urban setting with readily accessible, and multiple, trauma facilities it makes sense to extract the patient
and get them to the closest center, performing limited, but lifesaving interventions during transport. In
a rural environment, where access to a hospital may be greatest distances by road or prolonged wait for
rotary wing care, it may be best to provide care on site allowing for stabilization of the patient’s
injuries. Further studies are necessary to decide which of these two paradigms provide the best care for
the patient.
Table 20-1 Prehospital Assessments and Interventions
SCENE ASSESSMENT AND MANAGEMENT PRIORITIES

Airway
1 It is paramount once on scene for the EMT to determine the status of the patient’s airway. Evaluating
the patient’s Glasgow Coma Scale (GCS), chest rise, extent and nature of injuries provides vital insight
into whether or not the patient is and will be able to maintain their airway (Tables 20-1 and 20-2).
Supplemental maneuvers such as suctioning, chin lift/jaw thrust, placement of oropharyngeal airways,
and use of bag-mask devices can temporarily restore oxygenation in the acutely injured patient. These
maneuvers will usually maintain airway patency for the patient during their transport to definitive care;
for those who are unable to do so, advanced airway maneuvers are key to securing a patent airway.
Tracheal intubation provides a definitive airway with a cuffed endotracheal tube that will facilitate
oxygenation, ventilation, and prevent aspiration. The skills required to successfully intubate are difficult
to achieve and require remediation and oversight to maintain.8 There is conflicting literature to support
field intubation. Winchell and Hoyt completed a retrospective review of blunt trauma patients with
severe head injury in San Diego that found statistically significant decrease in mortality between
patients intubated in the field and those who were not.6 The only randomized controlled trial of
prehospital intubation versus bag-mask ventilation occurred in 2000 with pediatric patients, and it
577
booksmedicos.org
showed that the addition of out-of-hospital intubation did not improve survival or neurologic
outcomes.9 A retrospective review of prehospital intubation versus bag-mask ventilation by Stockinger
and McSwain showed no survival advantage to intubation and an increased prehospital time.8 The
majority of literature suggests that prehospital intubation does not improve survival and may prolong
time to definitive care.10 One meta-analysis evaluating emergency intubation for the acutely ill showed
no survival benefit in nontraumatic cardiac arrest prehospital intubation, as well as no evidence of
prehospital intubation benefitting trauma patients in the urban environment.11 While the majority of
situations in the prehospital setting do not require intubation, there are some that make sense to secure
an airway. Patients who have evidence of extensive facial trauma, patients who will require long
transport times to reach definitive care, and those patients who are apneic due to suspected cervical
injury are appropriate to intubate in the prehospital setting. The reflexive intubation to “protect” the
airway should be avoided, and further randomized studies are required to truly answer the question of
who and when to intubate in the prehospital setting.
Table 20-2 Listening to the Patient
There are alternative measures that can be taken for those who need to establish an airway but do not
have the skills for intubation. Laryngeal mask, Combitube, and King Airway all require less training and
skill for insertion, however, they have never been shown to increase survival. While the invention of
video-assisted airway insertion devices has taken hold in the hospital setting for “difficult” airways, its
use in the prehospital setting has not been studied in depth. A retrospective review of patients in Europe
showed the prehospital use of the Glidescope facilitated successful intubation when conventional direct
laryngoscopy failed.12 This study is limited by its small size and retrospective nature, however, as
technology advances the use of video-assisted airway devices may allow for more successful prehospital
intubation. Whether or not these devices will increase survival in patients is unknown at this time. A
surgical cricothyroidotomy (CRIC) can provide an emergency airway in the hands of skilled
practitioners. This maneuver requires much training and is usually utilized by military personnel in
austere environments, or after failed orotracheal intubation efforts. A retrospective review by the Israeli
Defense Force showed a 93% success rate with CRIC for patients requiring an emergency airway.13
Breathing
Assessment of patient’s breathing occurs simultaneously with airway assessment. Evaluation of
symmetric chest rise, obvious signs of chest trauma, and presence of bilateral breath sounds give the
first responder an idea of the patient’s status. The presence of a tension pneumothorax is a life-
threatening event that may lead to obstructive shock, hemodynamic collapse, and potentially death.
EMTs may also identify a patient with a tension pneumothorax with the presence of tracheal deviation,
neck vein distention, and cyanosis. Prompt decompression of the thoracic cavity with a needle is
necessary to reverse the tension effect. While the traditional landmark has been the midclavicular line,
cadaver and computerized tomography evaluations had demonstrated more consistent evacuation of air
using the anterior axillary, especially in females.14 Further management with tube thoracostomy will be
evaluated once the patient arrives at their receiving facility. Large sucking chest wounds, that permit
the rapid equilibration of pleural and atmospheric pressure, can be rapidly fatal. These wounds prevent
the lung from expanding and preclude alveolar ventilation. These large wounds cause hemodynamic
collapse rapidly unless an airway is obtained that allows for positive pressure ventilation. The very rare
smaller open chest wounds are amenable to a three-sided dressing that allows for gas to exit from the
chest wall defect but prevents gas from entering the chest wall. These can be fashioned in a field
expedient manner and function as a temporizing action until definitive therapy with a chest tube, in a
sterile environment, can be achieved.
578
booksmedicos.org
In addition to gross disturbances and threats to oxygenation and ventilation, prehospital personnel
should be aware of these specific interventions as occasionally they can lead to greater harm than the
injury itself. Over the last decade, the trauma literature has shown that the manner in which we
previously cared for the airway in traumatic brain injury (TBI) may have done more harm than
good.15,16 Hyperventilation in the prehospital setting had been previously advocated, and is
unfortunately still occasionally practiced, leading to acute vasospasm in the cerebral blood flow causing
an overall decrease in the cerebral blood flow in patients with a severe TBI. This has since been
abandoned in favor of normocapnea, decreasing the actual increase in overall cerebral blood flow (and
worse outcomes) with hyperventilation.15,17 Warner et al. in the Journal of Trauma showed that end-
tidal CO2 monitoring in the prehospital setting poorly correlated with the actual arterial blood gas
analysis pCO2, and as such suggested that using it to guide prehospital ventilation status may lead to
inadvertent hypercapnia.
Given that many prehospital personnel ventilate patients via bag-valve devices connected to either a
facemask or directly to an endotracheal tube, experts in the field and numerous investigators have
advocated for the use of end-tidal CO2 monitoring in these settings.18,19 Silvestri et al. showed that
there were no misplaced endotracheal tubes in patients who had continuous end-tidal CO2 monitoring
(0/93) whereas 23.5% of misplaced (14/60) prehospital intubation did not use monitoring in the
prehospital setting. With bag volumes in excess of 1,200 mL, uncontrolled bag ventilation can easily
lead to inadvertent hyperventilation. In fact, researchers have shown that almost 80% of end-tidal CO2
values for intubated TBI patients are <30 mm Hg in the field.20 Patients with severe TBI were shown to
have decreased mortality when their PaCO2 was maintained between 30 and 35, 21.2% versus 33.7% by
Warner et al. This paper suggests that prehospital monitoring, along with close continued monitoring of
arterial blood gases after admission to the hospital will lead to interval decrease in mortality.
Circulation
Evaluation and treatment of circulatory status in the prehospital setting has undergone much change in
the past 10 years. The experiences from the Global War on Terror have rapidly changed the way in
which we think about prehospital circulation and how we treat the abnormalities in circulation.
Evaluation of circulatory status begins with initial evaluation of mental status and inspection for
obvious signs of active hemorrhage. Direct pressure and hemostatic dressings can be used for control of
hemorrhage; however, large volume extremity hemorrhage may need to be addressed with placement
of a tourniquet. A prospective evaluation of tourniquets applied during Operation Iraqi Freedom showed
increased survival with tourniquet placement and no subsequent limb loss due to their use.21 Passos et
al. reviewed the use of emergency tourniquet use in the civilian setting and found that they prevented
exsanguination in the setting of both blunt and penetrating extremity trauma.20
Once the circulatory status of the patient has been addressed, sites of rapid compressible
exsanguination identified and treated, the decision is made for intravenous access and possible use of
intravenous fluid. In 2009 the Eastern Association for the Surgery of Trauma published their practice
management guidelines regarding prehospital fluid resuscitation of the injured patient. These guidelines
support placement of peripheral IV or intraosseus access only if it does not delay the transport of the
patient, as well as small fluid boluses of 250 cc of hypertonic (3% or 7.5%) saline being equivalent to
volume resuscitation with 0.9% normal saline or lactated ringers.22 These guidelines also support
minimizing fluid resuscitation until hemorrhage is addressed and not resuscitating those patients with
penetrating torso trauma. There is, however, data from the Resuscitation Outcomes Consortium (ROC)
that resuscitation with hypertonic fluids versus normal saline did not result in improved 28-day
survival.23 The patients were randomized 250 mL boluses of either hypertonic saline (7.5%) versus
hypertonic saline per 6% dextran versus 0.9% normal saline. The study was stopped early due to
potential safety concern based on increased mortality in the group that received hypertonic saline. As
such, current clinical guidelines do not recommend the regular use of hypertonic saline resuscitation in
the severely injured patient.
Further evaluation has led researches to push for earlier transfusion of blood product components as
in the prehospital setting. Studies from severe combat casualties showed that an aggressive approach to
prehospital blood transfusion was associated with large improvement in mortality; however, further
randomized studies were necessary.24 Severely injured patients are now receiving blood transfusion in
the civilian setting while en route to facilitate early hemostatic resuscitation and prevention of
coagulopathy complications. Brown and colleagues conducted a retrospective, case-controlled analysis
of patients who received prehospital packed red blood cells (240 patients) against those who did not
579
booksmedicos.org
(480 patients).25 Their study showed an increased likelihood of 24-hour survival, lower odds of shock,
and lower overall 24-hour blood transfused. A subsequent paper from these investigators evaluated over
2,000 blunt trauma patients arrived at one of eight subject institutions within 2 hours of injury.26 Of the
2007 patients, 50 (3.5%) received blood in the prehospital setting, and they were compared to controls
who did not. Those patients who received prehospital blood had a 95% reduction in the odds of 24-hour
mortality, 64% reduction in 30-day mortality, and an 88% reduction in the incidence of trauma-induced
coagulopathy.
In patients without evidence of hemorrhage or in prehospital settings where blood and blood products
are not available, numerous choices of fluid are available. However, most fluid options are actually
poor choices for resuscitation of injured patients. Normal saline (0.9% sodium chloride) has an average
pH of 5.5, with a sodium and chloride concentration of 154 mEq/L. Normal saline is often preferred as a
universal solution for prehospital settings as it is “compatible with blood,” contains no potassium, and is
cheap to carry; with a low overall cost and extended shelf life. Lactated Ringer’s, initially developed to
support organs in the lab (because of calcium content) and later championed for treating cholera, has
only a slightly better physiologic profile. Lactated Ringer’s gives the clinician a better average pH of
6.5, with lower sodium (130 mEq/L) and chloride content (109). The optimal fluid, however, is
Plasmalyte®/Normosol® which has an average pH of 7.4 and an electrolyte content that resembles a
normal metabolic profile (sodium – 140 mEq/L, potassium – 5.0 mEq/L, chloride – 98 mEq/L, and
magnesium – 3.0 mEq/L). In addition to its superior profile, Plasmalyte® is compatible with all blood
products and has been shown in a randomized trial to result in improved acid–base status and less
hyperchloremia at 24 hours postinjury.27 There is increased interest in the use of plasma as a prehospital
fluid, be it conventional or freeze dried, and this is reflected in the ongoing Prehospital Use of Plasma in
Traumatic Hemorrhage (PUPTH trial).28 The aim of this study is to compare prehospital resuscitation
with plasma versus normal saline in patients who are found to be in shock from either blunt or
penetrating mechanisms. While results are pending, hopefully this study will shed more light on the
ideal type and amount of prehospital fluid for resuscitation.
TRIAGE
Triage is an active process that takes into account multiple factors with the goal of transporting the
patient to the correct trauma center in the shortest amount of time. The Centers for Disease Control and
Prevention have published guidelines helping to facilitate proper triage of injured patients since 1999.
These guidelines underwent their most recent update in 2011 and use physiologic, anatomic, and the
mechanisms of the injury to guide the triage of the patient.29 Changes specific to the 2011 update
include lowering GCS for the physiologic criteria, broadening the definition of injuries in the anatomic
criteria, and addressing the differences in older adult trauma patients relative to young trauma patients.
The implementation of these guidelines is key to preventing both under- and overtriage of the acutely
injured patient. Undertriage is the practice of sending an acutely injured patient to a lower than needed
tier in the trauma system. This leads to prolongation to definitive care for injuries, multiple transfers to
identify the correct level of care, and overall worse care of the patient. Overtriage is transferring a
patient to a highest-level trauma system when their injuries do not warrant that level of care. This
allocates scarce resources to patients who ultimately do not need them, and as such may prevent those
who need that resource appropriately from getting it. In 2011, a review of the triage guidelines from
1999 compared to 2006 showed a statistically significant decrease in the number of patients who were
overtriaged when the guidelines were followed appropriately.
A special triage situation occurs when multiple patients are injured. A multicasualty event occurs
when a hospital is able to manage the number of casualties with local resources. The majority of level 1
trauma centers are able to take care of a small multicasualty event without significant strain on their
work environment. A mass-casualty event exists when the numbers, severity, and diversity of injuries
overwhelm the local medical resources. A recent example of a mass-casualty event is the April 15, 2013
bombing of the Boston Marathon. A terrorist attack by two terrorists, bent on causing fear and
destruction, deployed two homemade improvised explosive devices (IEDs) near the finish line of the
race. Two hundred sixty-four patients sought treatment for injuries from the event; there were three
fatalities on scene and numerous patients transferred to the five level 1 trauma centers located in
Boston.30 An active onsite triage team was able to identify those patients who needed immediate
transfer based on criteria and send them to one of the awaiting hospitals for immediate treatment.
Specifically, the Brigham and Women’s Hospital received a total of 31 patients immediately following
580
booksmedicos.org
the bombing, of which 23 arrived within the first hour.31 Of those transported to the Brigham that day,
fifteen patients were admitted to the hospital, nine went to the operating room, and none died. Mass-
casualty events require coordination at the state and national level, and extensive practice at
implementing triage criteria. Interestingly, in 2002 the city of Boston completed a citywide mass-
casualty practice event in response to the 9/11 Attack. Some credit for the successful actions that due
has been given to the experience gained from this practice and other drills.
ADVANCES AND CONTROVERSIES

Rapid Sequence Intubation Versus Non-RSI
The use of rapid sequence intubation (RSI) in the prehospital setting is one that engenders much
discussion in the prehospital setting. A standard of care in the inpatient setting, the use of RSI in the
prehospital setting is both supported and refuted by the literature over time. The drugs that are used for
RSI, while no one standard is accepted by everyone, include combinations of the following: diazepam,
succinylcholine, vecuronium, midazolam, rocuronium, lidocaine, ketamine, and etomidate. Many argue
that the complications that are associated with RSI, including the consequences of multiple failed
intubation attempts, unnecessary exposure of patients to dangerous procedure, and complications of the
medications do not value the implementation of RSI in the prehospital setting.
A 2005 paper published on the use of RSI in the out-of-hospital setting was unable to predict which
patients had severe TBI and over half the patients experienced a desaturation during the RSI procedure,
while only one-quarter of they were hypoxic before RSI.32 A further study from the United Kingdom
showed an incidence of 18.3% for hypoxemia during prehospital RSI and 13% developed hypotension
lower than pre-RSI blood pressures.16 This paper attributes its lower incidence of hypoxemia and
hypotension to the fact that in the United Kingdom board certified Physicians preform all the
prehospital RSI and intubations, while in the San Diego paper the entire procedure was carried out by
EMTs. Using a propensity-adjusted model, investigators showed no statistical difference in mortality
between prehospital intubations with and without RSI. Further randomized, prospective trials are
necessary to prove a benefit to prehospital RSI.
Aggressive Fluids Versus Permissive Hypotension

The concept of permissive hypotension involves keeping the blood pressure low enough to avoid
exsanguination while maintaining perfusion of end organs.33 It is an integral part of the new Damage
Control Resuscitation protocols that are being implemented; however, its root goes as far back as World
War I. The work of Walter Cannon and John Fraser while serving with the Harvard Medical Unit in
France involved the observation that artificial elevations in blood pressure may overcome the clot
preventing further hemorrhage, and the patient will lose sorely needed blood.34 Fast forward to 1994
when the plenary paper by Bickell et al. showed in a randomized prospective control trial delayed fluid
resuscitation in adults with penetrating torso injuries lead to greater survival and overall shorter
hospital length of stay.35 These results have been repeated in further subsequent studies by other
authors showing no benefit to early aggressive resuscitation, especially to supernormal levels. Finally,
Holcomb et al. in 2007 published the plenary paper on damage control resuscitation outlining the two
important principles of resuscitating to a systolic blood pressure no greater than 90 and using thawed
plasma in a 1:1 or 1:2 ratio with PRBC to restore intravascular volume.36
The concept of permissive hypotension is directly contradictory to the guidelines found in the ATLS
manual that advocate for 2 L of crystalloid resuscitation early in those patients manifesting signs of
shock. However, a recent multicenter, randomized study by the ROC suggests that a restrictive strategy
is warranted in blunt trauma patients as well.37 The investigators randomized hypotensive trauma
patients to receive small boluses of fluid (250 mL) if they had no radial pulse or a systolic blood
pressure lower than 70 mm Hg or to receive the standard 2-L fluid bolus and additional fluid needed to
maintain a systolic of 110 mm Hg or greater. Patients in the hypotensive resuscitation group (fluid for
systolic <70 mm Hg) had a lower 24-hour mortality compared to standard resuscitation group (3% vs.
18%).
Schreiber et al. conducted a randomized prehospital trial placing patients into either of two groups:
(1) standard resuscitation patients who received 2 L of crystalloid initially and fluid as needed to
maintain a systolic blood pressure of 110 mm Hg or greater, or (2) controlled resuscitation patients who
received 250 mL of fluid if they had no radial pulse or an SBP lower than 70 mm Hg, with additional
581
booksmedicos.org
250-mL boluses to maintain a radial pulse or SBP of 70 mm Hg or greater. The controlled resuscitation
group received 1 L less of fluid, had less deaths (5% vs. 15%) at 24 hours after admission, and among
patients with blunt abdominal trauma 24-hour mortality was 3% versus 18%, all statistically significant.
This paper showed that controlled resuscitation in the out-of-hospital setting may offer an early survival
advantage to the blunt trauma patient. There was, however, no difference in mortality among patients
with penetrating trauma.
2 Further studies are necessary to cement at which level the resuscitation should be stopped;
however, we now know that minimal intravenous fluids, tolerating systolic blood pressures in the 75 to
90 mm Hg range, and not resuscitating to supernormal values with crystalloid is the paradigm
prehospital trauma workers should follow.
Prehospital Blood Protocols

The lessons from the Global War on Terrorism have changed many paradigms regarding the prehospital
care of the acutely injured patient. Some argue that the advent of prehospital blood product transfusion
protocols will make the greatest impact on civilian trauma management. Early studies identified the
prehospital setting as an ideal place to begin early resuscitation with blood products, as hemorrhage
was identified to cause 33% to 56% of the prehospital casualties. In a multicenter study of over 1,400
injured patients with evidence of shock, Brown and colleagues demonstrated an increase in both 24-hour
and 30-day survival, as well as less coagulopathy on arrival in those patients receiving prehospital red
blood cell (RBC) transfusions.38 Building on this, the Houston group published their aeromedical
experience with prehospital plasma and RBC, which began in 2011.39 Similar to the data published from
the wars in Iraq and Afghanistan, the investigators noted in their study of almost 1,700 patients that
placing RBCs and plasma products in the prehospital setting, allowing for earlier infusion of life-saving
products to critically injured patients, was associated with improved early outcomes.
3 The more recent PROPPR trial included patients who received blood transfusion en route and
showed that more patients resuscitation in the 1:1:1 group versus 1:1:2 group achieved hemostasis and
fewer experienced death due to exsanguination by 24 hours.40 This study will hopefully spur further
prospective, randomized control trials trying to identify the proper type and amount of blood product
resuscitation in the prehospital setting.
ETCO2 Monitoring
4 The use of end-tidal CO2 (ETCO2) as a means for measurement of exhaled CO2 is the standard found
in the operating room and emergency room; however, its use in the prehospital setting was not
commonplace 10 years ago. ETCO2 is a reflection of metabolism, circulation, and ventilation. As
technology has advanced, the ease of use and application of ETCO2 monitoring has become more
commonplace. ETCO2 was first used as a way to confirm placement of endotracheal tubes in the
prehospital setting using colorimetric CO2 detector.8 The use of the colorimetric detector in conjunction
with auscultation and symmetric chest rise make the likelihood of esophageal intubation near zero. This
must be prevented as esophageal intubation rates have been reported as high as 17% to 25% in
emergency airway management of nonarrest patients.41 In-line capnography in the nonintubated patient
is key to assessing the adequacy of chest compressions in patients undergoing CPR. ETCO2 has been
shown to correlate linearly with coronary artery perfusion pressure, and hence is a simple and
noninvasive method to measure blood flow during CPR and can indicate return of spontaneous
circulation. In 2009 a study of out of Harborview Hospital showed that documented ETCO2 in
prehospital intubations did not correlate to ABG PaCO2, with patients most likely being under ventilated
(PaCO2 >40) 80% of the time and severely underventilated (PaCO2 >50) 30% of the time.42 As such,
the use of ETCO2 is to assess for proper endotracheal intubation as well as ascertain effectiveness of
CPR is established, however, its ability to predict PaCO2 will need further study.
Tourniquet Use in the Field

5 Tourniquet use for injury has documentation as far back as 6 BC in Hindu text for the treatment of a
snakebite.43 Over time it has fallen in and out of favor in the prehospital setting, however, experiences
during the recent Global War on Terror support its use as far forward as possible in the prehospital
setting. In the Vietnam War surgeons recognized that of the casualties killed in the war, 2,590 lives
could have been saved with better prehospital care namely tourniquets.21 Analysis of the casualties of
Operation Gothic Serpent, the 1993 battle fought between U.S. forces and the militias in Somalia,
582
booksmedicos.org
showed 7% of fatalities resulted from penetrating extremity trauma and that hemorrhage control in the
form of tourniquet use should be more widely adopted.43 The current conflict in Iraq and Afghanistan
brought out the strongest data supporting the use of prehospital tourniquets. A prospective study of
casualties over a 7-month period in 2006 at a combat hospital in Baghdad showed tourniquet application
with the abscence of shock was strongly associated with survival, no amputations resulted solely from
tourniquet use, and only four nerve palsies at the level of the tourniquet occurred all of which resolved
without issue.21 Further papers have gone on to show civilian application of this concept also saves lives
and limbs. In 2015, Scholl et al. published a retrospective review of civilian trauma patients admitted
with a prehospital tourniquet at nine institutions. Their data show overall mortality and limb
amputation rate in statistically similarly injured patients was less than that seen in military data
previously documented. A final, more fatal, type of hemorrhage is junctional hemorrhage defined as
bleeding from the pelvis, groin, perineum, axilla, and neck. These wounds were seen extensively in the
Global War on Terrorism as the use of IED increased. Holcomb et al. reviewed preventable causes of
death in U.S. Special Forces Soldiers in 2007 and found that junctional or noncompressible trauma was
implicated in 47% of deaths.44 A future place for research, the junctional tourniquet has shown in
healthy volunteers to occlude blood flow to the lower extremity.45 While these experiences are mainly
from combat environments, application to the civilian field has been successfully implemented.46 A
paper out of the trauma group at USC showed that prehospital use of tourniquet, be it Combat
Application Tourniquet, field expedient tourniquet, or pneumatic tourniquet placed in the emergency
room, is associated with no increased rate of complications.47 Of note from this study, only 50.6% of
the tourniquets were placed in the prehospital setting, leading to further question as to whether or not
full implementation of prehospital tourniquets would lead to further success in preventing mortality and
decreasing complications from traumatic extremity injuries. A subsequent multi-institutional
retrospective analysis of prehospital tourniquet use showed lower overall mortality and limb
amputation rates when compared to historical combat data.48 This paper showed that extrapolation of
military data, as well as practices, to the civilian trauma patient leads to increased survival and limb
salvation.
Resuscitative Endovascular Balloon Occlusion of Aorta

Resuscitative endovascular balloon occlusion of aorta (REBOA) is a balloon placed via the femoral
artery to occlude the aorta and prevent life-threatening hemorrhage (Fig. 20-1). While the technology is
new, the idea is not as it is described in an article in the journal Surgery in 1954 for controlling intra-
abdominal hemorrhage. Multiple animal studies have shown that REBOA is superior to emergency
thoracotomy with aortic clamping to control hemorrhagic shock in the porcine model.49 Control of
hemorrhage far forward in the military combat environment is the goal of the REBOA. A retrospective
analysis of UK combat casualties, 18.5% had an indication for REBOA when reviewing their injuries.50
While it is rapidly gaining popularity as a substitute for resuscitative thoracotomy, it is probably best
suited for quickly controlling pelvic hemorrhage (before the patient has lost pulses) prior to
embolization and interventional radiology availability. Research is now being produced that shows a
benefit to REBOA use for hemorrhage control. Brenner et al. published a series of six cases in 2013 that
outlined the successful implementation for hemorrhage control of REBOA.51 Successful implementation
of REBOA in these six cases showed that endovascular aortic occlusion supports myocardial and cerebral
perfusion until resuscitation can be initiated and hemostasis obtained, the same goals of aortic cross
clamping in a markedly less invasive manner. Further research published in 2015 compared the
outcomes of REBOA versus resuscitative thoracotomy for noncompressible truncal hemorrhage. In
clinically similar groups, the REBOA group had fewer early deaths, improved overall survival (37.5%
vs. 9.7%, p = 0.003) with less morbidity than the resuscitative thoracotomy group.52 While this took
place in only two centers with advanced skills with REBOA, it is feasible that continued training in
endovascular skills during both the training and attending years may lead to greater implementation of
this skill. The Japanese have published a retrospective review of their experience with the safety and
feasibility of REBOA for trauma in 2014.53 Their data show that REBOA was feasible for trauma
resuscitation, however, there was an increased risk of lower limb ischemia and possible amputation that
occurred in 12.5% of their patients. New technologic advances producing small sheaths and smaller
balloons may eliminate the need to close an arteriotomy required of larger sheaths and thus decrease
this risk. Further forward management of REBOA in the field environment may be on the horizon,
however, for now its implementation to control traumatic hemorrhage is still in its infancy and the risk–
benefit of placing these in the most skilled hands (much less in undertrained personnel or in the
583
booksmedicos.org
prehospital setting) has not been determined.54
Figure 20-1. Performance of REBOA. Steps of Insertion:

1. Use the percutaneous entry thin wall needle to access the common femoral artery via cutdown,
percutaneous access, or wired exchange of existing arterial line (A).
2. Insert the Rosen guide wire (0.035) through the needle, then remove the needle (B).
3. Open the CODA catheter kit: dilate with the gray 10-Fr then the 12-Fr dilator (C).
4. Through the 12-Fr dilator, exchange the 0.035 guidewire for the Amplatz super stiff guidewire.
5. Dilate with the 14-Fr dilator and then assemble the introducer sheath by placing the 14-Fr dilator
through the sheath (like a Cordis). Insert the dilator/sheath unit over the guidewire. Place the sheath
to a premeasured distance (arterial puncture to umbilicus) then remove the dilator but not the
584
booksmedicos.org
guidewire (D).
6. Open CODA balloon (yellow) and remove black tip. Do NOT test balloon (E).
7. Insert balloon catheter to premeasured distance + 10 cm.
8. Place three-way stopcock (packaged separately in balloon kit) to the end of the balloon catheter.
9. Gently inflate balloon through the sideport until loss of contralateral femoral pulse (can confirm with
Doppler US). Do not exceed 40 mL (can use air, saline, or 50% contrast diluted with saline). (E).
10. Secure catheter to the patient and document positioning with KUB or fluoroscopy.
CONCLUSION
Prehospital trauma care is a constantly evolving field. Much of our advances from recent military
conflicts are being rapidly implemented in the civilian prehospital setting. Further research and
developments are necessary to continue the previous success seen in saving the critically injured trauma
patient.
References
1. National Vital Statistics Reports. Vol. 62. No. 2. 2015. Available from:
www.cdc.gov/injury/images/lc-charts/leading_causes_of_death_age_group_2014_1050w760h.gift
2. Jacobs LM; Joint Committee to Create a National Policy to Enhance Survivability from Intentional
Mass-Casualty and Active Shooter Events. The Hartford consensus III: Implementation of bleeding
control: if you see something do something. Bull Ame Coll Surg 2015;100:40–46.
3. Beuran M, Paun S, Gaspar B, et al. Prehospital trauma care: a clinical review. Chirurgia
2012;107:564–570.
4. Lerner EB, Shah MN, Swor RA, et al. Comparison of the 1999 and 2006 trauma triage guidelines:
where do patients go? Prehosp Emerg Care 2011;15(1):12–17.
5. Haas B, Nathens AB. Pro/con debate: is the scoop and run approach the best approach to trauma
services organization? Crit Care 2008;12:224–240.
6. Winchell RJ, Hoyt DB. Endotracheal intubation in the field improves survival in patients with
severe head injury. Arch Surg 1997;132(6):592–597.
7. Gausche M, Lewis RJ, Stratton SJ, et al. Effect of out-of-hospital pediatric endotracheal intubation
on survival and neurological outcome: a controlled clinical trial. JAMA 2000;283:783–790.
8. Stockinger ZT, McSwain NE Jr. Prehospital endotracheal intubation for trauma does not improve
survival over bag-valve-mask ventilation. J Trauma 2004;56(3):531–536.
9. Struck MF, Wittrock M, Nowak A. Prehospital glidescope video laryngoscopy for difficult airway
management in a helicopter rescue program with anesthetists. Eur J Emerg Med 2011;18:282–284.
10. Katzenell U, Lipsky AM, Abramovich A, et al. Prehospital intubation success rates among Israel
Defense Forces providers: epidemiologic analysis and effect on doctrine. J Trauma Acute Care Surg
2013;75(suppl 2):S178–S183.
11. Lecky F, Bryden D, Little R, et al. Emergency intubation for acutely ill and injured patients.
12. Donald MJ, Paterson B. End tidal carbon dioxide monitoring in prehospital and retrieval medicine:
A review. Emerg Med J 2006;23:728–730.
13. Davis DP, Vadeboncoeur TF, Ochs M, et al. The association between field Glasgow come scale score
and outcome in patients undergoing paramedic rapid sequence intubation. J Emerg Med
2005;29(4):391–397.
14. Inaba K, Branco BC, Eckstein M, et al. Optimal positioning for emergent needle thoracostomy: a
cadaver-based study. J Trauma 2011;71:1099–1103; discussion 1103.
15. Warner KJ, Cuschieri J, Copass MK, et al. Emergency department ventilation effects outcome in
severe traumatic brain injury. J Trauma 2008;64:341–347.
16. Cudnik MT, Newgard CD, Daya M, et al. The impact of rapid sequence intubation on trauma patient
mortality in attempted prehospital intubation. J Emerg Med 2010;38(2):175–181.
585
booksmedicos.org
17. Kerby JD, Cusick MV. Prehospital emergency trauma care and management. Surg Clin North Am
2012;92:823–841.
18. Silvestri S, Ralls GA, Krauss B, et al. The effectiveness of out-of-hospital use of continuous end-tidal
carbon dioxide monitoring on the rate of unrecognized misplaced intubation within a regional
emergency medical services system. Ann Emerg Med 2005;45(5):497–503.
19. Davis DP, Hoyt DB, Ochs M, et al. The effect of paramedic rapid sequence intubation on outcome in
patients with severe traumatic brain injury. J Trauma 2003;54(3):444–453.
20. Passos E, Dingley B, Smith A, et al. Tourniquet use for peripheral vascular injuries in the civilian
setting. Injury 2014;45(3):573–577.
21. Kragh JF Jr, Walters TJ, Baer DG, et al. Survival with emergency tourniquet use to stop bleeding in
major limb trauma. Ann Surg 2009;249(1):1–7
22. Cotton BA, Jerome R, Collier BR, et al. Guidelines for prehospital fluid resuscitation in the injured
patient. J Trauma 2009;67(2):389–402.
23. Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after traumatic
hypovolemic shock: A randomized, placebo controlled trial. Ann Surg 2011;253(3):431–441.
24. O’Reilly DJ, Morrison JJ, Jansen JO, et al. Prehospital blood transfusion in the en route
management of severe combat trauma: A matched cohort study. J Trauma Acute Care Surg
2014;77(3 suppl 2):114–120.
25. Brown JB, Sperry JL, Fombona A, et al. Pre-trauma center red blood cell transfusion is associated
with improved early outcomes in air medical trauma patients. J Am Coll Surg 2014;78(1):781–790.
26. Brown JB, Cohen MJ, Minei JP, et al. Pretrauma center red blood cell transfusion is associated with
reduced mortality and coagulopathy in severely injured patients with blunt trauma. Ann Surg
2015;261(5):997–1005.
27. Young JB, Utter GH, Schermer CR, et al. Saline vs plasma-lyte A in initial resuscitation of trauma
patients: A randomized trial. Ann Surg 2014;259(2):255–262.
28. Reynolds PS, Michael MJ, Cochran ED, et al. Prehospital Use of Plasma in Traumatic Hemorrhage
(The PUPTH Trial): study protocol for a randomized controlled trials. Trials 2015;16:321.
29. Sasser SM, Hunt RC, Faul M, et al.Centers for Disease Control and Prevention Guidelines for Field
Triage of Injured Patients: Recommendations of the National Expert Panel on Field Triage, 2011.
MMWR Recomm Rep 2012;61:1–20.
30. Gates JD, Arabian S, Biddinger P, et al. The initial response to the Boston marathon bombing:
Lessons learned to prepare for the next disaster. Ann Surg 2014;260(6):960–966.
31. Walls RM, Zinner MJ. The boston marathon response: Why did it work so well? JAMA
2013;309(23):2441–2442.
32. Newton A, Ratchford A, Khan I. Incidence of adverse events during prehospital rapid sequence
intubation: A review of one year on the London helicopter emergency medical service. J Trauma
2008;64:487–492.
33. Geeraedts LM Jr, Kaasjager HA, van Vugt AB, et al. Exsanguination in trauma: A review of
diagnostics and treatment options. Injury 2009; 40(1):11–20.
34. Beuran M, Negoi I, Paun S, et al. [History of trauma care]. Chirurgia(Bucur) 2011;106(5):573–580
35. Bickell WH, Wall MJ Jr, Pepe PE, et al. Immediate versus delayed fluid resuscitation for
hypotensive patients with penetrating torso Injuries. N Engl J Med 1994;331:1105–1109.
36. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: Directly addressing the early
coagulopathy of trauma. J Trauma 2007;62(2):307–310.
37. Schreiber MA, Meier EN, Tisherman SA, et al. A controlled resuscitation strategy is feasible and safe
in hypotensive trauma patients: Results of a prospective randomized pilot trial. J Trauma Acute Care
Surg 2015;78(4):687–695.
38. Brown JB, Sperry JL, Fombona A, et al. Pre-trauma center red blood cell transfusion is associated
with improved early outcomes in air medical trauma patients. J Am Coll Surg 2015;220(5):797–808.
39. Holcomb JB, Donathan DP, Cotton BA, et al. Prehospital transfusion of plasma and red blood cells
in trauma patients. Prehosp Emerg Care 2015;19(1):1–9.
40. Holcomb JB, Tilley BC, Baraniuk S, et al. Transfusion of plasma, platelets, and red blood cells in a
1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: The PROPPR randomized
clinical trial. JAMA 2015;313(5):471–482.
586
booksmedicos.org
41. Bair AE, Smith D, Lichty L. Intubation confirmation techniques associated with unrecognized non-
tracheal intubations by pre-hospital providers. J Emerg Med 2005;28(4):403–407.
42. Hamrick JL, Hamrick JT, Lee JK, et al. Efficacy of chest compressions directed by end-tidal CO2
feedback in a pediatric resuscitation model of basic life support. J Am Heart Assoc 2014;3(2):117–
125.
43. Mabry RL, Holcomb JB, Baker AM, et al. United States Army Rangers in Somalia: An analysis of
combat casualties on an urban battlefield. J Trauma 2000;49(3):515–528.
44. Holcomb J, Caruso J, McMullin N, et al. Causes of death in US Special Operation forces in the
global war on terrorism: 2001–2004. US Army Med Dep J 2007:24–37.
45. Lyon M, Johnson D, Gordon R. Use of a novel abdominal aortic and junctional tourniquet to reduce
or eliminate flow in the brachial and popliteal arteries in human subjects. Prehosp Emerg Care
2015;19(3):405–408.
46. Scerbo MH, Mumm JP, Gates K, et al. Safety and appropriateness of tourniquets in 105 civilians.
Prehosp Emerg Care 2016;31:1–11.
47. Inaba K, Siboni S, Resnick S, et al. Tourniquet use for civilian extremity trauma. J Trauma Acute
Care Surg 2015;79(2):232–237.
48. Schroll R, Smith A, McSwain NE Jr, et al. A multi-institutional analysis of prehospital tourniquet
use. J Trauma Acute Care Surg 2015;79(1):10–14.
49. Morrison JJ, Ross JD, Houston R 4th, et al. Use of resuscitative endovascular balloon occlusion of
the aorta in a highly lethal model of noncompressible torso hemorrhage. Shock 2014;41(2):130–
137.
50. Morrison JJ, Galgon RE, Jansen JO, et al. A systematic review of the use of resuscitative
endovascular balloon occlusion of the aorta in the management of hemorrhagic shock. J Trauma
Acute Care Surg 2016;80(2):324–334.
2013;75(3):506–511.
52. Moore LJ, Brenner M, Kozar RA, et al. Implementation of resuscitative endovascular balloon
occlusion of the aorta as an alternative to resuscitative thoracotomy for noncompressible truncal
hemorrhage. J Trauma Acute Care Surg 2015;79(4):523–530.
53. Norii T, Crandall C, Terasaka Y. Survival of severe blunt trauma patients treated with resuscitative
endovascular balloon occlusion of the aorta compared with propensity score-adjusted untreated
patients. J Trauma Acute Care Surg 2015;78(4):721–728.
54. Inoue J, Shiraishi A, Yoshiyuki A, et al. Resuscitative endovascular balloon occlusion of the aorta
might be dangerous in patients with severe torso trauma: A propensity score analysis. J Trauma
Acute Care Surg 2016;80(4):559–567.
587
booksmedicos.org
Chapter 21
Head Trauma
Phiroz E. Tarapore, Geoffrey T. Manley, and Randall M. Chesnut
Key Points
1 Care must be taken to avoid hypotension and hypoxia, as these cause secondary injury.
2 In the setting of hypotension, ample volume resuscitation is the first line of therapy.
3 In the absence of intracranial hypertension, ventilation should be maintained with a target PaCO2
>35 mm Hg.
4 Hemoglobin should be maintained at or above 7 g/dL.
5 Traumatic CSF leak should be observed initially, without antibiotic prophylaxis. Persistent leak may
require temporary CSF diversion and, if that fails, operative management.
INTRODUCTION
In the field of trauma, other than for exsanguinating injuries, traumatic brain injury (TBI) is the injury
most commonly responsible for mortality, accounting for about half of deaths at the scene. In the
United States alone, the annual incidence is 2.5 million, and TBI results in over 52,000 deaths per year.1
The injuries are generally blunt, occurring most frequently in motor vehicle crashes (MVCs). As many as
two-thirds of all MVC victims sustain some degree of brain injury. The incidence of TBI is also
increasing globally, driven mainly by the increasing use of automobiles.
These data are generally applicable to children as well. Although the mechanisms vary, head injuries
are the major cause of morbidity and mortality in childhood trauma victims, accounting for an annual
mortality rate of 1 per 1,000 in this age group.2 Falls are the leading cause of TBI in those under age 14
years.
Interestingly, falls are also the leading cause of TBI in those over age 65 years. With the aging of the
baby-boomer generation, a new spectrum of brain injury is blossoming. For persons 65 years and older,
TBI-related hospital admissions increased more than 50% between the periods of 2001–2002 and 2009–
2010.3 These patients have less inherent neurologic plasticity, limiting their recovery potential.
Furthermore, they tend to have significant comorbidities and may be on one or more anticoagulants.
The management of these patients is often different from that which is optimal for the younger
population.
In patients with TBI, extracranial trauma is present in over half of cases. In these polytrauma patients,
the best predictor of outcome is severity of the TBI.4 It is therefore critical for a polytrauma patient to
be expeditiously transported to a trauma center that can offer the multidisciplinary specialized care that
is required. Patients with severe TBI, in particular, should be managed at a center with immediate CT
capability, neurosurgical care, and ICP monitoring capability.5 For these patients, direct transport to a
level I or level II is associated with up to a 50% decrease in mortality.6
PATHOPHYSIOLOGY
Traumatic injury to the brain involves a primary brain injury that occurs at impact and leads to
disruption of brain substance and blood vessels. In addition, secondary brain injury may result from
hypoxia, hypotension, hyperventilation, pyrexia, the effects of increased intracranial pressure (ICP), and
altered cellular biochemical processes that are often ongoing long after the primary insult.
Primary Injury
Energy transfer to the head causes direct disruption of neurons, glia cells, and microvasculature
localized at the area of impact. As the brain rebounds within the skull, it is also vulnerable to impact
588
booksmedicos.org
with the opposite inner table. Therefore, countercoup injury to the contralateral brain is relatively
common, in some cases being more severe than the damage at the primary impact site.
Particularly when the mechanism includes rotational forces, head trauma can result in widespread
disruption of white matter axons throughout the brain, producing the condition termed diffuse axonal
injury (DAI). Such injuries often damage a large number of widely distributed neurologic systems. When
such injuries involve ascending pathways in both hemispheres or in the brainstem, the result is a
depressed level of consciousness. The brain is also subject to torsion injury resulting from rotation
around the fixed brainstem. This type of injury can damage the reticular activating system, producing
unconsciousness.
Intracranial hemorrhage can take many forms. Direct laceration of epidural arteries from impact
fractures or bleeding from fracture lines produces epidural hematomas, which damage the brain by
compression. Disruption of bridging subdural veins and bleeding from cortical tissue damage produces a
subdural hematoma, which is generally associated with disruption of underlying brain tissue.
Intracerebral contusions, lacerations, and hematomas are caused by direct tissue disruption with
associated vascular injury, producing neuronal damage and intraparenchymal bleeding.
Penetrating injury damages the brain through tissue injury caused directly by the projectile and, in
the case of projectiles with relatively high velocity, result in disruption of neural tissue at a greater
distance from the track via cavitation injury. In survivors, the extent and degree of the cavitation injury
(related linearly to the mass and in a squared fashion to the velocity of the projectile) are often the
primary determinant of outcome. Another source of morbidity is vascular injury, producing aneurysms,
pseudoaneurysms, and other vascular anomalies that may present immediately or be delayed.
Whether a projectile or direct impact causes contusion, subdural hematoma, epidural hematoma, or
DAI, currently little can be done therapeutically to change the magnitude or location of the primary
injury once it has occurred. As such, most of our present care focus is on secondary injuries.
Secondary Injury
Once a primary brain injury has occurred, it sets off a variety of pathologic processes including
neurotransmitter release, gene activation, mitochondrial dysfunction, and neuroinflammatory responses
over the course of hours and days. These cascades, along with intracranial hypertension and cerebral
ischemia, can cause secondary brain injury. The prevention of these secondary injuries is the goal of
both medical and surgical management of TBI.
Biochemical and Genomic Processes

Primary tissue injury initiates a variety of biochemical processes, including free radical–mediated lipid
peroxidation, excitotoxic “superactivation” of glutamate-aspartate neurotransmitter systems, and
alterations in membrane receptor and ionic channel characteristics, among others. A variety of genomic
processes are also activated, including apoptotic cell death. These processes can proceed for significant
periods of time following primary injury and often are self-sustaining. The goal of the numerous clinical
trials involving treatment of patients with brain trauma with various pharmacologic agents is to
determine the means by which these processes may be attenuated or reversed. Unfortunately, to date,
no clinically useful tools have been obtained from such research.
Cerebral Hypoperfusion and Hypoxia

1 The most dangerous secondary injury processes that occur following brain injury are systemic
hypotension and hypoxia. Hypotension is the number one treatable determinant of severe head injury. A
single episode of systolic blood pressure less than 90 mm Hg occurring during the period from injury
through resuscitation doubles the mortality and significantly increases the morbidity of any given brain
injury.7,8 Furthermore, an early hypotensive episode strongly increases the probability of later
intracranial hypertension. For these reasons, rapid and complete restoration of blood pressure is the
most important goal in the resuscitation of the brain-injured patient.
Hypoxia (apnea or cyanosis in the field or a partial pressure of arterial oxygen [PaO2] 60 mm Hg) is
also an independent predictor of poor outcome.7–9 The frequency and magnitude of hypoxia have been
notably decreased by modern airway management techniques, particularly endotracheal intubation and
assisted ventilation, in addition to ensuring adequate oxygen-carrying capacity through the avoidance of
anemia. Recent studies suggest that intubation is safest in the hospital setting, and most emergency
medical systems will not intubate patients in the field so long as they are ventilating and oxygenating
adequately and transport time to the hospital is short.10–13
589
booksmedicos.org
Cerebral tissue oxygen tension (PBtO2) can be measured directly using implantable Clark electrodes.
This makes it possible to follow the partial pressure of oxygen in the brain tissue. Although absolute
thresholds have not been rigorously determined, values above 15 to 20 mm Hg are generally considered
adequate and values below 5 mm Hg are associated with increasingly poor outcome in a duration-
dependent fashion.14,15 The major limitation of this system is the focal nature of its monitoring – it
offers a single value relevant to a small volume of brain that is usually outside the region of injury.
Although there is theoretical attractiveness to monitoring at the border of focal injuries (the
“penumbra”), most monitoring is performed within normal brain. With the addition of a jugular venous
oxygen saturation monitor (JVO2), it becomes possible to measure global cerebral oxygen extraction
and distinguish hypermetabolic, high extraction states from hyperemic, low extraction states. Thus these
two oxygen monitoring tools are complimentary.
Intracranial Hypertension
ICP is a function of the aggregate volumes of brain, cerebrospinal fluid (CSF), and blood within the
fixed intracranial compartment. Mild or slow expansion of one or two of these compartments can be
buffered by compensatory decreases in either the CSF or blood compartments (into the spinal
subarachnoid space or the venous sinuses, respectively). When this buffering capacity is exceeded, the
compliance of the brain is compromised and small additional increases in any intracranial
compartmental volume will produce marked elevations in ICP.
Intracranial hypertension is considered deleterious via two somewhat separable mechanisms:
herniation and ischemia. Herniation occurs when a pressure gradient exists across an incomplete barrier,
such as the tentorium, falx cerebri, or foramen magnum. It is deleterious because of the tissue damage
that occurs and direct compression of adjacent vessels. Transtentorial herniation, the most recognized
form, is manifest by anisocoria, motor posturing, autonomic disturbances, and death. The specter of
herniation is the major determinant of the absolute threshold of ICP management, which is generally
accepted as 20 to 25 mm Hg (although this range has not been well determined empirically).
The second deleterious aspect of intracranial hypertension is elevated resistance to cerebral blood
flow (CBF), resulting in or exacerbating cerebral ischemia. This resistance can be very roughly
approximated by cerebral perfusion pressure (CPP), which is defined as the difference between mean
arterial blood pressure and ICP:
CPP = mean arterial pressure – ICP
Under normal circumstances, cerebral pressure autoregulation maintains CBF stable over a wide range
of CPP (approximately 50 to 150 mm Hg) (Fig. 21-1). Following injury to the brain, this autoregulation
is generally disrupted. This disruption can be complete, resulting in a pressure-passive system.16 Failure
of autoregulation is associated with worse outcome in patients with TBI.17 More frequently, the
disruption is incomplete, characterized by a normal sigmoid shape but with abnormal elevation of the
lower breakpoint above the normal value of 50 mm Hg (sigmoid dashed line). A probable consequence
of this disruption is that a CPP that is satisfactory for uninjured patients may be associated with a lower
CBF following head trauma (range of hypoperfusion).
In a pressure-passive system, cerebral blood volume (CBV) will increase in proportion to CPP. In such
an instance, the goal is to keep the CPP just above the level of cerebral ischemia, thereby minimizing
iatrogenic intracranial hypertension driven by increased CBV. In the situation of incomplete disruption,
the goal is to keep CPP within the range of autoregulation, because this not only avoids ischemia but
also may decrease ICP if autoregulatory vasoconstriction in response to increased CPP serves to
decrease CBV.
Keeping the CPP in a physiologically normal range of 50 to 70 mm Hg is the recommendation of the
most recent revision of the Guidelines for the Management of Severe Brain Injury.18,19 A CPP less than
50 mm Hg should be avoided. Driving CPP greater than 70 mm Hg with fluids and vasopressors should
also be avoided because of the risk of adult respiratory distress syndrome.20 The CPP target for an
individual patient depends on the status of cerebral autoregulation and determination of the optimal
CPP can be facilitated with neuromonitoring. Furthermore, since CPP is calculated from MAP – ICP, a
low CPP may be a result of low MAP and/or elevated ICP. Interventions taken to address low CPP must
therefore be targeted at the relevant component: blood pressure support in case of low MAP, and ICP
reduction for elevated ICP.
590
booksmedicos.org
Figure 21-1. Cerebral pressure autoregulation. The normal relationship is indicated by the solid line with autoregulatory
breakpoints at 50 and 150 mm Hg. Two disrupted states are also diagrammed. Complete loss of autoregulation (straight dashed line
B) results in a pressure-passive system wherein cerebral blood flow (CBF) (and cerebral blood volume [CBV]) increases linearly
with cerebral profusion pressure (CPP). The more common form of disruption is indicated by the sigmoid (dashed line A) where
the major alteration is a right shift in the lower breakpoint. The circles at the top of the figure represent the diameters of the
resistance vessels in the normal situation. The area of the circles represents CBV. Shifting this relationship to the right by 30 mm
Hg would represent the partially disrupted state. (© R.M. Chesnut, MD, reproduced with permission.)
CLINICAL ASSESSMENT
The objectives during early clinical assessment of the patient with head injury are multiple and must be
accomplished simultaneously. These include establishing adequate oxygenation, ventilation, and
circulatory stability and evaluating the extent of brain injury while treating ICP elevations. Although
some evidence indicates that systemic hypotension may infrequently be the result of a head injury,
always initially presume that hypotension in a trauma patient is the result of hypovolemia. It is a
significant error to withhold volume resuscitation in a misdirected effort to control cerebral edema.
During initial assessment, mental status changes cannot be presumed to be the result of drugs or
alcohol, although routine toxicology screening is appropriate. It should be presumed that any change in
mental status or the neurologic examination in general, or any evidence of herniation (e.g., anisocoria),
suggests an expanding intracranial mass lesion. Under such circumstances, therapeutic ICP reduction
becomes the first priority and diagnostic imaging or surgical decompression must be accomplished
emergently.
Do not assume that apparent neurologic unresponsiveness represents a lack of sensitivity to pain.
Noxious stimuli, such as placement of urinary drainage catheters, nasogastric tubes, or IV catheters, can
precipitate ICP peaks during resuscitation. These procedures should be done quickly and efficiently,
optimally after sedation. Endotracheal intubation is particularly likely to induce herniation in borderline
cases. Whenever practical, consider premedication with analgesics, sedatives, or IV or endotracheal
lidocaine before airway instrumentation.
With regard to the brain injury, several critical assessments are necessary and should be precisely
recorded because trends are at least as important as any single observation. The three key parameters
are level of consciousness, pupillary reflexes and size, and the motor examination.
Glasgow Coma Scale

The single most important assessment for a patient with head injury is to evaluate the level of
consciousness. In this regard, the Glasgow Coma Scale (GCS) has become an international standard that
is easily, rapidly, and reliably obtained (Algorithm 21-1).21 Components of the GCS include assessment
of eye opening (E), verbal response (V), and motor response (M). The Guidelines for the Prehospital
Care of Severe Brain Injury support the use of the GCS for all prehospital care providers.22 Special
training has been developed by the Brain Trauma Foundation to optimize its accuracy
(http://www.braintrauma.org/).
591
booksmedicos.org
For individual patients, it is recommended that all three components be reported separately (e.g.,
E4V5M6) instead of a sum score (e.g., GCS = 15).23 The derived sum score is more relevant for
comparisons at the group level, and for classification and prognosis. For triage purposes, patients can be
stratified using their GCS scores into those with severe injuries (GCS ≤8), moderate injuries (GCS 9 to
12), or mild injuries (GCS ≥13; see Algorithm 21-1).
Assessment requires either a spontaneous response or response following application of a stimulus. At
more severely disturbed levels of consciousness, the motor score has better discrimination, but in milder
injuries the eye and verbal components are more relevant. Thus each component of the scale provides
complementary information. Strengths of the GCS are that it covers a broad spectrum of disorders of
consciousness, is widely applicable, and offers an important tool for monitoring changes in the level of
consciousness. Standardized approaches to both its assessment and its reporting are required in order to
be able to compare evaluations over time or when communicating with other healthcare professionals.
Spontaneous responses are first observed without stimulating the patient in any way. First verbal
stimuli are applied, such as asking a patient to obey commands and at the same time observing whether,
for example, an eye opening occurs. If a patient is not responsive, a stimulus is applied to elicit a
response. The location of the stimulus (central or peripheral) should be standardized and used
consistently. To describe the motor response, only the reaction of the arms should be observed, not the
legs.24
Algorithm 21-1. Glasgow Coma Scale (GCS) triage guide for initial evaluation of head injury. For the motor scale, the best
response for any limb is recorded.
If a GCS component is untestable due to intubation, sedation, or other confounder, the reason for this
should be recorded (e.g., E1VTM2, with “T” indicating “intubated” and not a testable verbal
component). A score of “1” should not be assigned because differentiation between a “true 1” and an
untestable component is relevant.
Pupils
Pupillary asymmetry, dilation, or loss of light reflex in an unconscious patient usually reflects herniation
because of the mass effect from intracranial hemorrhage ipsilateral to the dilated pupil. The probability
of an intracranial mass lesion can be roughly approximated given the degree of anisocoria (1 mm or 3
mm), the mechanism of injury (MVC), and age (Fig. 21-2).21 Occasionally, pupillary signs may indicate
direct second or third nerve injury or trauma to the globe, but this must always be a diagnosis of
exclusion. An unequal and nonreactive pupil is the cardinal sign that herniation is occurring, and rapid
lowering of ICP is essential. An ovoid pupil is also ominous and is associated with injuries that result in
herniation in approximately 15% to 20% of patients.
Figure 21-2. Estimated percentage chance of an extra-axial intracranial mass lesion greater than 25 mL as a function of degree of
592
booksmedicos.org
anisocoria, age, and mechanism of injury. Mechanism of injury was defined as motor vehicle accident (MVA) or other mechanism
(not MVA). (Reproduced with permission from Chesnut RM, Gautille T, Blunt BA, et al. The localizing value of asymmetry in
pupillary size in severe head injury: relation to lesion type and location. Neurosurgery 1994;34:840–845.)
Recently, handheld pupillometry has gained acceptance as a method for quantifying pupillary
response. Traditionally, the measurement of pupil function has been subjective, using a flashlight and
pupil gauge with a qualitative assessment of reactivity, often resulting in poor interrater reliability.25
The currently available devices measure the rate and degree of pupillary contraction and calculates a
normalized neurologic pupillary index, or NPi.26,27 NPi >4 is indicative of normal function, while NPi
<4 raises suspicion for pupil contractility dysfunction. It should be noted that, although one etiology of
decreased NPi is increased ICP, other causes such as direct cranial nerve III dysfunction or diabetic
pupillary paresis must also be considered.
Motor Examination
The motor system is examined for asymmetry, abnormal posturing, or lack of movement. Hemiparesis,
paraparesis, or quadriparesis suggests a cervical or thoracolumbar spine fracture with spinal cord injury.
Hemiparesis secondary to brainstem herniation from the mass effect may be either ipsilateral or
contralateral to the side of the dilated pupil or an intracranial mass lesion.21 Hemiparesis may also
result from significant brain contusion. In the unconscious patient, a painful stimulus should be used to
evaluate motor function. All four extremities should be examined and the results noted, because only
the response of the best limb will be reflected in the GCS score.
RADIOGRAPHIC DIAGNOSIS
Neurosurgical evaluation and assessment are initiated as soon as the potential for significant head injury
is realized. Prompt radiographic evaluation is essential and CT scanning is the imaging modality of
choice for virtually all acute neurologic conditions. Patients with mild head injuries can usually be
observed with sequential examinations and radiographic evaluation may be unnecessary unless the
results determine whether the patient can be discharged from the hospital. In contrast, however, a
cogent argument can be made for the liberal application of CT scanning to even patients with minimal
evidence of TBI as a method of making safe, efficient, and economic triage decisions.30 In any instance,
evidence of neurologic deterioration or the occurrence of a situation wherein the neurologic
examination cannot be followed (e.g., the need for general anesthesia) mandates CT scanning,
intraoperative ICP monitoring, or both. General indications for neurologic imaging (generally, CT
scanning) are listed in Table 21-1.
Patients with moderate or severe injuries require prompt neurosurgical consultation and rapid
radiographic evaluation using the CT scanner. Hemodynamically stable patients with significant
neurologic deterioration should go to the CT scanner immediately following ATLS resuscitation. In
hemodynamically unstable patients who require immediate surgical intervention to sustain intravascular
volume, lifesaving exploratory thoracotomy or laparotomy must take precedence. In such cases, it is a
mistake to delay further investigation of the intracranial compartment pending the end of the case and
transport to the CT scanner. A number of methods can be employed to evaluate the intracranial
compartment during such lifesaving, extracranial surgery, including insertion of an ICP monitor or
ventriculostomy (with air ventriculography, if deemed necessary), transcranial Doppler evaluation, or
even placement of exploratory burr holes in the instance of herniation. For this reason, neurosurgical
consultation should be initiated on arrival in theater rather than at the finish of the case.
Table 21-1 Indications For Neurologic Imaging
593
booksmedicos.org
At the other end of the spectrum, in cases where there is an obvious surgical brain injury, the choice
and timing of diagnostic systemic maneuvers should be subject to modification. Such patients should be
transported directly to theater and examinations such as focused assessment with sonography in trauma
(FAST) or diagnostic peritoneal lavage performed as the patient is being prepped for craniotomy. In
such instances, obviously, early communication between the trauma surgery and neurosurgery
departments is critical.
The spine should be cleared radiographically or immobilized and protected in every patient with a
severe head injury. Although only 13% of patients with severe head injuries have spinal cord injuries,
the potentially devastating consequences of an overlooked spine injury require constant vigilance.
Plain Skull Radiographs

With the routine availability of 24-hour CT scanning capabilities, plain skull radiography has largely
become obsolete in TBI. The likelihood of a surgical intracranial hematoma is strongly correlated with
the presence or absence of a skull fracture if the neurologic examination is factored in.31 Nevertheless,
the superiority of CT imaging in all aspects of evaluating TBI has relegated the use of skull films to
unusual circumstances.
Computed Tomography
The CT finding that correlates most highly with intracranial hypertension is compression or obliteration
of the basilar cisterns (Fig. 21-3). Not only does this finding portend a stormy ICP course, but also the
primary predictor of outcome in patients with this CT picture is the peak level of intracranial
hypertension occurring during the first 72 hours.32,33 When cisternal compression is paired with a
midline shift of more than 5 mm, the prognosis is even more ominous. ICP monitoring should be
immediately initiated in any patient with cisternal compression and intracranial hypertension should be
vigorously treated. Such patients, particularly those with minimal evidence of contusions, die primarily
from secondary brain insults, which implies that they are potentially salvageable.
Figure 21-3. A computed tomography scan that is highly predictive of intracranial hypertension. The basilar cisterns are
obliterated and the sulci are flattened.
Acute epidural hematomas correlate well with skull fractures. The most common association is a
linear, nondisplaced fracture in the temporoparietal region, crossing the middle meningeal artery. The
classic clinical course involving a lucid interval following a brief loss of consciousness with subsequent
suspicion must remain high. The typical CT appearance is a high- or mixed-density concave extra-axial
hematoma with smooth borders (Fig. 21-4).
594
booksmedicos.org
Figure 21-4. Typical computed tomography scan appearance of mixed-density, lens-shaped, acute epidural hematoma with mass
effect.
Acute subdural hematomas occur over the convexity of the brain. The hematoma may evolve from
rupture of bridging cortical veins or bleeding from the underlying parenchymal injury, the latter being a
common source. It is this subjacent tissue damage that generally determines the neurologic outcome of
patients not succumbing to intracranial hypertension. On CT scan, a subdural hematoma appears as an
extra-axial high- or mixed-density crescentic mass that spreads out over the hemisphere, following the
cortical irregularities (Fig. 21-5). The midline shift may be out of proportion to the size of the
hematoma because of the contributing mass effect from an underlying brain contusion or hemispheric
swelling.
Intracerebral hemorrhage and cerebral contusion are common after trauma and are readily visualized
with CT scanning. Brain contusion appears as a focal, heterogeneous density with hemorrhage
interspersed with injured tissue (Fig. 21-6). Intracerebral hematomas are generally more homogeneous
in their high-density appearance. Both of these lesions tend to “blossom” over time because of some
continued hemorrhage and the development of edema. It is important, therefore, to closely observe and
monitor the ICP of such patients because significant and hazardous mass effect may evolve, requiring
surgical extirpation.
With temporal or deep frontal contusions, late deterioration may occur, generally because of
progressive edema development. The peak of such deterioration appears to be around 1 week, although
cases have occurred as late as 10 to 14 days. Most of these patients will complain of severe or
increasing headache or their CT images will show progressive edema formation. As such, a high index of
suspicion must be accompanied by liberal use of follow-up CT imaging and, in particular, not dropping
the level of surveillance until both the clinical situation and the CT appearance are stable. In the
instance of such lesions showing progressive mass effect, the insertion of an ICP monitor may be
considered, even in a patient with a relatively high GCS score.
595
booksmedicos.org
Figure 21-5. Usual computed tomography scan appearance of a crescent-shaped, high-density blood collection conforming to the
contour of the cerebral hemisphere in a subdural hematoma.
Figure 21-6. Contusion and associated intracerebral hematoma in the frontotemporal area.
The typical CT appearance of subarachnoid hemorrhage is a layer of blood over the cerebral cortex,
layering over the tentorium and commonly filling the basal cisterns. Cerebral edema appears as areas of
decreased density, which may be either focal or diffuse. Posttraumatic edema formation generally takes
hours to days to develop unless compounded by hypoxia or hypotension. The “swollen brain” commonly
seen in the setting of trauma may be caused by edema or increased CBV (unclotted, intravascular blood
is low density). DAI, typical of acute acceleration–deceleration injury, appears on CT scan as small areas
of focal hemorrhage in the brainstem, thalamus or deep nuclear region, corpus callosum, and
hemispheric white matter and may be accompanied by cerebral swelling. Finally, gunshot wounds or
other penetrating injuries can be evaluated with CT scanning to allow accurate preoperative assessment
of the anatomic injury for prognostic and therapeutic planning purposes.
One significant issue of recent origin is the “blossoming” or appearance of new lesions subsequent to
CT images obtained at very short intervals following injury. Most of the “classic” TBI studies presented
initial CT data from studies done hours following trauma. With improved prehospital transport and the
ready availability of CT imaging, many initial studies are now performed 15 to 30 minutes after injury.
As a result of such ultra-early CT scanning, there is now a risk of missing significant intracranial lesions
596
booksmedicos.org
by obtaining imaging before their appearance or during an early phase of their evolution. For this
reason, in any patient with moderate or severe TBI, intracranial hypertension, or
anticoagulation/antiplatelets, we routinely obtain an early follow-up CT image at 4 to 6 hours after
admission. In patients with mild TBI who have a stable neurologic examination and none of the
aforementioned risk factors, routine repeat head CT rarely changes management and may be
skipped.28–31
It should be noted that absence of CT findings in a patient with a history of TBI does rule out a TBI.
Recent data suggest that a significant number of patients seen at a level I trauma center with a negative
CT will have pathologic findings with 3T MRI imaging.32 Advanced MRI techniques, such as diffusion
tensor imaging and functional MRI hold great promise for improved diagnosis and prognosis, especially
in mild TBI/concussion.33
Ancillary Imaging
As noted earlier, there is a significant association between TBI and injury to the axial skeleton,
particularly to the cervical spine. In addition, particularly when associated with basilar skull fractures or
facial fractures, TBI suggests the possibility of damage to the major arteries of the neck. As such,
particular attention should be given to careful radiographic clearance of the spine and consideration of
studies such as CT angiography of the great vessels rostral to the aortic arch.
MANAGEMENT
Evidence-based Medicine and the Management of Traumatic Brain Injury
Wherever possible, the recommendations in this text are evidence based. For details, the reader is
referred to the source documents.
The publication of the first edition of the Guidelines for the Management of Severe Brain Injury in
1996 represented a significant step in standardizing the management of TBI based on published, peer-
reviewed literature.22 This document represents the application of a strict evidence-based process to 14
topics relevant to TBI care. Following an exhaustive, explicitly defined literature search covering each
topic, the recovered literature was carefully classified along a three-point continuum of scientific rigor.
As such, each article was ranked as class I, class II, or class III and the analysis of the scientific basis of
each topic was predicated on the most scientifically rigorous (highest literature class) reports available.
This process produced a set of standards, guidelines, and options for treatment where standards (based
on class I evidence) represent principles with a high degree of clinical certainty, guidelines (based on
class II evidence) reflect principles with a moderate degree of clinical certainty, and options (based on
class III evidence) reflect principles for which unclear clinical certainty exists. By specifically defining
the scientific foundation on TBI management issues, the Guidelines for the Management of Severe Brain
Injury provided an unbiased reference focused on facilitating scientific management of TBI.
Since the initial publication of the Guidelines for the Management of Severe Brain Injury, it has
undergone updating and revision10,11 encompassing more recently published data and revising earlier
practice recommendations where indicated as well as expanding the scope of covered topics. The same
evidence-based process has also been applied in the generation of other sets of brain injury guidelines.
The Guidelines for the Prehospital Management of Traumatic Brain Injury were published in 2002,20
spawning the training efforts mentioned previously. In 2001, the Guidelines for the Management of
Penetrating Brain Injury (PBI) were published.23 The Guidelines for the Management of Pediatric Brain
Injury were published in 2003.18 The Guidelines for the Surgical Management of Traumatic Brain Injury
were published in 2001.24 The third edition of the Guidelines were published in 200734 and work on the
fourth edition is now underway.
General Considerations
Although there is no present technology for its quantification before the insertion of an ICP monitoring
device, early intracranial hypertension may certainly exert a detrimental influence on outcome. Not
only do all treatment modalities for intracranial hypertension have serious potential complications, but
also many of them can directly interfere with resuscitation procedures (e.g., use of osmotic diuretics).
The efficacy of successful systemic resuscitation in improving the likelihood of survival from trauma in
general is well accepted. In addition, the acknowledged negative influence of secondary insults (e.g.,
hypotension and hypoxia) on outcome from severe head injury renders systemic resuscitation essential.
597
booksmedicos.org
Therefore, all treatment must be consistent with optimal systemic resuscitation.
The composition and volume of the IV fluids used to resuscitate patients with head injuries should be
selected with the purpose of restoring intravascular blood volume. Although the widely disseminated
but scientifically unsupported adage of “keeping TBI patients dry” has now been discarded, the concept
of restricting free water remains desirable. As such, isotonic crystalloid solution in the form of 0.9%
normal saline (NS) is preferable to lactated Ringer solution as a resuscitation fluid for TBI.35 For some
time, a growing body of indirect scientific support appeared to support the use of 250 mL of 7.5%
hypertonic saline as the first resuscitation fluid in TBI victims. However, a recent randomized controlled
trial from Australia has suggested that this may not be of benefit under optimal resuscitation
conditions.28
The endpoints of resuscitation do not change depending on the presence or absence of a head injury.
Blood volume should be normal, with an appropriate blood pressure and central venous pressure,
adequate urine output and peripheral perfusion, and progressive improvement of any base deficit. The
systolic blood pressure should never be allowed to drop below 90 mm Hg. Some evidence indicates an
advantage to targeting a mean arterial pressure of 80 to 90 mm Hg during resuscitation until ICP
monitoring can be initiated. Once ICP is available, a minimal CPP of 60 mm Hg should initially be the
goal.
Initial Resuscitation
Resuscitation in the Absence of Clinical Signs of Herniation
2, 3 Algorithm 21-2 is based on the Guidelines for the Management of Severe Brain Injury and the
Guidelines for the Prehospital Management of Severe Brain Injury for use by prehospital and initial at-
hospital care providers and emergency physicians to guide decision making in resuscitating TBI victims
and determining the necessity of ICP-lowering therapy.22,34 “Signs of increased ICP” implies pupillary
abnormalities, motor posturing, or neurologic deterioration not related to medications. When these
signs are not present, mannitol is not given and the goal of ventilation is eucapnia (i.e., no
hyperventilation). When signs of herniation are present, the patient is hyperventilated to a PaCO2 of 30
to 35 mm Hg and mannitol may be given if the patient’s volume status is normal.
Algorithm 21-3 is based on the Guidelines for the Management of Severe Brain Injury for evaluation
and treatment of the severe TBI patient from arrival at the trauma center prior to the placement of an
ICP monitor.34 As with any trauma patient, the first step is Advanced Trauma Life Support (ATLS)
resuscitation. When appropriate, brain-specific therapies are incorporated into the treatment course.
Brain-friendly initial ICU management should lead directly to monitoring of ICP.
Elevating the head of the bed (reverse Trendelenburg position in the absence of clearance of the axial
skeleton), a standard maneuver to improve cerebral venous outflow and reduce ICP, has also been
shown to generally lower the CPP in the absence of adequate volume resuscitation. Because the
reduction in CPP may elevate the ICP per se, it is not advised until complete resuscitation has been
accomplished.
598
booksmedicos.org
Algorithm 21-2. Prehospital evaluation and treatment of a patient with severe traumatic brain injury. “Signs of increased ICP” is
the decision point for determining the necessity of intracranial pressure (ICP)-lowering therapy. These signs include pupillary
abnormalities, motor posturing, or neurologic deterioration not related to medications. The order of steps is determined by the
risk–benefit ratio for individual treatment maneuvers. This algorithm should be viewed as “expert opinion” and used as a
framework, which may be useful in guiding an approach to field management of such patients. (© R.M. Chesnut, MD, FCCM,
reproduced with permission.)
The confusion and agitation often associated with head injury can increase intracranial hypertension.
Therefore, patients with suspected head injury should generally receive sedatives and analgesics
whenever possible. Particularly in the TBI patient, the difference between sedation and analgesia should
be kept in mind and the two agents titrated specific to their respective indications. Short-acting agents
such as propofol are preferable in the interest of following the neurologic examination.
In addition to eliminating any possibility of spontaneous ventilation and mandating complete
ventilatory control, pharmacologic relaxation has the undesirable effect of limiting the neurologic
examination to the pupils and the CT scan. Its use in the absence of evidence of herniation, therefore,
should be limited to situations where sedation and analgesia alone are not sufficient to optimize safe
and efficient patient transport and resuscitation.
The “prophylactic” administration of mannitol is not suggested, because of its volume-depleting
diuretic effect. In addition, although it is desirable to approximate the lower end of the normal range of
PaCO2 during transport of a patient suspected of having brain injury, the risk of exacerbating early
ischemia by vigorous hyperventilation outweighs the questionable benefit in the patient without
evidence of herniation. Therefore, ventilation parameters consistent with optimal oxygenation and
“normal” ventilation are recommended. The minute ventilation should be targeted at 100 mL/kg per
minute until quantitative measurement of end-tidal carbon dioxide (EtCO2) or PaCO2 is available. The
Guidelines for the Prehospital Management of Severe Brain Injury suggest the use of EtCO2 monitoring
during prehospital resuscitation and transport whenever possible. In the absence of signs of intracranial
hypertension, ventilation should be adjusted to accomplish a PaCO2 of 35 mm Hg when arterial gas
values become available.
Resuscitation in the Presence of Clinical Signs of Herniation
Signs of intracranial hypertension consist of evidence of transtentorial herniation (pupillary dilation or
loss of reactivity or motor posturing or flaccidity) or progressive neurologic deterioration not
attributable to other causes (e.g., sedation). When such signs occur, aggressive treatment of suspected
intracranial hypertension is indicated. Hyperventilation to a PaCO2 target of approximately 30 mm Hg
599
booksmedicos.org
should be accomplished by increasing the minute ventilation to approximately 120 to 140 mL/kg per
minute or as directed by quantitative CO2 monitoring. Because hypotension can produce both
neurologic deterioration and intracranial hypertension, the use of mannitol is less desirable unless
adequate volume resuscitation has been accomplished. If such is the case, however, mannitol should be
administered by bolus infusion to establish the optimal osmotic gradient. Under such circumstances, it is
critical that the diagnosis and treatment of the neurologic injury be accomplished with utmost haste.
Aggressive restoration of intravascular volume, maintenance of adequate CPP, and avoidance of
hypoxia are essential for the management of intracranial hypertension. Volume resuscitation should be
vigorous and thorough, with a target of euvolemia. Restrict free water by using isotonic fluids, which
makes NS preferable to lactated Ringer solution. Optimally, continuous monitoring of central venous
and arterial pressures should be instituted early.
Algorithm 21-3. Evaluation and treatment of the patient with severe traumatic brain injury on arrival at the trauma center. The
order of steps is determined by the risk–benefit ratio for individual treatment maneuvers. This algorithm should be viewed as
“expert opinion” and used as a framework, which may be useful in guiding an approach to initial hospital management of such
patients prior to the initiation of ICP monitoring. (© R.M. Chesnut, MD, reproduced with permission.)
Neuromonitoring
Intracranial Pressure Monitoring
All patients with survivable, severe brain injuries and a significant percentage of those with moderate
injuries require continuous ICP monitoring. The most recent revision of the Guidelines for the
Management of Severe Brain Injury indicates that class II evidence supports monitoring of all patients
with a postresuscitation GCS score equal to or less than 8 who have any CT evidence of intracranial
pathology.36 Class III level evidence supports monitoring in patients with severe TBI and a normal CT
scan if they have two or three of the following: (a) age older than 40 years, (b) any history of
hypotension, or (c) abnormal motor posturing. ICP monitoring in other patients is left to the discretion
of the physician. ICP monitoring should be considered in any patient with a GCS score of 12 or less who
cannot be closely monitored clinically or whose CT scan demonstrates evidence of intracranial
hypertension (i.e., mass lesion, obscured or absent basal cisterns, or midline shift).
600
booksmedicos.org
Although many techniques are available, the most common involve small fiberoptic or strain gauge
catheter tip pressure sensors placed several millimeters into the brain or fluid-coupled catheters placed
into the lateral ventricles. The minimally invasive catheters are reliable and have a very low
complication rate,37 making them an ideal choice in instances where a minimum-risk ICP monitoring
technique is desired (e.g., in a moderate head injury that needs general anesthetic). They are also useful
when the ventricles are too small to cannulate or there is an uncorrected coagulopathy. Ventriculostomy
catheters have the added capability of allowing CSF drainage for ICP control. They are technically more
difficult to place, and the complication rate is somewhat higher at 1% to 7%.38 Rarely, however, do
catheter-associated hemorrhages require surgical drainage.
Monitoring ICP not only provides early warning of herniation but also, by allowing calculation of
CPP, opens up the possibility of more precisely optimizing CBF and preventing ischemic secondary
brain injury. Because all methods of lowering ICP or raising CPP have potentially harmful side effects,
using such agents to treat suspected intracranial hypertension without monitoring ICP is not
recommended. In hospital settings where ICP monitoring is not possible, recent evidence suggests that
hourly neurologic examination by a physician may serve as a proxy for ICP monitoring. In most of the
developed world, such routine reevaluation by a physician would be extremely resource intensive, and
invasive ICP monitoring remains the preferred method when it is available.39,40
Monitoring of Cerebral Perfusion and Oxygenation

Preventing cerebral ischemia is a mainstay in the management of severe TBI patients. There are
currently several methods that are readily available for ICU measurement of the adequacy of cerebral
oxygen delivery.
Placing a catheter into the jugular bulb via a retrograde venous route allows sampling of the
saturation of oxygen in the blood leaving the brain. Jugular venous oxygen saturation values below
50% are associated with cerebral ischemia and worsened recovery, whereas saturations above
approximately 85% suggest hyperemic flow.41 It should be noted that this method averages a large
volume of the brain and does not include blood from all of the supratentorial parenchyma so that it
cannot completely rule out ischemia.
An alternative monitoring method is the insertion of an oxygen-sensing (Clark) electrode into the
brain parenchyma to measure PBtO2. PBtO2 values of less than 20 mm Hg are associated with reduced
CBF and poor oxygenation.42,43 There is a growing body of evidence supporting the utility of this
method, and PBtO2-directed therapy has been associated with improved outcomes.44,45 This technique
samples only a very small, focal volume of tissue, so is typically placed into normal brain with the
intent of preserving healthy tissue.
Cerebral microdialysis constitutes a third method of monitoring for evidence of cerebral metabolism
by allowing the measurement of tissue lactate and pyruvate and calculating the lactate/pyruvate ratio.
Like PBtO2 monitoring, this newer technique also samples a very focal region. At present, although
cerebral microdialysis is very sensitive and is being used with growing frequency,46 it is primarily
considered as a research tool.
Monitors that directly measure CBF are also available for clinical use. These monitors measure flow
through a thermal dilution method, and can also provide real-time brain temperature and tissue thermal
conductivity, which is a measure of parenchymal water content. In conjunction with CPP data, a CBF
monitor can help determine the status of a patient’s autoregulatory function.47 Additionally, noninvasive
optical techniques for measuring CBF are showing promising preliminary results, although they have
yet to be adopted into mainstream clinical practice.48–51
Of note, these monitors are not mutually exclusive. They may be used to supplement each other or to
verify findings from one technique that are suspect. Such a consideration becomes particularly
important when significant prolongation or escalation of therapy is being considered based on an
abnormal value from one monitoring system. In many practices, cerebral oxygenation monitors are
placed in any patient who receives an ICP monitor.
Medical Intervention
Neurocritical Care after Stabilization
Once stabilized, most patients with a positive CT scan merit observation in a neurologic intensive care
unit for hourly observation for at least 24 hours. For patients with severe TBI, the length of ICU stay is
typically several days. In these patients, the importance of meticulous general critical care is important,
because the protracted ICU stay and the necessity for intubation, mechanical ventilation, and other
601
booksmedicos.org
artificial support systems significantly increase the risk of nosocomial and iatrogenic complications.
Venous drainage of the brain should be facilitated by avoiding constriction of the jugular system in
the neck and elevating the head of the bed in euvolemic patients. In addition, attention should be paid
to intrathoracic pressures, particularly when considering the use of positive end-expiratory pressure
(PEEP) or continuous positive airway pressure (CPAP). Increased intra-abdominal pressure can also
decrease venous return, compromise jugular drainage, and elevate ICP.
Fever will elevate ICP and is independently correlated with decreased recovery in severe TBI. Local
measures (e.g., cooling blankets, fans) should be used in conjunction with acetaminophen to keep
temperatures below 37.5°C to 38°C when ICP requires treatment.
In patients presenting with radiographic evidence of intracranial injury or GCS less than 8,
administration of prophylactic antiepileptic drugs is indicated for 7 days postinjury to prevent early
seizures.52 Patients with early seizures should continue antiepileptics and follow up with an epilepsy
specialist for subsequent management.
4 Recent investigations in the trauma population have demonstrated an increased risk of complications
in patients who undergo blood transfusion, such as the acute respiratory distress syndrome and the
systemic inflammatory response syndrome. A recent randomized controlled trial demonstrated more
complications when patients were transfused to maintain a hemoglobin of 10 g/dL versus 7 g/dL.53
Based on this trial, hemoglobin should be maintained at or above 7 g/dL.
Control of Established Intracranial Hypertension

All of the previously discussed “pre-ICP monitoring” steps may be used in direct response to intracranial
hypertension, their application and intensity tapered to achieve ICP control. These interventions should
be considered the basic steps in this respect and should be optimized prior to adding further treatments.
CSF drainage, hyperventilation, mannitol, barbiturates, and so on are the mainstays of therapy to
control intracranial hypertension. Each, however, has significant potential complications, which can
obviate their beneficial effects. Therefore, they should not be employed unless intracranial hypertension
is established by monitoring ICP, and caution and vigilance must attend their usage. Although the
treatment of intracranial hypertension is not the primary focus of this chapter, some brief comments
will be useful.
As noted, the treatment of intracranial hypertension should be initiated on a base of adequate
sedation and analgesia, control of fever, and optimization of systemic physiologic conditions that might
exacerbate ICP elevation (e.g., intrathoracic pressure). Neuromuscular blockade may be added to
sedation and analgesia if further ICP control is desired. It does not always work, so a trial should be
initiated to determine whether the patient is a “responder” before considering long-term use. Blockade
to the level of one to two twitches out of a train-of-four is a reasonable target in this population.
Treatment for intracranial hypertension in adults from the original edition of the Guidelines for the
Management of Severe Brain Injury is outlined in Algorithm 21-4. When consulting this algorithm,
remember that it represents a consensus opinion (class III evidence) and that, for this reason, a
treatment algorithm was not included in the 2008 revision. When this algorithm was developed, the
role of hypertonic saline was not addressed. More recently, a consensus-based best practices for TBI was
developed by the American College of Surgeon’s Trauma Quality Improvement Program.24 These best
practices are an extension of the Severe Brain Injury Guidelines and are meant to provide expert opinion
where class I and II evidences are lacking. A depiction of how these guidelines might be applied in
clinical practice is depicted in Figure 21-7.
When available via ventriculostomy, CSF drainage should be the first method of managing
intracranial hypertension. There is no consensus on what pattern of drainage is most efficacious. It must
be noted that ICP measurement cannot be performed when the ventricular catheter is open to drain. For
this reason, we generally drain intermittently for several minutes, then reclamp the catheter and
measure the ICP. Requiring such cycling more than five times in 1 hour constitutes a need for
consideration of therapeutic escalation.
Cerebral Edema and Osmolar Therapy

Cerebral edema during the early postinjury period is generally cytotoxic (intracellular). Later, vasogenic
(extracellular) edema may also play a role in brain swelling. Although resulting from different
mechanisms (cellular membrane dysfunction and blood–brain barrier breakdown), our present
treatment for cerebral edema in trauma is limited to the administration of osmotic agents, most
classically mannitol. Generalizing the documented efficacy of corticosteroids to decrease tumor-related
cerebral edema to the setting of trauma-induced edema has proven to be ineffective and actually
602
booksmedicos.org
harmful and is now considered contraindicated.54
Algorithm 21-4. Treatment of established intracranial hypertension, based on the Guidelines for the Management of Severe Brain
Injury. The order of steps is determined by the risk-benefit ratio for individual treatment maneuvers. This algorithm should be
viewed as “expert opinion” and used as a framework, which may be useful in guiding an approach to elevated ICP.
Figure 21-7. A tiered approach to management of intracranial hypertension: increasing levels of intervention are associated with
increased complications.
Hyperosmolar agents increase the osmotic gradient, drawing fluid from the interstitial compartment
into plasma, thereby reducing brain volume. In regions where the blood–brain barrier has been
disrupted, however, such agents are minimally effective and can actually leak into tissues.55 The
extravasated hyperosmolar agent then functions as an osmotic sink, drawing in free water and
paradoxically increasing parenchymal edema. Fortunately, the area of blood–brain barrier breakdown is
generally much smaller than the area of edema that it creates so that hyperosmolar therapy is generally
effective in lowering ICP. Caution should be exercised, however, as mannitol can produce significant
603
booksmedicos.org
diuresis. The resulting hypovolemia can result in hypotension which, as described above, can be
deleterious to patient outcomes.
More recently, the use of hypertonic saline to elevate serum osmolarity has become increasingly
incorporated into pediatric TBI management. In this population, it can help control intracranial
hypertension, although its use has not yet been confirmed with rigorous clinical study. In those studies,
3% sodium chloride solution has generally been used, infused at 0.5 to 1.0 mL/kg per hour. As a result
of such publications, the Guidelines for the Management of Severe Pediatric Brain Injury contained
recommendations placing the use of hypertonic saline–based osmotherapy at the same level as the use
of mannitol, leaving the choice to the physician.56
In the treatment of adult TBI, no evidence exists for the routine usage of hypertonic saline infusion to
induce iatrogenic hypernatremia. In bolus form, 23.4% saline is effective in acutely lowering ICP, while
at the same time increasing the intravascular volume. Because it does not cause diuresis, it may be
preferred over mannitol when hypotension is present. Rigorous, randomized comparison data on its
relative efficacy and duration with respect to mannitol are lacking.57,58 There is some data to suggest
there is a dose-dependent effect on the duration of ICP control.59 Regardless of which agent is chosen,
hyperosmolar agents are most effective at controlling ICP when given as a bolus. It should be noted,
however, that rapid infusion of higher concentrations of hypertonic saline through a central line can
produce temporary asystole.
If hyperosmolar agents have been administered multiple times, when withdrawing therapy, the serum
sodium and osmolarity should be allowed to return to within normal limits prior to removing the ICP
monitor. The risk of rebound intracranial hypertension associated with the administration of hypotonic
solutions such as half-NS or lactated Ringer solution can thereby be minimized.
Barbiturate Coma and Paralysis

In patients who have failed to respond to the above methods, barbiturate coma and paralysis can be
effective methods for controlling intracranial hypertension.60–62 These interventions do have the
drawback of reducing the neurologic examination to just pupillary response. In such cases,
neuromonitoring data such as ICP, PBrO2, and JVO2 must be used to evaluate whether the patient has
responded adequately to the intervention, or if surgical intervention is required. Barbiturate coma can
also cause hypotension, so care should be taken to maintain adequate MAP and CPP in during its use.63
Surgical Intervention
When ICP control does not respond to medical management steps, surgical management must be
considered. Indeed, with each escalation in medical therapy, surgical intervention should be considered:
large mass lesions, for example, or widespread cerebral contusions will often require eventual surgical
decompression, so it is preferable to operate before all medical options are exhausted.
Skull Fracture (Including Basal Skull Fractures)

Skull fractures are a common result of head trauma and, when closed and not displaced, rarely require
treatment per se. Depressed skull fractures are easily seen on plain frontal or lateral skull films and on
CT. The mechanism of injury is usually a direct blow to the skull by a blunt object. Closed depressed
skull fractures that are comminuted and those with a fragmented outer margin displaced beneath the
inner table have characteristically been treated surgically, although growing evidence indicates that
many may be treated nonoperatively if there is no neurologic dysfunction or CT evidence of underlying
tissue injury. The best available evidence does not support elevation for the prevention or treatment of
epilepsy.
Open fractures are also generally treated surgically, although, again, growing evidence indicates that
fresh, noncomminuted fractures without neurologic deficit, CSF or brain extrusion, gross contamination,
or underlying tissue injury can be closed and treated with prophylactic antibiotics. When surgery is
indicated, the primary goal is to avoid infection by containing CSF, and closing the wound in a manner
to ensure healing. Cosmesis is a secondary consideration. Once a fracture has been determined to be
operative, early operation is recommend to reduce the incidence of infection. All management strategies
for open (compound), depressed fractures should include antibiotics regardless of whether surgery is
undertaken. The exact nature of the antibiotics used and the duration of treatment remain inadequately
delineated in the existing literature. The general tendency is the use of broad-spectrum antibiotics (vs.
gram-positive and gram-negative aerobic and anaerobic bacteria) for 5 days if soft tissue coverage is
achieved.64–67 In cases where soft tissue coverage is impossible, the duration of antibiotic usage is not
604
booksmedicos.org
well studied, but should probably continue for at least 2 weeks. Indications for nonoperative
management are given in Table 21-2.
Table 21-2 Indications for Nonoperative Management of Compound Depressed

Skull Fractures
5 Basilar skull fractures are usually diagnosed with CT imaging or on clinical evidence, as they are
poorly visualized on plain films. Clinical signs include otorrhea or rhinorrhea, subcutaneous ecchymoses
overlying the mastoid region (Battle sign), bilateral periorbital ecchymoses (raccoon eyes), or
hemotympanum. A basilar skull fracture may involve the paranasal sinuses, piriform sinus, petrous
bone, sphenoid sinus, or sella turcica. Injuries to adjacent structures, such as the seventh or eighth
cranial nerves, brainstem, and carotid or basilar arteries, are not uncommon. These are generally
visualized with CT scanning, although special protocols may be required. If vascular injury is suggested
(such as by fracture lines involving the carotid canal), CT or catheter angiography should be considered.
In the acute CSF leak, no specific therapy is indicated. The leak should not be tamponaded unless it is
brisk. Antibiotics should not be administered solely for prophylaxis of meningitis. Most CSF leaks stop
spontaneously with minimal treatment (e.g., elevating the head of the bed). Leaks that continue more
than 72 hours generally require temporary CSF diversion (e.g., via lumbar drainage or
ventriculostomy). CSF drainage that does not respond to diversion will require surgery.68 Although
most instances of rhinorrhea cease without surgery, the most common operation for persistent CSF leaks
is exploration of the floor of the frontal fossa. The goal of such surgery is to identify the dural defect
(often associated with herniation of a small tongue of brain tissue) and either close it primarily, patch
it, or otherwise isolate the subarachnoid compartment from the skull base.
Epidural Hematomas
Epidural hematomas are frequently of arterial origin and have a tendency to expand. Prognosis varies
directly with level of consciousness at time of surgery, ranging from 0% mortality for patients conscious
throughout, to 27% with the classic lucid interval, to over 50% if the patient never regains
consciousness. Aggressive surgical management has resulted in an overall mortality of about 9%.33
The recommendations regarding the management of epidural hematomas contained in the Guidelines
for the Surgical Management of Traumatic Brain Injury24 can be summarized as follows: an epidural
hematoma larger than 30 mL, clot thickness greater than 15 mm, or midline shift over 5 mm should be
surgically evacuated regardless of the patient’s GCS score. In patients with a GCS score of 8 or less,
evacuation should be emergent. If the GCS score is higher than 8, evacuation should be done as soon as
possible but must not interfere with other resuscitative efforts unless there is evidence of progressive
deterioration. It is strongly recommended that patients with any acute epidural hematoma with
anisocoria undergo surgical evacuation as soon as possible. Epidural hematomas of less than 30 mL, clot
thickness below 15 mm, and midline shift less than 5 mm should be considered for evacuation because
the risk of evacuation appears less than the dangers of enlargement and neurologic injury. Epidural
hematomas of this size in patients with GCS scores above 8 may be considered for nonoperative
management, including frequent neurologic monitoring in an ICU setting and serial CT imaging.
Although the mean time for enlargement of such lesions is approximately 8 hours after trauma, they
may occur at intervals up to 36 hours.
Subdural Hematomas
Subdural hematomas are the more common extra-axial mass lesion, particularly in non–motor vehicle
trauma. For acute subdural hematomas, the prognosis is less optimistic, with mortality rates of
approximately 50%. To a great extent, this is related to the often significant injury to the underlying
brain.
The recommendations regarding the management of subdural hematomas contained in the Guidelines
605
booksmedicos.org
for the Surgical Management of Traumatic Brain Injury24 can be summarized as follows: an acute
subdural hematoma with a thickness greater than 10 mm or midline shift above 5 mm on CT should be
surgically evacuated, regardless of the patient’s GCS score. Evacuation should be on an emergency basis
if the initial GCS score is less than 8. In patients with higher GCS scores, evacuation should be as soon
as reasonably possible. A comatose patient (GCS score 8) with a subdural hematoma with less than 10
mm thickness and midline shift below 5 mm should undergo surgical evacuation of the lesion if any of
the following apply:
The GCS score decreased between the time of injury and hospital admission by 2 or more GCS points.
The patient presents with asymmetric or fixed and dilated pupil(s).
The ICP exceeds 20 mm Hg for more than 5 to 10 minutes.
Patients with subdural hematomas of less than 10 mm thickness and midline shift below 5 mm and
GCS scores greater than 8 can be treated nonoperatively, but should be closely observed.
It appears that outcome from subdural hematomas is proportional to the timing of evacuation. When
surgery is planned, it should be performed within 4 hours whenever possible.69 If surgical evacuation of
an acute subdural hematoma in a comatose patient (GCS score 8) is indicated, it should be done using a
full craniotomy with or without bone flap removal and duraplasty.
Frequently, consideration is given to leaving off the bone flap following the evacuation of acute
subdural hematomas, particularly when the surgeon feels that there is evidence of brain swelling (e.g,
brain herniation above craniotomy), or a perceived risk of subsequent brain swelling (e.g., significant
preoperative midline shift). Unfortunately, there is a relative dearth of information on this group of
patients.
Parenchymal Lesions
Surgery for intraparenchymal mass lesions remains controversial. Arguments against surgery include the
risks of the operation itself as well as damage to tissue that may otherwise go on to recover. Arguments
for surgery focus on preventing the hazards of intracranial hypertension caused by the lesion itself or
progressive edema formation as the lesion matures. Much of the difficulty in determining the
applicability of surgery in individual situations arises from our inability to consistently predict which
patients will rapidly deteriorate (e.g., proceed on to herniation) or fail nonoperative therapy by
developing intracranial hypertension refractory to medical therapy.
Recommendations regarding the management of traumatic parenchymal lesions contained in the
Guidelines for the Surgical Management of Traumatic Brain Injury24 can be summarized as follows: in
general, patients with any lesion greater than 50 mL in volume should be treated operatively.
Additionally, patients who have parenchymal mass lesions and signs of progressive neurologic
deterioration referable to the lesion, medically refractory intracranial hypertension, or signs of mass
effect on CT scan should be considered for surgery.
Patients with GCS scores of 6 to 8 should be treated operatively if they have frontal or temporal
contusions greater than 20 mL in volume with either midline shift over 5 mm or cisternal compression
on CT scan.
Patients with parenchymal mass lesions may be managed nonoperatively if they do not show
evidence for neurologic compromise, have controlled ICP, and have no significant signs of mass effect
on CT scan. Such patients should be managed with intensive monitoring, frequent clinical examination,
and serial imaging. Surgery should be readdressed if difficulties with control of intracranial
hypertension lead to consideration of “higher-tier” therapies (e.g., hypothermia or barbiturate coma) so
as to avoid the secondary complications of such therapy. In all nonoperatively treated patients with
parenchymal mass lesions, surgery should be considered before reaching the medical “point of failure.”
Surgical management may involve decompression to “make room” for the lesion-induced swelling,
evacuation and débridement of the offending lesions, or a combination. Because evacuation of such
lesions does not always eliminate the development of intracranial hypertension, extensive craniotomy
with expansible duraplasty and without replacing the bone flap should be considered at the time of
operation.
Diffuse Injury
The mortality rate of diffuse brain injury is directly related to the significance of the associated
intracranial hypertension. As such, the mortality rate of diffuse injury with open basilar cisterns is
approximately 13%, whereas compression or absence of cisterns has an associated mortality rate of
about 38%. Diffuse injuries are not amenable to surgical therapy unless decompressive craniectomy is
606
booksmedicos.org
indicated for control of intractable intracranial hypertension. Although a recent study suggested that
decompressive bifrontal craniectomy led to unfavorable outcomes in these patients, flaws in its design
(most notably, significant dissimilarity in the severity of neurologic injury between the treatment and
the control groups) called into question the validity of its conclusions.70–72
DAI is a reasonably distinct subset of diffuse brain injury. It is characterized on CT scan as small areas
of focal hemorrhage in the brainstem, thalamus or deep nuclear region, corpus callosum, and
hemispheric white matter, which may be associated with cerebral swelling. Intracranial hypertension is
an inconsistent part of this syndrome. When ICP is elevated, however, successful management improves
outcome. These patients tend to recover to varying extents; many of them will significantly improve in
their level of consciousness but will generally be left with diffuse neurologic deficits (e.g., spasticity,
cognitive impairments). Although a favorable prognosis seems to be correlated with fewer lesions on
imaging studies and early improvement in level of consciousness, prognostication is difficult in
individual cases of DAI.
Posterior Fossa Lesions

Posterior fossa lesions are particularly dangerous because the progression from a benign lesion to a
critical lesion is so precipitous and deadly. Patients may rapidly deteriorate from awake and alert to
comatose, with signs of herniation (“upward” [caused by uncompensated swelling in the posterior fossa]
or “downward” [from hydrocephalus]). Because of difficulties with the technology and uncertainty as to
what pressures might be critical, monitoring of posterior fossa ICP is rarely performed. Vigilant clinical
observation, tempered with a high degree of preemptive concern, therefore, represents the only form of
monitoring currently applicable.
The recommendations regarding the management of traumatic posterior fossa lesions contained in the
Guidelines for the Surgical Management of Traumatic Brain Injury24 can be summarized as follows:
rapid suboccipital craniectomy for evacuation of acute traumatic posterior fossa mass lesions is
recommended in patients with neurologic dysfunction or deterioration referable to the lesion or mass
effect on CT scan. Mass effect on CT scan appears as distortion, dislocation, or obliteration of the fourth
ventricle; compression or loss of visualization of the basal cisterns; or presence of obstructive
hydrocephalus.
In general, surgery is recommended for any clot larger than 3 cm in diameter, whereas conservative
management may be considered with clots smaller than 3 cm when not associated with acute subdural
or epidural hematomas. Because of the potential for rapid, unheralded deterioration, evacuation should
be performed as soon as possible in patients with indications for surgical intervention.
Penetrating Injuries
Penetrating injuries to the brain present several unique management problems, including the
prophylaxis and treatment of intracranial infection, the possibility of epilepsy, and the risk of occult
vascular injuries. The recommendations regarding the management of penetrating brain trauma
contained in the Guidelines for the Management of PBI23 can be summarized as follows: Although plain
radiographs may be useful in determining intracranial trajectory, CT scanning of the head is the
modality of choice in PBI. In addition to the standard axial views with bone and soft tissue windows,
coronal sections may be helpful in patients with skull base or high convexity involvement.
Angiography or CT angiography should be considered in patients with PBI. It is strongly
recommended in cases in which the wound’s trajectory passes through or near the Sylvian fissure,
supraclinoid carotid, cavernous sinus, or a major venous sinus because of the increased risk of traumatic
aneurysm or arteriovenous malformation. Sentinel signs of vascular abnormalities are large initial
hematomas or the delayed development of substantial and otherwise unexplained subarachnoid
hemorrhage or hematoma. When discovered, such vascular lesions should be definitively managed.
A major complication of penetrating injury is infection, both meningitis and abscess. Most infections
occur within 3 weeks (55%) to 6 weeks (90%). The major risk factors appear to be CSF leaks, air sinus
wounds, or wound dehiscence. The incidence of infection with the use of broad-spectrum antibiotic
treatment ranges from 1% to 11%. Although the main causative agent appears to be Staphylococcus,
gram-negative bacteria are also frequent and Clostridium or other anaerobic organisms may be found
with appropriate culture techniques. As such, antibiotic prophylaxis is indicated in all penetrating
injuries. Broad-spectrum regimens, including anaerobic coverage, lasting for 7 to 14 days appear to be a
reasonable approach.
Seizures are much more frequent following PBI than nonpenetrating injury in general. Between 30%
and 50% of patients with PBI develop seizures. Although class I data are lacking, the increased incidence
607
booksmedicos.org
of early seizures has led to the recommendation that antiseizure medications (e.g., phenytoin,
carbamazepine, valproate, phenobarbital) should be used during the first week after PBI. Prophylactic
treatment with anticonvulsants beyond the first week after PBI has not been shown to prevent the
development of new seizures and is not recommended.
The surgical management of penetrating wounds to the brain has undergone significant evolution
over the past two decades. At present, surgical débridement of the missile tract in the brain is not
recommended in the absence of significant mass effect. As well, routine surgical removal of fragments
lodged distant from the entry site or reoperation solely to remove retained bone or missile fragments is
not recommended.
Treatment of small bullet entrance wounds to the head in patients whose scalp is not devitalized and
have no significant intracranial pathology should consist of local wound care and closure. In more
extensive wounds with nonviable scalp, bone, or dura, surgical management with more extensive
débridement followed by primary closure or grafting to secure a watertight wound is recommended.
Closure of the dura and prevention of CSF leakage are extremely important goals in managing
penetrating wounds. In patients with significant fragmentation of the skull, débridement of the cranial
wound with either craniectomy or craniotomy is recommended.
Figure 21-8. Location for placement of initial exploratory burr hole in the temporal region for emergency diagnosis and
decompression.
Mass lesions should be surgically managed to prevent intracranial hypertension. As such, débridement
of necrotic brain tissue and safely accessible bone fragments is recommended when they produce
significant mass effect. As well, evacuation of intracranial hematomas is recommended if they produce
significant mass effect as defined by the production of midline shift of over 5 mm or intracranial
hypertension. This is one of the reasons that monitoring of ICP in penetrating injuries is an important
adjunct to surgical decision making.
Repair of an open air sinus injury with watertight closure of the dura is recommended.
Exploratory Burr Holes/Craniotomy

If there is a high clinical suspicion for a mass lesion and CT imaging is unavailable, exploratory burr
holes can be a useful and lifesaving option. If signs of herniation are present, all attempts should be
made to reverse it medically (with hyperventilation and hyperosmolar agents as described above) so
that the patient may be transferred to a facility equipped with CT capabilities.
If no such facility is reachable, or if herniation is refractory to medical management, emergency burr
holes is a useful and lifesaving option. The first burr hole is placed in the ipsilateral temporal region and
the dura is opened if an epidural hematoma is not in evidence (Fig. 21-8). If this exploration is negative,
a second hole is placed in the opposite temporal region, then at the region of the parietal boss and the
frontal convexity, first on the ipsilateral side, then contralaterally. A burr hole exploration is considered
negative when six holes have been drilled. Any positive burr hole is turned into a craniotomy, and the
hematoma is thoroughly evacuated.
Decompressive Craniectomy for Control of Intracranial Hypertension

In the eventuality that lower-tier interventions have been unsuccessful at controlling intracranial
hypertension, decompressive hemicraniectomy should be considered. By effectively expanding the
608
booksmedicos.org
intracranial volume, decompressive hemicraniectomy allows the swollen brain additional room to
expand and can improve ICP.
These craniectomies involve intentionally removing large, fronto-temporo-parietal bone flaps, leaving
them out, and widely opening the dura to prevent it from constraining the bulging brain. The most
common scenario is that of diffuse swelling wherein the more affected side is chosen for decompression.
In cases where edema is bilaterally symmetric, bilateral decompressive craniectomies can be performed.
In a recent randomized controlled trial, bilateral frontal hemicraniectomy was not found to improve
outcomes,70 but this result is controversial because of technical flaws in the study.72 Regardless of which
method is chosen, the bone flaps are as large as possible and particular attention is paid to
decompressing the temporal lobe by removing the temporal bone forming the lateral wall of the middle
cranial fossa.
Complications related to surgical management of TBI, especially after craniectomies, occur in a
predictable temporal progression.73 In the hours and days following surgery, pre-existing hemorrhagic
lesions may undergo expansion partly because this is their natural history, and partly because of
decreased tamponade on the lesion itself.74 Wound infection and CSF leaks are most commonly seen in
the initial week following surgery, and the incidence of complication ranges from 4% to 35%.75,76
Posttraumatic hydrocephalus is a delayed complication presenting weeks to months following injury.
Ventriculomegaly, secondary to encephalomalacia of injured brain tissue or alterations of CSF dynamics
after TBI, is found in up to 45% of patients with hemicraniectomy following severe TBI.77,78
Given the high rates of morbidity from hemicraniectomy, this procedure should be applied cautiously,
and only after an honest appraisal of the patient’s recovery potential. Patients who have suffered
prolonged periods of hypotension or hypoxemia, patients without evidence of brainstem function, and
patients with advanced age or multiple medical comorbidities have increased postsurgical and overall
risk and are less likely to benefit from surgery.79 Additionally, patients on anticoagulation or
antiplatelet agents that are irreversible are unlikely to benefit from hemicraniectomy. Finally, patients
with catastrophic injury on computerized tomography scan, as quantified by the prognostically oriented
Rotterdam score, make poor surgical candidates.80 Judiciously applied, surgical decompression can be a
lifesaving operation that has an acceptable risk profile given a severe TBI.
References
1. TBI: Get the Facts. 2016. Available from:
http://www.cdc.gov/traumaticbraininjury/get_the_facts.html
2. Faul M, Coronado V. Epidemiology of traumatic brain injury. Handb Clin Neurol 2015;127:3–13.
3. National Hospital Discharge Survey. 2015. Available from: http://www.cdc.gov/nchs/nhds.htm
4. Gennarelli TA, Champion HR, Copes WS, et al. Comparison of mortality, morbidity, and severity of
59,713 head injured patients with 114,447 patients with extracranial injuries. J Trauma
1994;37(6):962–968.
5. Badjatia N, Carney N, Crocco TJ, et al. Guidelines for prehospital management of traumatic brain
injury 2nd edition. Prehosp Emerg Care 2008;12(suppl 1):S1–S52.
6. Hartl R, Gerber LM, Iacono L, et al. Direct transport within an organized state trauma system
reduces mortality in patients with severe traumatic brain injury. J Trauma 2006;60(6):1250–1256;
discussion 1256.
7. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining
outcome from severe head injury. J Trauma 1993; 34(2):216–222.
8. Manley G, Knudson MM, Morabito D, et al. Hypotension, hypoxia, and head injury: frequency,
duration, and consequences. Arch Surg 2001;136(10):1118–1123.
9. Jones PA, Andrews PJ, Midgley S, et al. Measuring the burden of secondary insults in head-injured
patients during intensive care. J Neurosurg Anesthesiol 1994;6(1):4–14.
10. Bossers SM, Schwarte LA, Loer SA, et al. Experience in prehospital endotracheal intubation
significantly influences mortality of patients with severe traumatic brain injury: a systematic
review and meta-analysis. PLoS One 2015;10(10):e0141034.
11. Gaither JB, Spaite DW, Bobrow BJ, et al. Balancing the potential risks and benefits of out-of-
hospital intubation in traumatic brain injury: the intubation/hyperventilation effect. Ann Emerg Med
2012;60(6):732–736.
609
booksmedicos.org
12. Karamanos E, Talving P, Skiada D, et al. Is prehospital endotracheal intubation associated with
improved outcomes in isolated severe head injury? A matched cohort analysis. Prehosp Disaster Med
2014;29(1):32–36.
13. Tuma M, El-Menyar A, Abdelrahman H, et al. Prehospital intubation in patients with isolated severe
traumatic brain injury: a 4-year observational study. Crit Care Res Pract 2014;2014:135986.
14. Kiening KL, Unterberg AW, Bardt TF, et al. Monitoring of cerebral oxygenation in patients with
severe head injuries: brain tissue PO2 versus jugular vein oxygen saturation. J Neurosurg
1996;85(5):751–757.
15. van Santbrink H, Maas AI, Avezaat CJ. Continuous monitoring of partial pressure of brain tissue
oxygen in patients with severe head injury. Neurosurgery 1996;38(1):21–31.
16. Lang EW, Chesnut RM. A bedside method for investigating the integrity and critical thresholds of
cerebral pressure autoregulation in severe traumatic brain injury patients. Br J Neurosurg
2000;14(2):117–126.
17. Czosnyka M, Miller C; Participants in the International Multidisciplinary Consensus Conference on
Multimodality Monitoring. Monitoring of cerebral autoregulation. Neurocrit Care 2014;21(suppl
2):S95–S102.
18. Brain Trauma Foundation, American Association of Neurological Surgeons, Congress of
Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. I.
Blood pressure and oxygenation. J Neurotrauma 2007;24(suppl 1):S7–S13.
Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. IX.
Cerebral perfusion thresholds. J Neurotrauma 2007;24(suppl 1):S59–S64.
20. Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe
head injury. Crit Care Med 1999;27(10):2086–2095.
21. Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet
1974;2(7872):81–84.
22. Gabriel EJ, Ghajar J, Jagoda A, et al. Guidelines for prehospital management of traumatic brain
injury. J Neurotrauma 2002;19(1):111–174.
23. Teasdale G, Maas A, Lecky F, et al. The Glasgow Coma Scale at 40 years: standing the test of time.
Lancet Neurol 2014;13(8):844–854.
24. Best Practices in the Management of Traumatic Brain Injury. Trauma Quality Improvement
Program. 2015: American College of Surgeons. Available on:
https://www.facs.org/~/media/files/quality%20programs/trauma/tqip/traumatic%20brain%20injury%20guid
25. Du R, Meeker M, Bacchetti P, et al. Evaluation of the portable infrared pupillometer. Neurosurgery
2005;57(1):198–203; discussion 198–203.
26. Chen JW, Gombart ZJ, Rogers S, et al. Pupillary reactivity as an early indicator of increased
intracranial pressure: the introduction of the Neurological Pupil index. Surg Neurol Int 2011;2:82.
27. Chen JW, Vakil-Gilani K, Williamson KL, et al. Infrared pupillometry, the Neurological Pupil index
and unilateral pupillary dilation after traumatic brain injury: implications for treatment paradigms.
Springerplus 2014;3:548.
28. Aziz H, Rhee P, Pandit V, et al. Mild and moderate pediatric traumatic brain injury: Replace routine
repeat head computed tomography with neurologic examination. J Trauma Acute Care Surg
2013;75(4):550–554.
29. Bata SC, Yung M. Role of routine repeat head imaging in paediatric traumatic brain injury. ANZ J
Surg 2014;84(6):438–441.
30. Joseph B, Aziz H, Pandit V, et al. Low-dose aspirin therapy is not a reason for repeating head
computed tomographic scans in traumatic brain injury: a prospective study. J Surg Res
2014;186(1):287–291.
31. Joseph B, Friese RS, Sadoun M, et al. The BIG (brain injury guidelines) project: defining the
management of traumatic brain injury by acute care surgeons. J Trauma Acute Care Surg
2014;76(4):965–969.
32. Yuh EL, Mukherjee P, Lingsma HF, et al. Magnetic resonance imaging improves 3-month outcome
prediction in mild traumatic brain injury. Ann Neurol 2013;73(2):224–235.
33. Yuh EL, Hawryluk GW, Manley GT. Imaging concussion: a review. Neurosurgery 2014;75(suppl
610
booksmedicos.org
4):S50–S63.
Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury.
Methods. J Neurotrauma 2007;24(suppl 1):S3–S6.
35. Rowell SE, Fair KA, Barbosa RR, et al. The impact of pre-hospital administration of lactated ringer’s
solution versus normal saline in patients with traumatic brain injury. J Neurotrauma 2016.
Neurological Surgeons, et al. Guidelines for the management of severe traumatic brain injury. VI.
Indications for intracranial pressure monitoring. J Neurotrauma 2007;24(suppl 1):S37–S44.
37. Poca MA, Sahuquillo J, Arribas M, et al. Fiberoptic intraparenchymal brain pressure monitoring
with the Camino V420 monitor: reflections on our experience in 163 severely head-injured patients.
J Neurotrauma 2002;19(4):439–448.
38. Bauer DF, Razdan SN, Bartolucci AA, et al. Meta-analysis of hemorrhagic complications from
ventriculostomy placement by neurosurgeons. Neurosurgery 2011;69(2):255–260.
39. Chesnut RM. Intracranial pressure monitoring: headstone or a new head start. The BEST TRIP trial
in perspective. Intensive Care Med 2013; 39(4):771–774.
40. Chesnut RM, Temkin N, Carney N, et al. A trial of intracranial-pressure monitoring in traumatic
brain injury. N Engl J Med 2012;367(26):2471–2481.
41. Robertson CS, Gopinath SP, Goodman JC, et al. SjvO2 monitoring in head-injured patients. J
Neurotrauma 1995;12(5):891–896.
42. Rosenthal G, Hemphill JC 3rd, Manley G. Brain tissue oxygen tension is more indicative of oxygen
diffusion than oxygen delivery and metabolism in patients with traumatic brain injury. Crit Care
Med 2009;37(1):379–380.
43. Rosenthal G, Hemphill JC, Sorani M, et al. The role of lung function in brain tissue oxygenation
following traumatic brain injury. J Neurosurg 2008;108(1):59–65.
44. Nangunoori R, Maloney-Wilensky E, Stiefel M, et al. Brain tissue oxygen-based therapy and
outcome after severe traumatic brain injury: a systematic literature review. Neurocrit Care
2012;17(1):131–138.
45. Oddo M, Levine JM, Mackenzie L, et al. Brain hypoxia is associated with short-term outcome after
severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion
pressure. Neurosurgery 2011;69(5):1037–1045; discussion 1045.
46. Sanchez JJ, Bidot CJ, O’Phelan K, et al. Neuromonitoring with microdialysis in severe traumatic
brain injury patients. Acta Neurochir Suppl 2013;118:223–227.
47. Rosenthal G, Sanchez-Mejia RO, Phan N, et al. Incorporating a parenchymal thermal diffusion
cerebral blood flow probe in bedside assessment of cerebral autoregulation and vasoreactivity in
patients with severe traumatic brain injury. J Neurosurg 2011;114(1):62–70.
48. Lin BS, Wang CC, Chang MH, et al. Evaluation of traumatic brain injury by optical technique. BMC
Neurol 2015;15:202.
49. Wang CC, Kuo JR, Chen YC, et al. Brain tissue oxygen evaluation by wireless near-infrared
spectroscopy. J Surg Res 2016;200(2):669–675.
50. Davies DJ, Su Z, Clancy MT, et al. Near-infrared spectroscopy in the monitoring of adult traumatic
brain injury: a review. J Neurotrauma 2015;32(13):933–941.
51. Plomgaard AM, van Oeveren W, Petersen TH, et al. The SafeBoosC II randomized trial: treatment
guided by near-infrared spectroscopy reduces cerebral hypoxia without changing early biomarkers
of brain injury. Pediatr Res 2016;79(4):528–535.
52. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the
prevention of post-traumatic seizures. N Engl J Med 1990;323(8):497–502.
53. Robertson CS, Hannay HJ, Yamal JM, et al. Effect of erythropoietin and transfusion threshold on
neurological recovery after traumatic brain injury: a randomized clinical trial. JAMA
2014;312(1):36–47.
54. Edwards P, Arango M, Balica L, et al. Final results of MRC CRASH, a randomised placebo-
controlled trial of intravenous corticosteroid in adults with head injury-outcomes at 6 months.
Lancet 2005;365(9475):1957–1959.
55. Kaufmann AM, Cardoso ER. Aggravation of vasogenic cerebral edema by multiple-dose mannitol. J
611
booksmedicos.org
Neurosurg 1992;77(4):584–589.
56. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe
traumatic brain injury in infants, children, and adolescents. Chapter 11. Use of hyperosmolar
therapy in the management of severe pediatric traumatic brain injury. Pediatr Crit Care Med
2003;4(3 suppl):S40–S44.
57. Burgess S, Abu-Laban RB, Slavik RS, et al. A systematic review of randomized controlled trials
comparing hypertonic sodium solutions and mannitol for traumatic brain injury: implications for
emergency department management. Ann Pharmacother 2016;50(4):291–300.
58. Wakai A, McCabe A, Roberts I, et al. Mannitol for acute traumatic brain injury. Cochrane Database
Syst Rev 2013;8:CD001049.
59. Sorani MD, Morabito D, Rosenthal G, et al. Characterizing the dose-response relationship between
mannitol and intracranial pressure in traumatic brain injury patients using a high-frequency
physiological data collection system. J Neurotrauma 2008;25(4):291–298.
60. Marshall GT, James RF, Landman MP, et al. Pentobarbital coma for refractory intra-cranial
hypertension after severe traumatic brain injury: mortality predictions and one-year outcomes in 55
patients. J Trauma 2010;69(2):275–283.
61. Pérez-Bárcena J, Llompart-Pou JA, Homar J, et al. Pentobarbital versus thiopental in the treatment
of refractory intracranial hypertension in patients with traumatic brain injury: a randomized
controlled trial. Crit Care 2008;12(4):R112.
62. Eisenberg HM, Frankowski RF, Contant CF, et al. High-dose barbiturate control of elevated
intracranial pressure in patients with severe head injury. J Neurosurg 1988;69(1):15–23.
63. Majdan M, Mauritz W, Wilbacher I, et al. Barbiturates use and its effects in patients with severe
traumatic brain injury in five European countries. J Neurotrauma 2013;30(1):23–29.
64. Luce EA. Discussion: severe infectious complications following frontal sinus fracture: the impact of
operative delay and perioperative antibiotic use. Plast Reconstr Surg 2013;132(1):163–164.
65. Zix J, Schaller B, Iizuka T, et al. The role of postoperative prophylactic antibiotics in the treatment
of facial fractures: a randomised, double-blind, placebo-controlled pilot clinical study. Part 1:
orbital fractures in 62 patients. Br J Oral Maxillofac Surg 2013;51(4):332–336.
66. Schaller B, Soong PL, Zix J, et al. The role of postoperative prophylactic antibiotics in the treatment
of facial fractures: a randomized, double-blind, placebo-controlled pilot clinical study. Part 2:
mandibular fractures in 59 patients. Br J Oral Maxillofac Surg 2013;51(8):803–807.
67. Bellamy JL, Molendijk J, Reddy SK, et al. Severe infectious complications following frontal sinus
fracture: the impact of operative delay and perioperative antibiotic use. Plast Reconstr Surg
2013;132(1):154–162.
68. Rodriguez ED, Stanwix MG, Nam AJ, et al. Twenty-six-year experience treating frontal sinus
fractures: a novel algorithm based on anatomical fracture pattern and failure of conventional
techniques. Plast Reconstr Surg 2008;122(6):1850–1866.
69. Seelig JM, Becker DP, Miller JD, et al. Traumatic acute subdural hematoma: major mortality
reduction in comatose patients treated within four hours. N Engl J Med 1981;304(25):1511–1518.
70. Cooper DJ, Rosenfeld JV, Murray L, et al. Decompressive craniectomy in diffuse traumatic brain
injury. N Engl J Med 2011;364(16):1493–1502.
71. Sahuquillo J, Martinez-Ricarte F, Poca MA. Decompressive craniectomy in traumatic brain injury
after the DECRA trial. Where do we stand? Curr Opin Crit Care 2013;19(2):101–106.
72. Honeybul S, Ho KM, Lind CR. What can be learned from the DECRA study. World Neurosurg
2013;79(1):159–161.
73. Stiver SI. Complications of decompressive craniectomy for traumatic brain injury. Neurosurg Focus
2009;26(6):E7.
74. Flint AC, Manley GT, Gean AD, et al. Post-operative expansion of hemorrhagic contusions after
unilateral decompressive hemicraniectomy in severe traumatic brain injury. J Neurotrauma
2008;25(5):503–512.
75. Yang XF, Wen L, Shen F, et al. Surgical complications secondary to decompressive craniectomy in
patients with a head injury: a series of 108 consecutive cases. Acta Neurochir (Wien)
2008;150(12):1241–1247; discussion 1248.
76. Sughrue ME, Bloch OG, Manley GT, et al. Marked reduction in wound complication rates following
612
booksmedicos.org
decompressive hemicraniectomy with an improved operative closure technique. J Clin Neurosci
2011;18(9):1201–1205.
77. Poca MA, Sahuquillo J, Mataró M, et al. Ventricular enlargement after moderate or severe head
injury: A frequent and neglected problem. J Neurotrauma 2005;22(11):1303–1310.
78. Honeybul S, Ho KM. Incidence and risk factors for post-traumatic hydrocephalus following
decompressive craniectomy for intractable intracranial hypertension and evacuation of mass
lesions. J Neurotrauma 2012;29(10):1872–1878.
79. Steyerberg EW, Mushkudiani N, Perel P, et al. Predicting outcome after traumatic brain injury:
development and international validation of prognostic scores based on admission characteristics.
PLoS Med 2008;5(8):e165; discussion e165.
80. Maas AI, Hukkelhoven CW, Marshall LF, et al. Prediction of outcome in traumatic brain injury with
computed tomographic characteristics: a comparison between the computed tomographic
classification and combinations of computed tomographic predictors. Neurosurgery
2005;57(6):1173–1182; discussion 1173–1182.
613
booksmedicos.org
Chapter 22
Maxillofacial Injuries
Batya R. Goldwaser, Leonard B. Kaban, and Maria J. Troulis
Key Points
1 Due to the widespread use of seatbelts and airbags, the overall incidence of MVC-related injuries has
decreased, but improved survival has resulted in increased complexity of injuries requiring
treatment.
2 Life-threatening maxillofacial injuries involve upper airway obstruction and/or hemorrhage.
3 Identification of injuries to specialized structures including the facial nerve, parotid duct, the globe
and lacrimal system is critical.
4 Fractures of the maxilla and mandible are unique because of the presence of teeth which are the
most important landmark for reduction. The primary goal of treatment is restoration of the dental
occlusion.
5 Maxillary fractures involve the pterygoid plates and are classified as Le Fort I, II or, III depending on
the superior extent of the injury.
6 Indications for operative treatment of zygomaticomaxillary complex (ZMC) fractures include
cosmetic deformity, enophthalmos or diplopia, paresthesia, and limitation of mouth opening from
coronoid impingement.
7 The status of the medial canthal ligament and its attachment to bone is the key to proper diagnosis
and treatment of naso-orbital–ethmoid (NOE) fractures.
8 Retrobulbar hematoma and extraocular muscle entrapment are surgical emergencies that require
immediate treatment to prevent permanent visual deficits.
9 Indications for operative treatment of frontal sinus fractures include cosmetic deformity, intracranial
extension, and nasofrontal outflow tract obstruction. Complications include meningitis and mucocele
formation which can occur even years later.
10 Indications for open treatment of mandible fractures include edentulism, severe displacement, or
comorbid conditions that preclude closed reduction with maxillomandibular fixation, or the presence
of concomitant midface fractures.
11 All mandible fractures of the tooth-bearing region are considered open fractures and antibiotic
treatment must be instituted.
12 In panfacial fractures, various treatment approaches including “top-down,” “bottom-up,” and
“outside-in” exist, and are chosen based on the specific injury pattern.
1 The etiology of facial trauma in adults is most commonly motor vehicle crashes, followed by
interpersonal violence, sports injuries, and falls, with the exact incidence varying by geographic
location. Among children, falls predominate followed by sports injuries and motor vehicle collisions.1
Although firearm-related deaths have declined, head and neck injuries continue to make up
approximately 15% of gunshot wounds, often a result of suicide or homicide.2 Young males (age 20 to
30) make up the largest group demographically for all causes of facial trauma, while children account
for less than 10%.3 In adults, the most commonly injured structures are the nose, dentoalveolar
complex, zygoma, and mandible given their protrusive position relative to the rest of the face. Orbit
and midface (i.e., Le Fort level) injuries are less common. The opposite is true in children whose
cranium grows rapidly and results in a prominent forehead and orbits and a larger skull-to-face ratio
with the midface relatively protected. Mandibular, nasal and dentoalveolar trauma is most common.4
Due to the widespread use of seatbelts and airbags, the incidence of MVC-related injuries has decreased.
However, severely injured patients have improved survival resulting in an increase in the complexity of
midface and mandibular fractures and overlying soft tissue injuries now seen.5,6
614
booksmedicos.org
TREATMENT OF LIFE-THREATENING CONDITIONS
2 The initial management of a patient with facial trauma, like all trauma patients, begins with the
standard ATLS protocol including breathing, airway, and circulation.7 Specific life-threatening
maxillofacial injuries involve upper airway obstruction and/or hemorrhage and must be addressed
acutely.8,9 Aspiration of blood or foreign bodies (including teeth, dentures, debris, and stomach
contents), the tongue position especially in unconscious patients or those with certain unstable mandible
fractures (i.e., “bucket-handle”), or midface fractures with resultant impaction of the maxilla can
obstruct the airway. The high correlation between facial trauma and C-spine injuries requires clinical
and radiographic exclusion of concomitant fractures and/or ligamentous injury.
Facial injuries causing significant bleeding are not common, with the exception of scalp and tongue
lacerations which must be addressed quickly. The ethmoidal arteries as well as branches of the internal
maxillary artery can also be a source of significant bleeding (Fig. 22-1). Hemostasis is usually attained
with head elevation, pressure and packing with gauze, an inflated Foley catheter, or Rhinorockets. If
bleeding continues despite these measures, diagnostic imaging such as CTA, and fracture reduction and
immobilization, with or without direct ligation or embolization may be required (Fig. 22-2).9–12
3 The secondary survey involves examination of soft tissue and bony injuries, including specialized
structures such as the facial nerve, the parotid duct, the globe, and the lacrimal system. Stepoffs and/or
mobility of the orbital rims, malar eminences, zygomatic arch, nasal bones, and mandible signify
displaced fractures. Mobility of the maxilla should be determined and all teeth should be accounted for,
either by direct visualization or ruling out aspiration by chest x-ray. Nerve paralysis, any sensory
deficits, or malocclusion almost always correlate with a significant facial injury.
Figure 22-1. Sources of bleeding in facial trauma.
SOFT TISSUE INJURIES

Important anatomic regions of the face that must be precisely reapproximated include the vermillion
border of the lip, the eyebrow, and the eyelid where even small inaccuracies in repair can become
larger deformities later. Defects of up to 25% of the lip or eyelid can be closed primarily with good
results. Eyelid lacerations involving the medial third must be closely evaluated to identify the punctum
and canaliculus which drains into the nasolacrimal duct to the inferior meatus in the nose. Retrobulbar
hematoma is a surgical emergency that must be immediately decompressed to prevent permanent vision
loss. Signs include decreasing visual acuity, elevated intraocular pressure (IOP) (>40), pain, tense
globe, proptosis, and often a visible hematoma on imaging. Treatment is with immediate lateral
canthotomy and cantholysis for decompression (Figs. 22-3 and 22-4).13
The nasal septum and ear pinna must be checked for hematoma which can lead to cartilage necrosis
(with subsequent “saddle nose deformity” or “cauliflower ear”) if not evacuated. Following drainage, a
bolster should be placed to prevent reaccumulation. Any injury along the course of the facial nerve
proximal to the lateral canthus should be suspect for injury to a major branch and repaired primarily
(Fig. 22-5).
Injuries to the parotid gland and duct must be identified. To identify ductal injury or continuity
615
booksmedicos.org
defects, the Stenson duct orifice (best found at the papilla adjacent to the maxillary second molar) is
visualized while simultaneously “milking” the parotid gland from extraorally in the direction of salivary
flow. If the duct is intact, saliva should be visible flowing from the orifice into the mouth. However,
lack of salivary flow does not confirm ductal injury, as flow can be minimal in multiple conditions such
as dehydration or autoimmune disorders. Comparison to the contralateral or uninjured side can help in
differentiating acute injury. Another maneuver that can be diagnostic is cannulating the duct using a
lacrimal probe and following the path as far proximally as possible. If the duct has been transected, the
probe may be visible within the facial wound. Midductal injuries require proximal and distal segment
reanastamosis, usually over a catheter which is left in place for 10 to 14 days. Distal ductal injuries can
be left open to the mouth with creation of a neoorifice.14,15 For intraglandular injury, the parotid
capsule may be closed and a pressure dressing placed to prevent development of a sialocele (Fig. 22-6).
Figure 22-2. The patient was acutely stabilized by the trauma service (Drs DeMoya and Velmahos). A,B: Bleeding was acutely
controlled by packing for the ascending pharyngeal artery, cauterization of the ethmoidal arteries, and immobilization of the
midface. C: The laceration was temporarily closed.
Figure 22-3. A,B: At the initial operation, the right globe was found to be ruptured and thus exenterated. The left globe had
increased intraocular pressure, was tense and had limited extraocular movements on forced duction so an emergent lateral
canthotomy was performed with immediate decompression. The nasolacrimal apparatus was cannulated by the oculoplastics
service and noted to be severed.
4 Fractures of the maxilla and mandible differ from other fractures because of the presence of teeth
which are the most important landmark for reduction and render fractures as “open.” The goal of
treatment is not only reduction, fixation, and immobilization, improved contour, and range of motion,
but also restoration of occlusion. Although in the acute or emergent setting the airway should be
secured by any means necessary, when planning definitive treatment, the requirement for access to the
occlusion will determine whether oral, nasal, or submental intubation is most appropriate. An oral tube
can be used if the patient is edentulous or has many missing teeth without a reproducible occlusion.
Nasal intubation is generally safe even with significant midface trauma, but is best performed under
616
booksmedicos.org
direct visualization with fiberoptic guidance to prevent inadvertent intracranial injury. When nasal
intubation is not possible and the occlusion must be established, submental intubation is a useful
alternative. Oral intubation is followed by passing the oral end of the endotracheal tube through an
incision in the floor of mouth and submental neck. Postoperatively, the tube is passed back into the
mouth and the patient can be extubated. If prolonged assisted ventilation is anticipated, an elective
tracheostomy should be considered preoperatively.
Figure 22-4. Lateral canthotomy. A: Canthal tendon anatomy. B: Lateral canthotomy. After clamping the tissue for hemostasis, a
horizontal cut is made with scissors through skin, orbicularis oculi, and conjunctiva of the lateral palpebral fissure. This is usually
not sufficient to reduce intraocular pressure (IOP). C: Inferior cantholysis. Next, the lower lid is retracted to expose the inferior
limb of the canthal tendon which is oriented horizontally. After dissecting it free, the tendon is cut with scissors oriented vertically.
Though not usually required, if IOP is still elevated, the superior limb can be dissected free and transected as well.
Related to choice of airway, fractures of the tooth-bearing maxilla and/or mandible require the
patient to be on a nonchew diet for 6 weeks. After a 1-week inflammatory phase, a soft callus forms
over 2 to 3 weeks. At this point the fracture is stable enough to prevent shortening but it is still
susceptible to angular forces. A hard callus then replaces the soft callus and can take up to 3 to 4
months. For this reason, it is generally recommended to limit chewing forces for 6 weeks (in adults) and
to avoid additional trauma for 3 months.16 If there are minimal concomitant injuries, most patients are
able to maintain nutritional requirements with enteral intake, often with oral supplements. If there are
other significant injuries, especially those resulting in altered mental status or prolonged ICU stay, a
nasogastric tube or gastrostomy tube may be needed.
MAXILLARY FRACTURES
5 The famous study by Rene Le fort in 1901 is the basis for the current classification system of
maxillary fractures (Fig. 22-7).17 Physical examination reveals periorbital ecchymosis and edema,
epistaxis, a retruded midface, palatal ecchymosis, malocclusion, numbness in the V2 distribution,
mobility of the maxilla at the piriforms, nasofrontal or zygomaticotemporal sutures. Epiphora results if
the nasolacrimal duct is obstructed.
Computed tomography (CT) is the imaging modality of choice for midface injuries, especially if the
orbit is involved or if an operation is planned. Treatment includes reduction, and usually disimpaction
of the maxilla, using the occlusion as a guide when possible, followed by immobilization (either
maxillomandibular fixation or rigid fixation to an adjacent stable facial structure) (Fig. 22-8).
617
booksmedicos.org
Figure 22-5. A,B: The left facial nerve was explored given the location of the laceration (i.e., proximal to the lateral canthus) and
a severed branch to the upper lip was anastomosed under microscopic visualization by Dr. Hadlock.
ZYGOMATICOMAXILLARY COMPLEX FRACTURES

The zygoma articulates with the frontal, sphenoid, temporal and maxillary bones, forming a “complex”
(Fig. 22-9). It also forms the infraorbital rim and orbital floor. Physical examination shows periorbital
ecchymosis and edema, flattening of the cheek, downslanting of the lateral canthus, enophthalmos, or
stepoff at the infraorbital rim. Paresthesia of the infraorbital distribution suggests nerve entrapment in
the line of fracture. Less common is limitation of mouth opening which occurs if the zygomatic arch is
depressed and impinges on the coronoid process of the mandible. Because of the close association with
the orbit, a preoperative ophthalmology examination is prudent.18
CT scan is the gold standard in order to best appreciate the degree of rotation and/or depression, as
well as to evaluate the orbital floor component. Historically, the Water view radiograph was used, and
it is with this image that the well-known and still used Knight and North Classification system was
developed.19 This classification system which describes zygomaticomaxillary complex (ZMC) fractures
by rotation, depression, and comminution, predicts fracture stability after reduction. With the use of CT
scans and rigid fixation, this classification system may not be as relevant. Another classification system
developed by Manson in 1990 divides ZMC fractures into low-energy, mid-energy, and high-energy
fractures.20
Figure 22-6. A,B: The left parotid duct was cannulated and clear salivary flow identified. A stent was left in place for 21 days.
618
booksmedicos.org
Figure 22-7. A: Le Fort I fractures are horizontal fractures that span across the piriform rims along the floor of the nose, through
the maxillary sinus around to the pterygoid plates posteriorly. Le Fort II fractures are pyramidal in shape and include the nasal
bones, infraorbital rims, in addition to the zygomaticomaxillary buttress and pterygoid plates. Le Fort III is a separation of the
entire face from the skull base and includes the nasofrontal suture and medial orbit, zygomaticotemporal suture at the lateral orbit
around to the pterygoid plates. B,C: Maxillofacial CT of the same patient as above, showing Le Fort I, II, III level fractures and
significantly displaced bilateral mandibular body fractures. A CTA and subsequent angiogram showed transection of the bilateral
internal maxillary arteries without a target for embolization.
6 Surgical treatment is usually delayed until swelling resolves to better evaluate any cosmetic
deformity and to allow easier surgical access if needed. Nondisplaced, stable fractures can be observed.
Indications for open treatment include cosmetic deformity, enophthalmos, or diplopia when the orbital
floor component is significant, paresthesia of the V2 distribution and limitation of mouth opening from
coronoid impingement. If there is enophthalmos, or high likelihood of future enophthalmos secondary
to herniation of orbital contents into the maxillary sinus, dystopia, or diplopia that does not resolve
once the swelling goes down, the orbital floor will also require reconstruction (see also orbital
fractures) (Figs. 22-8 and 22-10).21–24
NASO-ORBITAL–ETHMOID FRACTURES
Naso-orbital–ethmoid (NOE), a term coined in 1973, describes a facial subunit that is widely considered
to be the most complex of all facial fractures that is uncommonly injured, comprising only 2% to 15% of
all facial fractures, and rarely occurs in isolation (usually accompanied by midface or frontal sinus
fractures).25 The complex consists of the medial orbital walls, nasal bones, frontal process of the
maxilla, nasal process of the frontal bone, and the ethmoid sinuses. Bleeding may be secondary to injury
of the anterior or posterior ethmoidal arteries along the medial orbital wall. The clinical examination is
most notable for periorbital ecchymosis and edema, subconjunctival hemorrhage, a depressed nasal
radix with a wide or flattened dorsum and upturned tip, and telecanthus with increased intercanthal
distance to over 35 mm. CSF rhinorrhea may be present if the cribiform plate is involved, as can
enophthalmos, depending on the degree of medial orbital volume increase. Epiphora may also be
present if there is damage to the lacrimal drainage system. A complete ophthalmologic examination is
required to rule out ocular injury.18
619
booksmedicos.org
Figure 22-8. Same patient after open reduction and internal fixation of the bilateral Le Fort I, II, and III fractures, after repairing
the mandible and using the occlusion as a guide to work from bottom-up. A: Intraoperative photos of Le Fort I ORIF. B: Postop CT
scan.
Figure 22-9. A: Lateral view of CT scan from same patient showing partial facial amputation. B: ZMC fracture and mandibular
subcondylar and angle fractures highlighted. C,D: Postop CT scan showing reduction and fixation of ZMC and mandible fracture.
620
booksmedicos.org
Figure 22-10. The zygomaticofrontal suture was reduced and plated. After releasing the infraorbital nerve from the fractured
orbital floor, the zygomas were rigidly fixated at the piriform rims, the zygomaticomaxillary buttresses and infraorbital rims.
7 The status of the medial canthus and its attachment to bone is the key to proper diagnosis and
treatment. In 1991, Markowitz and Manson published one of the most well-known studies on NOE
fractures (Fig. 22-11).26 CT scan is the gold standard for diagnosing and classifying NOE fractures.
Though it is difficult to visualize the tendon itself, the fracture can be classified based on the degree of
comminution.
Definitive treatment can be delayed for swelling or stabilization of other injuries, but ideally not
beyond 2 weeks as reduction becomes difficult. The goals of treatment include restoring the intercanthal
distance, orbital volume, dorsal support, and nasal tip projection and length. Incompletely reduced
telecanthus is one of the most difficult complications to treat so overcorrection should always be
attempted.27–32
Figure 22-11. A: They classified fractures into type I (medial canthal tendon attached to a single large segment of bone), type II
(comminuted bony segment but canthus remains attached to sizeable fragment) and type III (severe comminution and/or avulsion
of the canthal tendon). B: Intraoperative view of same patient showing reduction and fixation of nasofrontal suture and left
infraorbital rim. The medial canthal tendon was also identified and resuspended under the nasal bones to the contralateral medial
orbit.
ORBITAL FRACTURES
621
booksmedicos.org
Related to, and often part of both ZMC and NOE fractures are orbital fractures. The superior, lateral,
and inferior orbital rims are very dense, while the medial orbital rim and wall, as well as the orbital
floor are very thin, often less than 0.5 mm; therefore, trauma to the orbit usually results in fracture of
the thin floor or medial wall, termed “blow-out” fractures if isolated (Fig. 22-12).
8 Extraocular muscle entrapment is a surgical emergency, evaluated by testing extraocular
movements in the awake patient, or forced duction testing in a noncooperative or comatose patient, in
all ZMC, NOE, and isolated orbital fractures. Entrapment is most common in young patients who have
elastic bone and periosteum with a small “trapdoor” seen on CT scan of the floor or medial orbit (Fig.
22-13).
The other indication for open treatment is enophthalmos. This can be treated in a delayed fashion and
can often be predicted based on CT findings even before the swelling has resolved if the defect is large
(>50%), there is significant herniation of orbital contents into the sinus or if the orbital rim is
displaced. Immediate (within 2 weeks) versus delayed repair often depends on surgeon preference (Fig.
22-8).33–35
FRONTAL SINUS INJURIES

9 Frontal sinus fractures often occur in conjunction with NOE or other midface fractures. Anterior table
fractures may result in significant cosmetic deformity if displaced. The nasofrontal outflow tract drains
the frontal sinus to the ethmoid sinuses. If this passage is found to be obstructed, it must be sealed off
with temporalis fascia, pericranium, cranial bone, or tissue sealants, followed by obliteration of the
sinus mucosa and filling the dead space to prevent infection and delayed mucocele formation.
Posterior table fractures can cause intracranial injury and should be evaluated in conjuction with
neurosurgery. If the displacement is significant or there is evidence of dural tear or frontal lobe injury,
the posterior table should be removed along with the sinus mucosa and the nasofrontal outflow tract
obstructed. Then the sinus is cranialized and the anterior table can be reconstructed.36–38
MANDIBLE FRACTURES
The diagnosis of a mandible fracture can usually be made by history and physical examination alone. In
addition, a panoramic radiograph (actually a sagittal view) is underappreciated in terms of its ability to
show the presence and type of fracture. The panoramic x-ray, together with another plain film at 90
degrees (i.e. PA skull film), identifies the degree and direction of displacement, and can obviate the
need for a CT scan. In reality however, a CT is often obtained in the emergency room for screening of
other injuries.
On examination, findings often include numbness of the inferior alveolar nerve distribution (if the
fracture is between the mandibular and mental foramina), malocclusion, gross mobility, jaw deviation,
and gingival lacerations or sublingual ecchymosis. Bleeding from the external auditory meatus should
raise suspicion for a mandibular condyle or temporal bone fracture. Because the mandible is U-shaped,
force from one blow is distributed around the arch and often results in a second fracture. Common
patterns include a blow to the symphysis resulting in bilateral condylar fractures, or a blow to the
parasymphysis resulting in a contracoup injury to the opposite condyle. The presence of teeth also
impact fracture pattern, the most common of which is the third molar, especially if impacted, which
increases the risk of a mandibular angle fracture. Teeth in the line of fracture may be left in place as
they can aid in reduction; if they impede reduction, extraction is required.39,40
622
booksmedicos.org
Figure 22-12. A,B: The left orbital floor was explored and reconstructed with titanium mesh. A silastic implant holder was placed
into the right orbit to provide contour for a future prosthetic implant by the oculoplastics team.
Figure 22-13. A different patient who sustained a left orbital floor blow-out fracture with entrapment of the inferior rectus muscle.
A: Clinical photo demonstrating limitation of upward gaze. B: Sagittal reformat of CT showing entrapment of left inferior rectus.
C: Coronal reformat showing the same.
Some mandible fractures can be treated with closed reduction and maxillomandibular fixation in
dentate patients. Severely comminuted fractures, such as in a gunshot wound, may also be treated
closed, to avoid stripping the periosteum and therefore blood supply from small fragments (Fig. 22-14).
Immobilization is maintained for 4 to 6 weeks in adults, 6 to 8 weeks in the elderly, and 2 to 4 weeks in
children (Fig. 22-15).
10 Indications for open treatment include fractures in edentulous patients as there are no teeth to
guide reduction and the bone is often atrophic, requiring load-bearing rigid fixation. Other indications
include severe displacement that is not easily reduced, or comorbid conditions that preclude wiring the
patient closed (i.e., seizure disorder, alcoholism, and psychiatric issues). In the presence of concomitant
midface fractures, a mandible fracture may be treated open in order to establish a stable landmark and
building block to work from (Figs. 22-8, 22-9, and Fig. 22-15).41–46
623
booksmedicos.org
Figure 22-14. Patient with comminuted mandible fracture treated with closed reduction and maxillomandibular fixation to avoid
stripping small bone fragments of periosteal blood supply.
Figure 22-15. A: Reduction and immobilization was performed using maxillomandibular fixation. B: The left mandibular angle
fracture was rigidly fixated. The right subcondylar fracture (see above) was treated with closed reduction and immobilization.
Treatment of mandibular condyle fractures remains with some controversy in maxillofacial trauma. In
general, high subcondylar or intracapsular fractures are generally treated closed as there is little bone to
plate and bleeding into the joint increases the risk of ankylosis.47–52 These fractures are treated with
early mobilization to maintain range of motion. Low subcondylar fractures are generally treated similar
to other extra-articular mandibular fractures. In the past few decades, minimally invasive endoscopic
approaches to treatment of mandibular condyle fractures have been used for open treatment with good
results.53–55
11 Because any fracture within the tooth-bearing segments is considered an open fracture, and is at
higher risk of infection, antibiotics and immobilization should be initiated as soon as possible. Postop
antibiotics, while common practice, have not been shown to decrease the infection risk.56 Long-term
complications following mandible fractures include malocclusion, infected hardware, or osteomyelitis.
Delayed initial treatment or inadequate immobilization increases the risk.
624
booksmedicos.org
Figure 22-16. The patient recovered well. His residual deficits were left facial nerve weakness as well as loss of the right eye.
APPROACH TO PANFACIAL FRACTURES

12 Various approaches including “top-down,” “bottom-up,” and “outside-in” exist and are chosen based
on the specific injury pattern. In general, the uninjured cranial base is used as the building block for
repair of the upper face while the maxillomandibular complex is used to rebuild the lower face. Then
these two subunits are unified at the Le Fort I level. For the cranio-orbital subunit, reduction can
commence at lateral orbital rims and move inward, or at the NOE and move outward. The dentition is
the most useful landmark for rebuilding the maxillomandibular subunit in conjunction with establishing
the posterior vertical facial height by reducing the mandibular ramus/condyle unit (Fig. 22-16).20,57–61
Lack of sufficient projection is the usual problem (Fig. 22-17).
In summary, maxillofacial trauma presents a wide range of diagnostic and treatment challenges.
Following acute treatment of life-threatening airway and bleeding concerns, definitive treatment
involves careful repair of hard and soft tissue structures, ideally within 2 weeks. With improved
survival, presenting injuries are more complex and successful reconstruction requires an appreciation of
facial subunits and their interconnection.
625
booksmedicos.org
Figure 22-17. A: Patient treated after 5-story fall. Inadequate projection and resultant facial widening. B: Reoperation with
osteotomies and bone repositioning lead in better projection and normalized width.
References
1. Gassner R, Tuli T, Hachl O, et al. Cranio-maxillofacial trauma: a 10 year review of 9543 cases with
21067 injuries. J Cranio-Maxillofac Surg 2003;31(1):51.
2. Kraft A, Abermann E, Stigler R, et al. Craniomaxillofacial trauma: synopsis of 14,654 cases with
35,129 injuries in 15 years. Craniomaxillofac Trauma Reconstr 2012;5(1):41.
3. Mendes M, Borba M, Sawazaki R, et al. Maxillofacial trauma and seat belt: a 10-year retrospective
study. J Oral Maxillofac Surg 2013;17:21.
4. Perry M. Advanced Trauma Life Support (ATLS) and facial trauma: can one size fit all?: Part 1:
dilemmas in the management of the multiply injured patient with coexisting facial injuries. Int J
Oral Maxillofac Surg 2008;37:209.
5. Perry M, Morris C. Advanced Trauma Life Support (ATLS) and facial trauma: can one size fit all?:
Part 2: ATLS, maxillofacial injuries and airway management dilemmas. Int J Oral Maxillofac Surg
2008;37:309.
6. Perry M, Moutray T. Advanced Trauma Life Support (ATLS) and facial trauma: can one size fit all?
Part 4: ‘can the patient see?’ timely diagnosis, dilemmas and pitfalls in the multiply injured, poorly
responsive/unresponsive patient. Int J Oral Maxillofac Surg. 2008;37(6):505.
7. Crecelius C: Soft tissue trauma. Atlas Oral Maxillofacial Surg Clin North Am 2013;21:49e60.
8. Goetsch KE, Annest JJ, Mercy JA, et al. Surveillance for fatal and nonfatal firearm related injuries:
United States, 1993–1998. MMWR Morb Mortal Wkly Rep 2001;50:1.
9. Kaban LB. Diagnosis and treatment of fractures of the facial bones in children 1943–1993. J Oral
Maxillofac Surg 1993;51:722.
10. Forshey J, Troulis MJ, Kaban LB. Changing Treads in CMF Trauma AAOMS. 1999.
11. Bynoe RP, Kerwin AJ, Parker HH, et al. Maxillofacial injuries and life-threatening hemorrhage:
treatment with transcatheter arterial embolization. J Trauma 2003;55:74.
12. Yang WG, Tsai TR, Hung CC, et al. Life threatening bleeding in a facial fracture. Ann Plast Surg
2001;46:159.
13. Mehrotra ON, Brown GE, Widdowson WP, et al. Arteriography and selective embolization in the
control of life-threatening haemorrhage following facial fractures. Br J Plast Surg 1984;37:482.
14. Demetriades D, Chawan S, Gomez H, et al. Initial evaluation and management of gunshot wounds
to the face. J Trauma 1998;45:39.
15. Steinberg MJ, Herrera AF. Management of parotid duct injuries. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2005;99:136.
16. Ito, K, Perren SM. Biology of fracture healing. In: Ruedi TP, Buckley RE, Moran CG, eds. AO
Principles of Fracture Management. New York, NY: Thieme Publishing Group;2007.
626
booksmedicos.org
17. Le Fort R. Experimental study of fractures of the upper jaw: parts I and II. Rev Chir Paris
1901;23:208.
18. Peacock ZS, Boulos T, Miller JB, et al. Orbital fractures and ocular injury: is a postoperative
ophthalmology examination necessary? J Oral Maxillofac Surg 2014;72(8):1533.
19. Knight JS, North JF. The classification of malar fractures: an analysis of displacement as a guide to
treatment. Br J Plast Surg 1961;13:325.
20. Manson PN, Markowitz B, Mirvis S, et al. Toward CT-based facial fracture treatment. Plast Reconstr
Surg 1990;85(2):202.
21. Ellis E 3rd, el-Attar A, Moos KF. An analysis of 2,067 cases of zygomatico-orbital fracture. J Oral
Maxillofac Surg 1985;43(6):417.
22. Ellis E, Kittidumkerng W. Analysis of treatment for isolated zygomaticomaxillary complex
fractures. J Oral Maxillofac Surg 1996;54:386.
23. Ellis E, Perez D. An Algorithm for the treatment of isolated zygomatico-orbital fractures. J Oral
Maxillofac Surg 2014;72(10):1975.
24. Kelley P, Hopper R, Gruss J. Evaluation and treatment of zygomatic fractures. Plast Reconstr Surg
2007;120:5S.
25. Cunningham LL, Haug RH. Frontal Sinus and NOE fractures. In: Miloro M, ed. Peterson’s Principles of
Oral and Maxillofacial Surgery. 2nd ed. Hamilton, Ontario: BC Decker Inc;2004.
26. Markowitz BL, Manson PN, Sargent L, et al. Management of the medial canthal tendon in
nasoethmoid orbital fractures: the importance of the central fragment in classification and
treatment. Plast Reconstr Surg 1991;887(5):843.
27. Papadopoulos H, Salib NK. Management of naso-orbital-ethmoidal fractures. Oral Maxillofacial Surg
Clin North Am 2009;21:221.
28. Ellis E. Sequencing treatment for naso-orbito-ethmoid fractures. J Oral Maxillofac Surg 1993;51:543.
29. Heine RD, Catone GA, Bavitz JB, et al. Naso-orbital-ethmoid injury: report of a case and review of
the literature. Oral Surg Oral Med Oral Pathol 1990;69:542.
30. Pawar SS, Rhee JS. Frontal sinus and naso-orbital-ethmoid fractures. JAMA Facial Plastic Surg
2014;16(4):284.
31. Nguyen M, Koshy JC, Hollier LH. Pearls of nasoorbitoethmoid trauma management. Semin Plast
Surg 2010;24:383.
32. Herford AS, Ying T, Brown B. Outcomes of severely comminuted (type III) nasoorbitoethmoid
fractures. J Oral Maxillofac Surg 2005;63:1266.
33. Burnstine MA. Clinical recommendations for repair of isolated orbital floor fractures. Ophthalmology
2002;109:1207.
34. Coyle P, Boyd V, Banergi S, et al. Comprehensive management of orbital fractures. Plast Reconstr
Surg 2007;120:57S.
35. Raskin EM, Millman AL, Lubkin V, et al. Prediction of late enopthlamos by volumetric analysis of
orbital fractures. Ophthal Plast Reconst Surg 1998;14(1):19.
36. Rodriguez ED, Stanwix MG, Nam AJ, et al. Twenty-six year experience treating frontal sinus
fractures : a novel algorithm based on anatomical fracture pattern and failure of conventional
techniques. Plast Reconstr Surg 2008;122(6):1850.
37. Manolidis S, Hollier LH. Management of frontal sinus fractures. Plast Reconstr Surg 2007;120:32S.
38. Echo A, Troy JS, Hollier LH. Frontal sinus fractures. Semin Plast Surg 2010;24:375.
39. Ellis E. Outcomes of patients with teeth in the line of mandibular angle fractures treated with stable
internal fixation. J Oral Maxillofac Surg 2002;60:863–865.
40. Stacey DH, Doyle JF, Mount DL, et al. Management of mandible fractures. Plast Reconstr Surg
2006;117:48e.
41. Madsen MJ, Haug RH, Christenen BS, et al. Management of atrophic mandible fractures. Oral
Maxillofacial Surg Clin North Am 2009;21:175.
42. Van Sickels JE, Cunningham LL. Management of atrophic mandible fractures: are bone grafts
necessary? J Oral Maxillofac Surg 2010;68:1392.
43. Bruce RA, Ellis E. The second Chalmers J. Lyons Academy study of fractures of the edentulous
mandible. J Oral Maxillofac Surg 1993;51:904.
627
booksmedicos.org
44. Ellis E, Price C. Treatment protocol for fractures of the atrophic mandible. J Oral Maxillofac Surg
2008;66:421.
45. Cawood JI, Howell RA. A classification of the edentulous jaws. Int J Oral Maxillofac Surg
1998;17:232.
46. Luhr HG, Reidick R, Merten HA. Results of treatment of fractures of the atrophic edentulous
mandible by compression plating: a retrospective evaluation of 84 consecutive cases. J Oral
47. Lindahl L. Condylar fractures of the mandible: classification and relation to age, occlusion and
concomitant injuries of the teeth and teeth-supporting structures and fractures of the mandibular
body. In J Oral Surg 1977;6:12.
48. Walker RV. Condylar fractures: nonsurgical management. J Oral Maxillofac Surg 1994;52:1185.
49. Walker RV, Kerr HR. The consultant. J Oral Surg 1966;24:367.
50. Haug RH, Dodson TB, Morgan JP. “Trauma surgery”—Parameters and Pathways: Clinical Practice
Guidelines for Oral and Maxillofacial Surgery. Rosemont, IL: AAOMS; 2001:p TRA/15.
51. Zide MF, Kent JN. Indications for open reduction of mandibular condyle fractures. J Oral Maxillofac
Surg 1983;41(2):89.
52. Brandt MT, Haug RH. Open versus closed reduction of adult mandibular condyle fractures: a review
of the literature regarding the evolution of current thoughts on management. J Oral Maxillofac Surg
2003;61:1324–1332.
53. Troulis MJ, Kaban LB. Endoscopic approach to the ramus/condyle unit: clinical applications. J Oral
54. Troulis MJ. Endoscopic open reduction and internal rigid fixation of subcondylar fractures. J Oral
55. Kellman RM. Endoscopically assisted repair of subcondylar fractures of the mandible: an evolving
technique. Arch Facial Plast Surg 2003;5(3):244–250.
56. Miles BA, Potter JK, Ellis E. The efficacy of postoperative antibiotic regimens in the open treatment
of mandibular fractures: a prospective randomized trial. J Oral Maxillofac Surg 2006;64(4):576.
57. Manson PN, Hoopes JE, Su CT. Structural pillars of the facial skeleton : an approach to the
management of Le Fort fractures. Plast Reconstr Surg 1980; 66:54.
58. Markowtiz BL, Manson PN. Panfacial fractures : organization of treatment. Clin Plast Surg
1989;16:105.
59. Gruss JS, Mackinnon SE. Complex maxillary fractures : role of buttress reconstruction and
immediate bone grafts. Plast Reconstr Surg 1986;78:9.
60. Gruss JS, Phillips JH. Complex facial trauma : the evolving role of rigid fixation and immediate
bone graft reconstruction. Clin Plast Surg 1989;16:93.
61. He D, Zhang Y, Ellis E. Panfacial fractures: analysis of 33 cases treated late. J Oral Maxillofac Surg
2007;65(12):2459.
628
booksmedicos.org
Chapter 23
Neck Injuries
Brandon R. Bruns and Thomas M. Scalea
Key Points
1 An intimate understanding of the neck anatomy is imperative for optimal management.

2 Obtaining a secure airway is vital for management of all injuries, especially those in the neck.
3 Gentle digital pressure or balloon tamponade presents opportunities to control life-threatening
hemorrhage from vascular injuries in the neck.
4 Though classic teaching mandated exploration of zone II injuries, modern practice has strayed from
this concept.
5 Blunt cerebrovascular injury must be considered, diagnosed, and treated in patients at risk for the
disease.
6 Blunt cerebrovascular injury is often present in patients who do not manifest traditional screening
criteria.
7 A combination of endoscopy and contrast-enhanced radiography presents the best opportunity to
diagnose esophageal injury when present.
1 Many vital structures reside within the neck and exist in close proximity to one another. These include
aerodigestive, vascular, bony, and neurologic organs. These intimate relationships can lead to multiple
injuries of varying complexity in a wide variety of structures within a relatively small area. Of
penetrating injuries to the neck, the vast majority are caused by stab wounds.1–3 Blunt injury to the
neck is the result of various mechanisms of injury including direct blows, automobile shoulder belts, and
various hanging mechanisms with neck hyperextension. The anatomic complexity and diverse injury
mechanisms make diagnosing and treating neck injuries challenging.
FUNCTIONAL ANATOMY
The exterior anatomic barriers of the neck include the lower border of the mandible anteriorly to the
nuchal line of the occipital bone posteriorly. Inferiorly, the clavicles serve as the anterior border with a
line drawn toward the seventh cervical vertebral spinous process encompassing the posterior border.
Triangles are classically used to divide the neck into zones, however they are only rarely used to
classify and plan treatment in the trauma patients. The posterior triangles are bordered by the
sternocleidomastoid muscles anteriorly, the trapezius muscles posteriorly, and the clavicles inferiorly.
The anterior triangles are bordered by the sternocleidomastoid muscles, the midline, and the angles of
the mandible bilaterally.
In 1969, Monson and colleagues4 arbitrarily divided the neck into three anatomic zones: zone I
consisted of the area below the sternal notch, zone II was the area between the clavicles and the
mandibles, and zone III was described as the upper cervical region and consisted of the area above the
mandibles. Roon and Christensen5 introduced a more modern version of the neck zones in 1979 and
defined zone II as the area between the cricoid and the angle of the mandible, zone I as the area below
the cricoid cartilage, and zone III remained the area above the mandibular angle (Fig. 23-1).
The zones of the neck are important as the approach to injury within each zone is different. This is
particularly true when one considers vascular exposure. All major vascular structures in zone II can be
readily accessed via a standard sternocleidomastoid neck incision. Via a single incision, proximal and
distal vascular control can both be obtained within zone II and injuries repaired.
However, proximal control for zone I injuries requires control within the chest. A variety of incisions
can be used depending on the location of the injury. A full sternotomy provides access to the
mediastinal great vessels and the proximal left subclavian artery, along with the origin of the left
629
booksmedicos.org
common carotid artery. If a smaller incision is indicated, a partial sternotomy allows control of the
innominate artery. A periclavicular incision provides access to the bilateral subclavian arteries. In short,
a variety of incisions may be needed for full exposure. After proximal control, subsequent distal control
can then be obtained in zone II.
Proximal control for zone III injuries can be obtained in zone II without much difficulty. However,
distal control may be very difficult as the mandible and skull base prevent wide exposure. Several
methods such as mandibular subluxation or osteotomy have been described to control the carotid artery
at the base of the skull.6 A muscle splitting incision can also help give access to the carotid artery and
the base of the skull.7
Figure 23-1. Zones of the neck.
The inferior and lateral extensions of zone I are often contested and debated. While this is not well
described, our practice is to classify lateral and inferior (superior mediastinal) injuries by zone I
principles. Because proximal control involves a thoracic incision, we believe zone I extends to the
junction of the subclavian and axillary arteries laterally and inferiorly to the mediastinal great vessels.
Injury to the posterior neck should be treated differently than injury to the anterior neck. It makes
sense that tracheal and esophageal injuries would be less common with posterior injury, as they are
protected by the spine. Injuries to the spine should be more common in this anatomic region.
Often, more than one zone can be injured by a single trajectory; such as an injury through both zone
II and zone I. Management of these “multizone” injuries is guided by the standard principles used for
the more challenging zone, usually zone I or zone III.
The platysma muscle envelops the neck and originates from the pectoralis major and deltoid muscles.
Though clinical practice has evolved, most classic algorithms of treating penetrating neck trauma stated
that injuries penetrating the platysma muscle in zone II of the neck mandated direct operative
intervention, whereas those penetrating the platysma in zones I and III mandated additional studies via
either angiography or other imaging modalities.5
INITIAL MANAGEMENT
2 Basic trauma management of patients with injury to the neck should proceed as outlined in the
American College of Surgeons course Advanced Trauma Life Support (ATLS).8 Initial priority is given to
securing the patient’s airway. Every patient with a neck injury should be considered for early airway
control. A wise clinician should plan airway control in all patients with evidence of neck injury and
select the few in whom airway control is not needed. Even in seemingly stable and hemostatic patients,
rebleeding can produce sudden and disastrous symptoms and sequlae. An airway that had previously
been straightforward to control is now much more complicated and may require advanced techniques.
Obvious injury to the neck, with the presence of an expanding hematoma or other hard signs of
vascular injury, should lead the provider to obtain definitive endotracheal access as the first step in the
resuscitation. Similarly, air bubbling through the wound, hoarseness, or an obviously transected trachea,
should guide the treatment team toward immediate and definitive airway control.
In the event that orotracheal intubation cannot proceed (rapidly expanding hematoma, destructive
laryngeal trauma, patient habitus, excessive debris within the oropharynx, etc.); an emergent surgical
airway should be expeditiously obtained. Cricothyroidotomy and emergency tracheostomy remain the
630
booksmedicos.org
safest and most reliable methods of emergent surgical control of the airway. Some investigators have
shown promising results with percutaneous tracheostomy performed in the emergency setting, though
this should only be contemplated by experienced clinicians.9 If tracheal transection is visualized in the
wound, intubation of the distal tracheal segment with an endotracheal tube or any available airway
device can be lifesaving (Fig. 23-2).
Though obtaining a safe and definitive airway is the priority in all injured patients with airway
compromise, awareness of potential concomitant cervical spine injury must be considered in patients
with blunt trauma. Maintaining cervical stabilization during movement and intubation is paramount and
is best accomplished by maintaining the head and neck in neutral position with the help of a competent
assistant trained in such maneuvers. The same caution is not needed in patients with penetrating
trauma, as patients presenting alive and neurologically intact are highly unlikely to have unstable
cervical spine fractures.10,11
Figure 23-2. Intubation of a distal tracheal transection in the neck.
3 After securing an adequate airway, patient care should proceed in an orderly fashion by using ATLS
principles with the next priories being breathing and circulation. In evaluating the chest, the clinician
must remain aware that penetrating injury to zone I can violate the cupula of the lung and result in
pneumothorax or hemothorax, which may require evacuation. Circulatory issues focus on intravenous
access with resuscitation and assessment of the blood pressure, but it also entails control of any
obviously bleeding focus. Pulsatile bleeding emanating from a neck wound is best managed with gentle
digital compression. Occasionally, a urinary catheter or a Fogarty catheter can be delicately placed into
a bleeding neck wound with gradual inflation of the balloon in an attempt to tamponade hemorrhage.
The catheter should be inserted as far as it goes easily and the balloon is then inflated and the catheter
gently pulled back until bleeding eases.
A rapid assessment of the neurologic state of the patient can give insight into the nature of a neck
injury, as a dense hemiplegia may be the result of carotid arterial injury and subsequent ischemic
stroke. It is imperative to recognize the patient with a lateralizing neurologic defect early, as
revascularization may result in hemorrhagic conversion of a cerebral infarction.
After the primary survey and adjunctive radiographic procedures (chest radiograph, abdominal
sonography), a thorough secondary survey should be performed, with focus on the structures of the
neck. A hematoma across the base of the neck, which was caused by an automobile seatbelt, may
portend a blunt cerebrovascular injury (BCVI). Extensive subcutaneous emphysema in the tissues of the
neck usually represents air tracking up from a pneumothorax, but can represent an injury to the airway.
Injury to the esophagus is possible, but subcutaneous air is rarely the only symptom of esophageal
injury. Similarly, an audible bruit or palpable thrill may indicate major vascular injury that requires
prompt attention.
SELECTIVE VERSUS MANDATORY EXPLORATION

Few would argue that penetrating injuries to the neck, with hard signs of injury (pulsatile hemorrhage,
expanding hematoma, shock, air emanating from the wound, massive hemoptysis), mandate immediate
surgical exploration. In the absence of these hard signs of injury, most favor a selective approach with
631
booksmedicos.org
clinical examination and diagnostic radiographs.
Overall Approach
4 Early surgical teaching mandated exploration for penetrating zone II neck injuries that violate the
platysma muscle, regardless of the presence or absence of hard signs of injury.Those who support the
concept of mandatory exploration have cited the low incidence of significant morbidity with surgical
exploration, despite the high likelihood of negative exploration.2,12 Proponents also point to the lack of
physical examination findings in patients that did proceed to surgical exploration that had injuries
present at operation.3 In contradistinction to mandatory exploration, many investigators advocate a
more selective approach to operative therapy, suggesting surgery only in symptomatic patients. Authors
supportive of the more limited approach cite a low morbidity and mortality associated with observation
of zone II injuries and high likelihood of negative exploration.1
While diagnostic exploration may make sense for zone II injuries, diagnostic preoperative evaluation
certainly makes sense for injuries in zone I and zone III. Penetrating injury in zone I puts vascular
structures, trachea, and esophagus at risk. Physical examination can be misleading and different
incisions may be needed depending on which structures are injured and the level at which they are
injured. Thus, in stable patients, diagnostic work up is wise. This generally involves endoscopy, contrast
studies, or both to investigate the possibility of an esophageal injury. While asymptomatic tracheal
injuries are quite rare, many have favored a diagnostic bronchoscopy in these injuries. In the past,
vascular structures were investigated by means of catheter angiography, with noninvasive axial imaging
as the most common modality in the current era.
Unfortunately, in unstable patients with a zone I trajectory, localization of the injury may not be
possible preoperatively. In such a case, the clinician should make an estimate as to which structures are
most likely to be injured. The initial incision should be tailored to quickly expose that area. If exposure
is inadequate or a different structure has been injured, the incision should be lengthened, or a second
incision should be made. This process continues until the injury is controlled or the patient has died.
Aerodigestive injuries are not an issue in zone III; however the difficulty in surgical management of
vascular injuries in zone III makes preoperative imaging very attractive. In the past, angiography was
used as the sole diagnostic test in stable patients. If patients are unstable, clinicians must weigh the
difficulty of diagnostic exploration against the time it would take to use alternative hemostatic methods.
In some cases, if catheter hemostasis is immediately available, temporary control with finger pressure
or a balloon, as a bridge to rapid diagnostic angiography and catheter hemostasis may actually be
quicker than direct operative exploration. In most areas of the world, this approach is only appropriate
in a few highly advanced centers. In most centers, while difficult, direct surgical exploration is the
wisest course in the unstable patient.
Current Imaging Technology

In recent years, computed tomography (CT) has become much more widely used to evaluate the
possibility of neck injury. CT is extremely attractive as it is a single study that is rapidly available in
virtually every center and provides a three-dimensional evaluation of the neck. In patients with injury
patterns that put the upper mediastinal structures at risk as well, CT can evaluate both areas for
potential injury, simultaneously. CT may be very effective at excluding injuries in some cases. For
example, a patient with a gunshot wound to the neck that has a clearly demonstrated CT trajectory that
avoids all vital structures, most likely only needs observation and no additional diagnostic testing.
Other patients, such as those with significant amounts of subcutaneous air or a trajectory that is close to
vital structures, such as the carotid artery and/or the esophagus, may need additional diagnostic testing.
Penetrating Neck Trauma

In 2002, Gonzalez et al. prospectively evaluated patients with penetrating injury to zone II of the neck
that did not have an indication for emergent surgical exploration.13 Patients then underwent dynamic
CT imaging and had a barium esophagram, followed by mandatory surgical exploration of the neck.
Investigators noted a total of four esophageal injuries, two of which were seen on surgical exploration
only and were not identified on either CT scan or esophagram. However, both injuries missed on
diagnostic evaluation were less than 0.5 cm and were the result of stab wounds. The authors speculated
that the injuries may have healed spontaneously. The most commonly missed injury by CT scan was
jugular venous injury; which likely needed no therapy.13
In a large prospective study involving Los Angeles County, University of Southern California Medical
632
booksmedicos.org
Center, and the R Adams Cowley Shock Trauma Center at the University of Maryland, all asymptomatic
patients presenting with a penetrating neck injury and no signs of injury were safely observed and
investigators reported zero missed injuries. In the same series, patients with soft signs of injury (venous
oozing, nonexpanding or nonpulsatile hematomas, minor hemoptysis, dysphonia, dysphagia, and
subcutaneous emphysema) underwent multidetector CT angiography (CTA). Investigators achieved
100% sensitivity and 97.5% specificity in detecting all clinically significant injuries.14
Blunt Neck Trauma

Plain film radiography is not adequate to identify injuries to structures in the neck. However
pneumothorax, hemothorax, air in the subcutaneous tissues, nasogastric tube displacement, or
mediastinal widening are all indicative of significant force that would be sufficient to injure structures
within the neck.
BCVI diagnosis deserves special mention, as disagreement still persists as to the optimal screening test
for diagnosis. In the past, BCVI was usually diagnosed late, after the patient had suffered a stroke.
Diagnostic angiography then virtually always demonstrated an internal carotid artery injury. Therapy
included anticoagulation, but was mainly supportive as the damage had already been done.
Additionally, catheter angiography is invasive and carries some risk of iatrogenic vascular injury and/or
periprocedural stroke.
5 As screening protocols were developed, the incidence of BCVI seemed to increase, even in patients
with no identifiable risk factors for BCVI.15 As CTA became more entrenched as a diagnostic tool, the
rate of vascular injury again seemingly radically increased.16,17 It seems obvious that the patients did
not change, but our ability to diagnose injuries did. This is very similar to recent experience with
pulmonary embolism, where our ability to diagnose these conditions is greatly increased with the use of
CTA. This obviated the need for multiple diagnostic studies such as ventilation perfusion scans and/or
pulmonary angiography. One must question whether some of these injuries, particularly those of low
grade, have significant clinical importance.
Additional debate has focused on the ideal test for diagnosis of BCVI, with some suggesting
angiography and some CTA. In a study of 146 patients at risk for BCVI, investigators imaged all patients
with 16-slice CTA and four-vessel cerebral angiography. They noted a sensitivity of 97.7% and a
specificity of 100% with the utilization of CTA for the diagnosis of BCVI.18 However, authors in
Memphis examined 684 patients and found the sensitivity of CTA to be 51% with a specificity of 97%.19
Despite the disparate findings, survey results illustrate that 90% of trauma surgeons utilize CTA as their
preferred diagnostic modality for BCVI.20
MANAGEMENT OF SPECIFIC INJURIES

Blunt Cerebrovascular Injury (BCVI)
Blunt injuries to the carotid and vertebral arteries are the result of a direct blow to the vessel itself or
an extreme flexion, extension, or lateral rotational injury. If located in the carotid artery, these injuries
typically occur at the base of the skull. Vertebral artery injury usually is located in the portion of the
vessel protected by the cervical spine. These areas are difficult to explore surgically.
6 BCVI is reported to occur in 1% to 2% of blunt trauma patients and the incidence of stroke is
approximately 25%, with a mortality rate of up to 13%, if left untreated.16,21,22–24 Treatment for these
injuries is centered on antiplatelet therapy and systemic anticoagulation to decrease the risk of stroke.
Early recognition and initiation of treatment has been shown to decrease the rate of cerebral
ischemia.25,26
The work of Biffl and colleagues in 199921,24 highlighted the importance of screening for BCVI when
certain anatomic injuries or injury patterns were observed (Table 23-1). Subsequently, organizational
guidelines have been disseminated by the Eastern Association for the Surgery of Trauma (EAST) based
on review of the literature with the aim of guiding screening practices for BCVI (Table 23-2).27
Investigators have shown that up to 30% of patients diagnosed with BCVI may have no radiographic or
clinical risk factor that would guide the clinician to screen for these injuries.15 Recent data has also
identified an association between BCVI and nontraditional risk factors such as serious chest injury.17
Thus, a high index of suspicion must be maintained in order to effectively diagnose and treat BCVI.
Given the seeming inability of screening guidelines to accurately identify patients at risk for BCVI,
633
booksmedicos.org
some centers have gone to blanket screening.15 All polytrauma patients with a blunt mechanism of
injury undergo CT scan of the cervical spine with contrast timed to image the carotid and vertebral
arteries in conjunction with a chest and abdominal CT scan, obviating the need for a second contrast
study. While data on this blanket screening is limited, it does enable the identification of injuries early
in the course of workup and identifies injuries in patients that would otherwise not be screened
secondary to lack of criteria.15 Patients with identified injuries generally receive a formal CT angiogram
as their follow-up study.
If stroke can be avoided with prompt initiation of therapy, functional outcomes after BCVI are
good.28 However, many patients with BCVI have multisystem trauma and are thus not deemed suitable
for antiplatelet therapy or systemic anticoagulation. In a 2009 study, almost one-third of patients with
BCVI were identified as not candidates for therapy, with an overall stroke rate of 12%. Stroke-related
mortality was 50%.16
Table 23-1 Signs and Symptoms of Blunt Cerebrovascular Injury
Table 23-2 Screening Criteria for Blunt Cerebrovascular Injury
It is tempting to assign treatment for BCVI to a relatively lower priority. Patients with BCVI often
have concomitant injuries such as intra-abdominal solid visceral injury or traumatic brain injuries. The
traditional approach has been to simply decide that these patients are not candidates for anticoagulation
and defer therapy. While this may be acceptable with low-grade injuries, given the relatively high rate
of stroke with higher-grade injuries, this may not be wise. Recent data suggest that in Grade IV carotid
injuries (complete occlusion), recanalization and subsequent stroke is extremely common.29 This would
seem to suggest that the presence of higher-grade injuries mandates therapy. For instance, in a patient
with splenic injury and carotid artery injury, one should consider whether splenectomy followed by
anticoagulation is wiser than nonoperative management and withholding treatment for the BCVI.
OPERATIVE EXPLORATION
After making the decision to proceed to the operating room, the operating surgeon and surgical team
should quickly consider the various anatomic injuries which may be present. This is important as many
general surgeons do not commonly operate in the neck. Simply considering what may be found and
reviewing treatment options may help.
The patient should be positioned in a supine manner with a full surgical prep from the chin to the
knees. Utilizing a widely prepped surgical field enables the surgical team to expeditiously access various
634
booksmedicos.org
body cavities as the operation mandates. If unilaterality of injury is assumed or known, it may be
beneficial to position the patient’s head in the direction opposite to the injury, which opens the surgical
field for better exploration. Given the very real possibility of a “multizone” injury, a sternal saw should
be immediately available for possible entry into the mediastinum. Similarly, a chest retractor and deep
vascular instruments should be immediately available.
Penetrating Vascular Injury

The presentation of penetrating vascular injury in the neck is dependent on the vessel injured and its
location. Arterial injuries, specifically the carotid arteries, present with pulsatile arterial hemorrhage
emanating from the wound or a rapidly expanding hematoma. Venous injuries tend to have a more
insidious presentation and may be clinically undetectable. Penetrating vertebral artery injury is rarer
given the relatively protected position of the artery within the osseous spinal canal.
Cerebral ischemia secondary to carotid artery injury can lead to stroke and long-term neurologic
sequelae, or even death. In some series, patients who present in hemorrhagic shock have a mortality of
41%, but have 50% mortality when presenting with stroke.30 Patients presenting with any neurologic
deficit short of coma should undergo carotid arterial repair with revascularization if technically feasible,
as results are improved with revascularization. In patients presenting with a glasgow coma score (GCS)
<8 (coma), a poor outcome is likely regardless of the therapy selected.31,32
Often, carotid artery injury is diagnosed intraoperatively, as there is no time for preoperative
imaging. These injuries are usually cared for using the standard principles to treat vascular injuries. The
neck is explored through a generous sternocleidomastoid incision. The proximal carotid artery is
controlled at the base of zone II. If possible, it is wise to control the artery distally, before entering the
hematoma. Unfortunately, this is often not possible. As the neck is a compact structure, during
dissection to control the distal carotid, the contained hematoma often ruptures. Digital control can then
be used to prevent exsanguinating hemorrhage while the distal dissection is carried out. Once the distal
carotid artery, whether it is the internal carotid artery or distal common artery, is controlled, distal
pressure can be released and more careful dissection continued.
Injuries to the common carotid artery can sometimes be repaired primarily, particularly if the injury
is caused by a stab wound. More complex injuries, as those from gunshot wounds, usually require
resection. Sometimes, even gunshot wound injuries can be managed with primary repair. Full
mobilization of the common carotid artery will often give additional length. For injuries located more
distally, ligating the external carotid artery will give additional mobility to the common carotid artery.
If primary repair is not feasible, a bypass graft using either saphenous vein or PTFE is equally
acceptable. PTFE, of course, should be avoided in the event of contamination or concomitant tracheal or
esophageal injury.
Internal carotid artery injury represents a distinct subset of carotid artery injuries. Unlike common
carotid artery injury, the initial neurologic presentation is not a good predictor of final neurologic
presentation. Injuries to the internal carotid artery have 20% mortality and the majority of these deaths
are secondary to cerebral ischemia.26 Interventional techniques including embolism may be effective in
some injuries, thus obviating the need for exploration.27
Control of the internal carotid artery proceeds along the same principles as with common carotid
artery injuries, though distal control may be problematic. During the dissection, one must take care not
to injure the hypoglossal nerve, which passes across the distal internal carotid artery. The surgeon
should ascertain adequacy of back bleeding from the distal internal carotid artery. Pulsatile back
bleeding confirms patency of the circle of Willis. In patients with poor back bleeding, use of a shunt
should be considered. We routinely use full dose IV heparin unless there is a contraindication.
The internal carotid artery can be repaired using the same principles as mentioned for the common
carotid artery, though several scenarios require special mention. If there is injury to the proximal
internal carotid artery and the distal vessel is thrombosed, dissection should be carried out as distal as
possible. If the vessel is thrombosed, as far as surgically accessible, the surgeon should avoid the
temptation to do catheter thrombectomy as this is virtually never complete and, once revascularized,
the patient has significant risks of embolic stroke. In addition, one should avoid ligating the thrombosed
internal carotid artery at the base. If one forcefully ligates the internal carotid artery, there is high
likelihood that distal clot will be dislodged, causing a stroke of clinical significance.
635
booksmedicos.org
Figure 23-3. A proximal internal carotid artery injury managed with resection and transposition of the external carotid artery to
obtain inflow to the native internal carotid artery.
Occasionally, one will encounter an injury in the very proximal internal carotid artery. Once the
vessels are controlled, consideration should be given to use the external carotid artery as the conduit, if
primary repair is not feasible. The damaged internal carotid artery can be dissected down to the level of
the bifurcation (Fig. 23-3). The external carotid can be ligated at the level of the first branch and the
external carotid artery rotated over to use as the conduit. A single vascular suture line then connects the
external to the internal carotid artery.
The external carotid artery, for the most part, is expendable. If an external carotid artery injury is
diagnosed at the time of surgical exploration, it can simply be ligated. Those that are diagnosed
preoperatively, with images, are often amenable to catheter-based hemostatic techniques.29 If there is a
distal injury to a branch of an external carotid artery, such as the facial or lingual arteries, particularly
if caused by penetrating facial trauma, catheter-based hemostasis is by far the most attractive option.
Proximal ligation of the external carotid artery will decrease inflow, but the robust collateral circulation
from the contralateral external carotid may be sufficient to cause continued hemorrhage. Angiographic
options are then essentially nil, as the ligated external carotid prevents an angiographic solution.
Secondary to the posterior anatomic location and protection provided by the cervical spine,
penetrating vertebral artery injuries are less likely. Additionally, injuries to the vertebral arteries are
less likely to cause neurologic sequelae than those to the carotids.30 Operative exposure of the vertebral
artery is quite difficult secondary to its protected location in the posterior neck. If necessary, it is best
approached via an anterior approach with proximal ligation of vertebral artery.31 Combined carotid and
vertebral artery penetrating injuries are very morbid, with mortality rates of approximately 50%.32
Occasionally, a vertebral artery injury will be discovered at the time of diagnostic neck exploration.
This is an extremely challenging situation, as direct pressure will only temporarily control the artery.
Rather than attempting to expose the artery by unroofing the cervical spine over the vessel, we have
generally maintained digital pressure or controlled the artery temporarily with a Fogarty balloon, after
which the patient can then be transported to a site where angiographic embolization is possible.
Trachea and Larynx

Blunt laryngotracheal trauma is uncommon33 and low-grade injuries, can be clinically occult. Thus, it
requires a high index of suspicion for accurate diagnosis and initiation of treatment. The most typical
mechanism of injury involves an anterior to posterior vector of force that drives the thyroid cartilage
into the rigid cervical spine. Such forces can be the result of a motor vehicle collision with compression
of the neck against the steering wheel or dash of the automobile. The most common symptoms include
hoarseness, dyspnea, and dysphagia.33,34 Careful attention must be paid to the airway as laryngotracheal
separation can be catastrophic. Definitive diagnosis is made with a combination of CT scanning and
endoscopy and definitive airway management is best obtained with tracheostomy, if endotracheal
intubation is not prudent.35
The presentation of penetrating laryngotracheal injuries are less subtle, as impressive symptoms and
physical findings almost always present in high-grade injuries. Management is focused on rapid airway
control, either via endotracheal intubation or via a surgical airway. In the rare instance of tracheal
transection in the neck with two visible lumens, the distal lumen should be intubated with any available
airway device. Concomitant esophageal injury is a source of major morbidity; therefore the esophagus
should be evaluated with endoscopy early or operative exploration in the course of treatment.36
Cervical tracheal injuries, particularly if they are isolated, are best approached via a collar incision
performed approximately two fingerbreadths above the sternal notch. If other injuries are present
636
booksmedicos.org
and/or if full exploration is needed, the trachea can be exposed and repaired using a
sternocleidomastoid incision. If a collar incision is used, subplatysmal flaps are created and the strap
muscles are then divided in the midline. The thyroid isthmus can be retracted cephalad and the entire
cervical trachea is then clearly visualized. If the location of the tracheal injury in the neck is clearly in
zone II, surgical exploration confirms the diagnosis and allows for prompt therapy.
However, sometimes the injury is located closer to the thoracic inlet. In those cases, preoperative
bronchoscopy is vital in order to plan the best operative course. If the injury is located in the upper
mediastinum, several options exist. The patient can be explored via a collar incision and the anterior
trachea identified. The trachea can be mobilized using digital dissection into the upper mediastinum.
The trachea can then be grasped with a tracheal hook and retracted up into the neck. It is possible to
mobilize the trachea for approximately three rings, thus allowing the surgeon to repair these injuries
with a relatively small incision. However, injuries that are located in the more distal mediastinum are
best approached with a right-sided posterolateral thoracotomy.
Occasionally, tracheal injuries will be located at a level above the endotracheal balloon. When
performing diagnostic bronchoscopy, the endotracheal tube must be withdrawn over the bronchoscope,
up to the level of the vocal cords. This allows complete visualization of the proximal trachea. Not doing
this, risks missing the proximal tracheal injury.
Injuries to the posterior membranous trachea are relatively difficult to approach. In patients with
blunt trauma, small injuries may be simply observed. However, if repair is thought to be prudent, the
best way to approach this is via the anterior trachea. The anterior trachea is opened transversely at the
level of the injury and the injury is then visualized and repaired. The anterior trachea is then closed
primarily. Intraoperative bronchoscopy can help locate the level of the injury.
The blood supply to the trachea enters posterolaterally on both sides. Therefore, circumferential
mobilization of the trachea, risks causing ischemia, which may manifest either as tracheal necrosis,
dehiscence of a repair, or postoperative tracheal stenosis. In addition, the recurrent laryngeal nerve runs
in the tracheoesophageal groove and care must be taken to avoid damage to it during mobilization or
tracheal repair. Postoperatively, patients should be extubated as soon as possible. It is often tempting to
think that the tracheal repair is protected with longer-term tracheal intubation, but the chances of
complication are less if the patient is extubated at the end of the operative procedure. One should avoid
a tracheostomy in a patient with tracheal repair, because stenosis at the level of tracheostomy and the
level of tracheal repair can make future reconstruction exceedingly difficult.
Figure 23-4. Partial sternal split for evaluation of tracheal injury. The endotracheal tube balloon is visualized within the lumen of
the injured trachea.
In the event that the injury extends into the thoracic inlet, a partial sternal split (Fig. 23-4) or full
sternotomy can be performed for better visualization. Tracheal injuries are preferentially repaired
primarily with single layer absorbable suture, though resection of up to 2 to 4 cm with primary
anastomosis is technically feasible. Suture lines are buttressed with autologous, well-vascularized tissue
such as strap muscle (Fig. 23-5).
637
booksmedicos.org
Esophagus
Figure 23-5. Divided strap muscle utilized to buttress tracheal injury/repair.
Expeditious diagnosis of esophageal injury is imperative, as missed injury and/or a delay in diagnosis
can lead to disastrous consequences. In a review of 109 penetrating esophageal injuries, the mortality
rate was 2% with immediate operation. Mortality increased to 44% with delayed diagnosis and
operation. In this same series, mortality increased to 100% for patients with a delayed diagnosis and no
operative procedure.37
As the course of the esophagus is relatively superficial within the neck, diagnosis can occasionally be
made on physical examination findings alone. Food particles or salivary secretions within the wound are
highly suggestive of esophageal injury. Additional physical examination findings may include
esophageal or oropharyngeal bleeding, subcutaneous emphysema, and neck hematoma. Plain film
radiographic findings may include air within the subcutaneous tissues and pneumomediastinum.38 In a
review of 77 patients with noniatrogenic esophageal injury, 58% occurred in the cervical esophagus but
physical examination findings were present in only 26% of the cohort.39
7 Given the pervasive nature of CT scanning in the trauma patient, investigators have evaluated the
utility of this imaging modality for esophageal injury. A study from the Aga Khan University Hospital
showed 53% sensitivity for CT scanning in diagnosing esophageal injuries.40 The gold standard for
diagnosis of most esophageal injuries remains a combination of esophagoscopy and contrast-enhanced
esophagography. When these two imaging modalities are used in combination, an accuracy of almost
100% is achieved.41 The sensitivity of esophagography alone varies from 50% to 90% while the
sensitivity of endoscopy alone varies from 29% to 100%.42
As with the trachea, the location of the esophageal injury defines the approach for repair. Those
injuries that are clearly in zone II can easily be approached via a sternocleidomastoid incision. Those in
the chest are best approached via a posterolateral right thoracotomy. As with the trachea, localization of
the injury, particularly those at the junction between the neck and chest, is the easiest way to ensure
optimal exposure. Intraoperative endoscopy can be very helpful in positively identifying the location of
an injury and helping to direct therapy.
Small, nondestructive injuries in the hypopharyngeal region can occasionally be managed
nonoperatively with antibiotics, upright positioning, limited oral intake, and close clinical
observation.43 However, the vast majority of cervical esophageal injuries are best managed operatively.
Cervical esophageal injuries are most easily approached via a left anterior sternocleidomastoid incision.
If a collar incision has been initiated, it can be extended to the left, along the anterior border of the
sternocleidomastoid muscle to facilitate better exposure. Preoperative placement of a nasogastric tube
may assist with identification of the esophagus in the neck, as the hard nasogastric tube can be palpated
within the lumen. After lateral retraction of the sternocleidomastoid muscle, the dissection progresses
medially until the esophagus is encountered. Care must be taken to avoid injury to the recurrent
laryngeal nerve in the tracheoesophageal groove.
Circumferential dissection of the esophagus and placement of large rubber drain around the organ can
facilitate retraction and mobilization. As the blood supply of the esophagus runs vertically within the
muscle, the esophagus can be circumferentially mobilized without risk of ischemia. Thus, injuries
located in the superior mediastinum can be mobilized into the neck and repaired. After repair, liberal
drainage of the injured area is highly recommended in an effort to avoid salivary fistula and deep neck
infection.38,43 Delays in diagnosis of more than 12 hours are associated with poor outcomes and in these
638
booksmedicos.org
cases, proximal diversion and wide drainage may be the safest option.
Primary repair of the injury is the goal in most circumstances. During repair, the entirety of the
mucosal injury must be visualized, as it may extend beyond the field of view under the longitudinal
outer muscle of the esophagus. Debridement of all devitalized tissue is required. Repairs are typically
performed in two layers with absorbable sutures, though single-layer repair is possible.38,44 Similar to
tracheal repair, a well-vascularized muscle is highly recommended to buttress the repair. Given the
likelihood that the patient will be on a restricted oral diet, placement of a small-bore enteral tube, distal
to the repair, should be considered intraoperatively. Imaging repairs at 7 to 10 days with a contrast-
enhanced swallow study is recommended prior to removal of drains.
Table 23-3 Common Complications After Neck Injury
COMPLICATIONS
As in all forms of injury, neck injuries are associated with a variety of morbidities (Table 23-3). The
most common complications after tracheal repair include postoperative suture granuloma, pneumonia,
and surgical site infection.45 Complications after tracheal repair were once thought to be numerous;
modern studies have questioned this supposition. In a 2013 paper, investigators showed that
complications after tracheal injury alone were associated with an exceedingly low rate of complications.
In patients with combined tracheal and esophageal injuries, the rate of complications is drastically
increased.46
Tracheoesophageal fistula occurs when an abnormal passage forms between the trachea and
esophagus, manifesting as respiratory distress and recurrent pulmonary infections. Management
includes a variety of operative techniques aimed at restoring the continuity of both the trachea and
esophagus and the interposition of well-vascularized tissue flaps between the repairs. Though
endoluminal stenting is discussed, its utility is currently minimal.47
Esophageal leak from repair dehiscence and anastomotic breakdown creates an ongoing source of
intrathoracic infection and inflammation, which makes primary management and repair exceedingly
difficult. Though relatively early in the experience, the use of endoluminal stenting in this situation has
shown promise and avoids the need for full operative exploration.48 Leaks in the neck are more easily
controlled by opening of the wound and wide drainage with avoidance of enteral nutrition past the site
of injury. In rare instances, cervical esophagostomy may be required.
SUMMARY
Management of injuries to the neck requires a thorough understanding of three-dimensional anatomy
and an appreciation for the severity of injuries possible in this region. A relatively small anatomic
region, the neck contains many structures vital to meaningful survival. Attention to airway is of the
utmost importance, because without a secure airway, the remainder of workup is meaningless. In the
presence of vascular injury, all management options must be rapidly reviewed and the most easily
obtained and efficacious maneuver should be chosen. As nonoperative management of many traumatic
injuries continues to expand, it is the obligation of the surgeon to remember basic surgical principles
and apply them in an expeditious and safe manner as the situation mandates.
References
1. Nason RW, Assuras GN, Gray PR, et al. Penetrating neck injuries: analysis of experience from a
Canadian trauma centre. Can J Surg 2001;44(2):122–126.
2. Bishara RA, Pasch AR, Douglas DD, et al. The necessity of mandatory exploration of penetrating
zone II neck injuries. Surgery 1986;100(4):655–660.
639
booksmedicos.org
3. Saletta JD, Lowe RJ, Lim LT, et al. Penetrating trauma of the neck. J Trauma 1976;16(7):579–587.
4. Monson DO, Saletta JD, Freeark RJ. Carotid vertebral trauma. J Trauma 1969;9(12):987–999.
5. Roon AJ, Christensen N. Evaluation and treatment of penetrating cervical injuries. J Trauma
1979;19(6):391–397.
6. Simonian GT, Pappas PJ, Padberg FT Jr, et al. Mandibular subluxation for distal internal carotid
exposure: technical considerations. J Vasc Surg 1999;30(6):1116–1120.
7. Shaha A, Phillips T, Scalea T, et al. Exposure of the internal carotid artery near the skull base: the
posterolateral anatomic approach. J Vasc Surg 1988; 8(5):618–622.
8. American College of Surgeons - Committee on Trauma. Initial Assessment and Management. In:
Advanced Trauma Life Support - Student Course Manual. 9th ed. Chicago, IL:American College of
Surgeons;2012:2–21.
9. Davidson SB, Blostein PA, Walsh J, et al. Percutaneous tracheostomy: a new approach to the
emergency airway. J Trauma Acute Care Surg 2012;73(2 Suppl 1):S83–S88.
10. Medzon R, Rothenhaus T, Bono CM, et al. Stability of cervical spine fractures after gunshot wounds
to the head and neck. Spine (Phila Pa 1976) 2005; 30(20):2274–2279.
11. Ramasamy A, Midwinter M, Mahoney P, et al. Learning the lessons from conflict: pre-hospital
cervical spine stabilisation following ballistic neck trauma. Injury 2009;40(12):1342–1345.
12. Jones RF, Terrell JC, Salyer KE. Penetrating wounds of the neck: An analysis of 274 cases. J
Trauma 1967;7(2):228–237.
13. Gonzalez RP, Falimirski M, Holevar MR, et al. Penetrating zone II neck injury: does dynamic
computed tomographic scan contribute to the diagnostic sensitivity of physical examination for
surgically significant injury? A prospective blinded study. J Trauma 2003;54(1):61–64; discussion
64–65.
14. Inaba K, Branco BC, Menaker J, et al. Evaluation of multidetector computed tomography for
penetrating neck injury: a prospective multicenter study. J Trauma Acute Care Surg 2012;72(3):576–
583; discussion 583–584; quiz 803–804.
15. Bruns BR, Tesoriero R, Kufera J, et al. Blunt cerebrovascular injury screening guidelines: what are
we willing to miss? J Trauma Acute Care Surg 2014; 76(3):691–695.
16. Stein DM, Boswell S, Sliker CW, et al. Blunt cerebrovascular injuries: does treatment always
matter? J Trauma 2009;66(1):132–143; discussion 143–144.
17. Lohrer L, Vieth V, Nassenstein I, et al. Blunt cerebrovascular injuries in acute trauma care: a
screening protocol. Eur Spine J 2012;21(5):837–843.
18. Eastman AL, Chason DP, Perez CL, et al. Computed tomographic angiography for the diagnosis of
blunt cervical vascular injury: is it ready for primetime? J Trauma 2006;60(5):925–929; discussion
929.
19. DiCocco JM, Emmett KP, Fabian TC, et al. Blunt cerebrovascular injury screening with 32-channel
multidetector computed tomography: more slices still don’t cut it. Ann Surg 2011;253(3):444–450.
20. Harrigan MR, Weinberg JA, Peaks YS, et al. Management of blunt extracranial traumatic
cerebrovascular injury: a multidisciplinary survey of current practice. World J Emerg Surg
2011;6:11–7922–6–11.
21. Biffl WL, Moore EE, Elliott JP, et al. Blunt cerebrovascular injuries. Curr Probl Surg
1999;36(7):505–599.
22. Miller PR, Chang MC, Hoth JJ, et al. Colonic resection in the setting of damage control
laparotomy: is delayed anastomosis safe? Am Surg 2007;73(6):606–609; discussion 609–610.
23. Cothren CC, Moore EE, Biffl WL, et al. Anticoagulation is the gold standard therapy for blunt
carotid injuries to reduce stroke rate. Arch Surg 2004;139(5):540–545; discussion 545–546.
24. Biffl WL, Moore EE, Offner PJ, et al. Blunt carotid arterial injuries: implications of a new grading
scale. J Trauma 1999;47(5):845–853.
25. Fabian TC, Patton JH Jr, Croce MA, et al. Blunt carotid injury. Importance of early diagnosis and
anticoagulant therapy. Ann Surg 1996;223(5):513–522; discussion 522–525.
26. Eastman AL, Muraliraj V, Sperry JL, et al. CTA-based screening reduces time to diagnosis and
stroke rate in blunt cervical vascular injury. J Trauma 2009;67(3):551–556; discussion 555–556.
27. Bromberg WJ, Collier BC, Diebel LN, et al. Blunt cerebrovascular injury practice management
640
booksmedicos.org
guidelines: the eastern association for the surgery of trauma. J Trauma 2010;68(2):471–477.
28. DiCocco JM, Fabian TC, Emmett KP, et al. Functional outcomes following blunt cerebrovascular
injury. J Trauma Acute Care Surg 2013;74(4):955–960.
29. Lauerman M, Feeney T, Sliker C, et al. Lethal now or lethal later: the natural history of Grade IV
blunt cerebrovascular injury. Abstract. American Association for the Surgery of Trauma Annual
Meeting. Philadelphia, PA; 2014.
30. Ramadan F, Rutledge R, Oller D, et al. Carotid artery trauma: a review of contemporary trauma
center experiences. J Vasc Surg 1995;21(1):46–55; discussion 55–56.
31. Feliciano DV. Management of penetrating injuries to carotid artery. World J Surg 2001;25(8):1028–
1035.
32. Liekweg WG Jr, Greenfield LJ. Management of penetrating carotid arterial injury. Ann Surg
1978;188(5):587–592.
33. Sofferman RA. Management of laryngotracheal trauma. Am J Surg 1981;141(4):412–417.
34. Myers EM, Iko BO. The management of acute laryngeal trauma. J Trauma 1987;27(4):448–452.
35. Fuhrman GM, Stieg FH 3rd, Buerk CA. Blunt laryngeal trauma: classification and management
protocol. J Trauma 1990;30(1):87–92.
36. Grewal H, Rao PM, Mukerji S, et al. Management of penetrating laryngotracheal injuries. Head
Neck 1995;17(6):494–502.
37. Sankaran S, Walt AJ. Penetrating wounds of the neck: principles and some controversies. Surg Clin
North Am 1977;57(1):139–150.
38. Glatterer MS Jr, Toon RS, Ellestad C, et al. Management of blunt and penetrating external
esophageal trauma. J Trauma 1985;25(8):784–792.
39. Defore WW Jr, Mattox KL, Hansen HA, et al. Surgical management of penetrating injuries of the
esophagus. Am J Surg 1977;134(6):734–738.
40. Kazi M, Junaid M, Khan MJ, et al. Utility of clinical examination and CT scan in assessment of
penetrating neck trauma. J Coll Physicians Surg Pak 2013;23(4):308–309.
41. Weigelt JA, Thal ER, Snyder WH 3rd, et al. Diagnosis of penetrating cervical esophageal injuries.
Am J Surg 1987;154(6):619–622.
42. Carducci B, Lowe RA, Dalsey W. Penetrating neck trauma: consensus and controversies. Ann Emerg
Med 1986;15(2):208–215.
43. Stanley RB Jr, Armstrong WB, Fetterman BL, et al. Management of external penetrating injuries
into the hypopharyngeal-cervical esophageal funnel. J Trauma 1997;42(4):675–679.
44. Winter RP, Weigelt JA. Cervical esophageal trauma. Incidence and cause of esophageal fistulas.
Arch Surg 1990;125(7):849–851; discussion 851–852.
45. Miller BS, Shafi S, Thal ER. Damage control in complex penetrating tracheal injury and silicone T-
tube. J Trauma 2008;64(2):E18–E20.
46. Lyons JD, Feliciano DV, Wyrzykowski AD, et al. Modern management of penetrating tracheal
injuries. Am Surg 2013;79(2):188–193.
47. Muniappan A, Wain JC, Wright CD, et al. Surgical treatment of nonmalignant tracheoesophageal
fistula: a thirty-five year experience. Ann Thorac Surg 2013;95(4):1141–1146.
48. David EA, Kim MP, Blackmon SH. Esophageal salvage with removable covered self-expanding
metal stents in the setting of intrathoracic esophageal leakage. Am J Surg 2011;202(6):796–801;
discussion 801.
641
booksmedicos.org
Chapter 24
Thoracic Trauma
Marc de Moya and George Velmahos
Key Points
1 The mortality associated with penetrating thoracic trauma is higher than blunt trauma.
2 The most common thoracic injury is rib fracture and the most effective pain relief is thoracic
epidural analgesia.
3 Not all pneumothoraces need to be drained but when necessary drainage can be accomplished
effectively with a pigtail catheter.
4 Hemothoraces may be drained by 28-Fr chest tubes and if there is significant retained hemothorax
early intervention with video-assisted thoracoscopy should be employed.
5 Aortic injury repair may be delayed and the injury medically managed in the face of significant
associated injuries.
INTRODUCTION
1 Thoracic trauma is a common occurrence with an incidence of approximately 25% of all traumas.1
Thoracic injuries are also commonly associated with head and abdominal trauma with a blunt
mechanism. The most common thoracic injury is rib fracture and mortality/morbidity increases as the
number of ribs fractured increases. Mortality is most pronounced in the elderly where there is a 19%
increase in mortality with each additional rib fracture.2 Penetrating trauma accounts for the majority of
deaths related to thoracic trauma but overall 85% of penetrating trauma to the chest can be managed
with a chest tube. Regardless of the mechanism or obvious injuries one should always proceed with a
systematic approach to the trauma patient, via Advanced Trauma Life Support (ATLS).
INITIAL IMAGING
The initial imaging in the trauma bay for suspected chest trauma is the screening chest X-ray (CXR) and
the extended FAST (eFAST) examination. The CXR is typically a supine anterioposterior (AP) single film
that helps the clinician determine if there are any bone fractures (ribs/clavicle/scapula), mediastinal
hematoma (widened mediastinum >8 cm, loss of aortic knob, loss of aortopulmonary window,
depression of left mainstem bronchus >110 degrees, deviation of nasogastric tube, apical cap, or
tracheal deviation), pneumothorax, hemothorax, lung contusions, elevated diaphragm, large
diaphragmatic rupture, or confirm position of endotracheal tube/any central lines in internal jugular or
subclavian positions.3 If the spine is cleared then an upright AP film may be obtained, which increases
sensitivity for hemothoraces and pneumothoraces. These films are often limited due to movement,
clothing, backboards, or inadequate exposure but serve as reasonable screening image.
The FAST (Focus Assessment with Sonography for Trauma) has become a standard adjunct in the
trauma bay. ATLS4 now has a module focused on the FAST examination and therefore, all physicians or
advanced practitioners who care for trauma patients should become familiar with how to perform the
FAST examination. The FAST examination views include the right upper quadrant, left upper quadrant,
pelvic view, and the pericardium. For the purposes of this chapter the pericardial view is the view that
will demonstrate hemopericardium. Hemopericardium is typically the result of penetrating trauma to
the heart but may also be due to blunt rupture of the heart.5 Rozycki et al.6 used the FAST examination
to determine if there was pericardial fluid in 1,540 patients with truncal injuries, with 100% sensitivity
and 99.3% specificity. The eFAST includes the evaluation of lung to determine presence or absence of a
large pneumothorax and evaluation for hemothoraces. The sensitivity of ultrasound to detect a
pneumothorax is approximately 90% and is more sensitive than the screening supine CXR.7
642
booksmedicos.org
Computed tomographic scans (CT scans) are often employed after the secondary survey and provide
important information. They are highly sensitive for hemo/pneumothoraces, bone fractures, vascular
injuries, and lung contusions/lacerations. CT scans are typically performed with intravenous contrast to
better visualize vascular injuries and lung parenchyma.
COMMON INJURIES
Rib Fractures
The most common injury in thoracic trauma is the rib fracture. There is a spectrum of injury patterns
ranging from single nondisplaced rib fractures to large flail segments with severe displacement. There
are two general patterns of injury related to age and degree of flexibility of ribs. The younger
population has innately more mobile/flexible ribs and therefore requires a higher force to create
fractures. This higher force also translates to a higher degree of underlying lung contusion. The older
population with more brittle ribs requires less force to fracture the ribs and therefore may not have as
severe of an underlying lung contusion. The diagnosis is usually made by initial physical examination
(tenderness and chest wall paradoxical movement for flails) and CXR (Fig. 24-1). However, CXR only
visualizes 30% of rib fractures. CT scan is extremely sensitive for rib fractures and also allows one to
quantify any associated hemothorax/pneumothorax.
Flail chests is defined as three or more segments of consecutive ribs broken in two or more places.
These segments move independently and may exhibit a “mechanical” flail which is the paradoxical
movement of the flail segment. As the patient inspires and expands the chest to produce a negative
pressure, the flail segment is pulled toward the lung. The opposite occurs during expiration and the flail
segment bulges outward (Fig. 24-2). The respiratory compromise that occurs in the face of a flail
segment is multifactorial; (1) underlying lung contusion, (2) pain with respirations, and (3) mechanical
disadvantage. The pain and the contusion are the most influential on clinical outcomes when compared
to the mechanical disadvantage.
Figure 24-1. Rib fractures on CXR.
Treatment
2 The most important aspect of care for rib fractures is pain management. The majority of
complications are directly related to lack of pain control. There are multiple studies suggesting that
thoracic epidurals are superior to intravenous narcotics for treatment of pain related to rib fractures.8,9
Pain relief can also be provided by intercostal blocks, paravertebral blocks, or lidocaine patches but
these methods are not as effective as administration of thoracic epidural analgesia. An aggressive pain
management program will allow the patient to be more mobile and promote good pulmonary toilet to
remove secretions and improve expansion of the lung.
There are two randomized clinical studies comparing surgical repair of ribs (open reduction and
internal fixation) versus mechanical ventilation alone.10,11 Both studies suggest a benefit in surgical
repair in terms of days on the ventilator, pneumonia, and function at 6 and 12 months. Therefore, it is
recommended for those with large flail chest (five or more ribs) on mechanical ventilation without a
reason for prolonged intubation, that is, severe traumatic brain injury, to undergo rib fixation. This
conclusion has also been supported by other nonrandomized trials.12,13 There are multiple types of rib
643
booksmedicos.org
fixators available (Fig. 24-3) and no repair has proven superior. The majority of ribs repaired are
number 4 to 9, approached via a thoracotomy incision (Fig. 24-4).
Figure 24-2. Pathophysiology of flail chest. A: Inspiratory phase: chest wall collapses inward, causing air to move out of the
bronchus of the involved lung into the trachea and bronchus of the uninvolved lung, causing a shift of mediastinum to the
uninvolved side. B: Expiratory phase: chest wall balloons outward so that air is expelled from the lung on the uninvolved side and
enters the lung on the involved side with an associated shift of mediastinum to the involved side.
Figure 24-3. Rib fixation with plates.
For patients who do not have large flail chests, which is the majority, the indications for rib fixation
remain elusive. In general, the author’s approach is to consider rib fixation for any patient with three or
more ribs fractured with severe displacement (more than the width of a rib). The patient population
that would significantly benefit from fixation is unclear and at this point the decision is made on a case-
644
booksmedicos.org
specific basis.
Pneumothorax
Pneumothoraces can be classified into three subtypes: occult, simple, and tension. The initial diagnosis
can be made with physical examination by auscultation. Auscultation is the first diagnostic test
performed during the “Breathing” portion of the primary survey. One should be sure to auscultate the
chest in two primary positions (bilateral midaxillary lines). This provides the examiner with the greatest
specificity since these positions represent the most distant portions of the hemithorax from the
contralateral hemithorax. Anterior positions can often be falsely positive for breath sounds secondary to
overlapping pleura or transmitted sounds from the contralateral side.
Figure 24-4. Rib Fixation with plates (photo).
The next most commonly used diagnostic test is ultrasound during the extended FAST examination
looking specifically for lung sliding. Lung sliding has a high sensitivity and specificity (78.6% and
98.4%)14 for the presence or absence of a pneumothorax as described above. The standard of care in the
trauma bay is upright (if spine is cleared) or supine AP X-ray if the spine is not cleared. Although
radiographs are less sensitive than ultrasound for small pneumothoraces they are used to screen for
other associated injuries as described above.
An occult pneumothorax is one that is seen on CT scan (which is the most sensitive test for
pneumothorax) but not seen on CXR (Fig. 24-5A, B). Subcutaneous emphysema is a sign that should
alert the clinician to pneumothorax (Fig. 24-6). A simple pneumothorax is one that is seen on either CT
scan or CXR but is not associated with hemodynamic compromise. Those patients with a pneumothorax
and hemodynamic compromise must be considered a tension pneumothorax until proven otherwise.
Tension pneumothorax is not a radiologic diagnosis but rather a clinical diagnosis. A tension
pneumothorax is a pneumothorax that has progressed to the point that the mediastinum is shifted
compromising in-flow to the heart. Kinking of the great vessels is the pathophysiology that leads to an
acute decrease in cardiac output and shock. Unless tension is released the patient will die. Signs and
symptoms of a tension pneumothorax include; shortness of breath, dyspnea, tachypnea, hypotension,
distended neck veins, and tracheal deviation (away from the site of injury). If any of these signs are
present immediate decompression is necessary.
Treatment of Pneumothorax
If the patient is unstable and a tension pneumothorax is suspected needle decompression may be
considered. A large–bore, 14- to 16-gauge angiocatheter is inserted into either the anterior second
intercostal space in the midclavicular line or the fifth intercostal space in the midaxillary line. There is
some cadaveric data that suggests that the fifth intercostal space in the midaxillary line has the least
distance from the skin to the pleural cavity and therefore, may be superior to the anterior position.15
This converts the tension pneumothorax to a simple pneumothorax which can subsequently be drained
with a proper tube.
3 If one has access to a chest tube quickly there is no need to perform a needle decompression.
Classically an open chest tube in the zone of safety may be placed. The zone of safety is outlined by the
pectoralis major lateral border, the nipple line in men (two fingerbreadths above the inframammary
645
booksmedicos.org
fold, women), and the anterior border of the latissimus dorsi. The triangle formed by these borders is a
guide for the practitioner for placement of the chest tube (Fig. 24-7). If the tube is placed too far caudal
it can easily enter the abdominal cavity. A standard 28-Fr chest tube may be placed as there is no
difference between a 36 Fr and 28 Fr in ability to adequately drain the chest of either pneumothorax or
hemothorax.16 In those patients with a pure pneumothorax a 14-Fr pigtail catheter is also acceptable and
may be superior given the significantly less pain/discomfort of the tube as described in a randomized
clinical trial.17 Pigtail catheters are placed using a Seldinger technique in the identical areas as the open
chest tube technique.
For those patients who have a simple (or occult) pneumothorax one should be guided by progression
of the pneumothorax or the development of signs/symptoms of cardiopulmonary compromise. In a
series of 146 patients with pneumothoraces, 90% of pneumothoraces that were 3.5 cm in widest
dimension were successfully observed. This holds true in the intubated patient on positive pressure
ventilation as well.18 Therefore, as a general rule, if the patient is stable one should repeat the CXR and
if the pneumothorax is significantly larger (definition of significantly larger varies) or if the patient
becomes symptomatic then a tube should be placed to reexpand the lung. No longer is there a need for a
mandatory chest tube for pneumothoraces, even for those on positive pressure ventilation.
Figure 24-5. A: AP CXR in trauma bay with no evidence of pneumothorax. B: Occult pneumothorax seen on CT scan C:
Measurement of largest air pocket in a line drawn perpendicular to the chest wall.
646
booksmedicos.org
Figure 24-6. Subcutaneous emphysema.
Figure 24-7. Zone of safety.
Pulmonary Contusion
In the presence of flail chest or multiple rib fractures one may observe a significant decrease in the
PaO2/FiO2 ratio. Rather than a function of the mechanics of the chest wall this is most consistently a
result of underlying lung contusion. Lung contusion is the extravasation of blood into the interstitial
space of the lung parenchyma. Bleeding may extend to the alveolar space as well in severe cases.
Treatment
The treatment for lung contusion complicated by hypoxia is primarily supportive, with administration of
positive end-expiratory pressure (PEEP). PEEP may be applied either noninvasively (face mask) or
through an endotracheal tube. In a small study, it was found that 100% of patients who had five or
more ribs fractures, two-thirds or more of lung affected by contusion, and a decrease in mental status
(GCS ≤14) required intubation.19 Intubations did not necessarily occur on the first day but often on the
second day. Therefore, it is important to identify patients at risk for intubation and place them in a
higher level of care. Other key aspects of care include minimizing intravenous crystalloid fluids, early
mobilization, and encouraging cough/deep breathing.
Hemothorax
Initial imaging is the screening CXR. This x-ray is often a supine AP film that may make the diagnosis of
a hemothorax challenging. In the supine film the blood layers in the posterior recess of the hemithorax
and the x-ray may appear hazy when compared to the contralateral side. In the face of a large
hemothorax the x-ray can appear as a white out. Ultrasonography during the extended FAST
647
booksmedicos.org
examination has a high sensitivity for detecting a hemothorax.
The causes of hemothorax are varied, the most common being rib fractures/intercostal muscle to
intercostal artery laceration, pulmonary laceration, or cardiac injury with communication to the pleura
via injury to the pericardium. The urgency of the treatment is dictated by the physiologic state of the
patient with rapid control of hemorrhage is the first priority.
4 Hemothoraces associated with hemodynamic instability or those that drain >1,500 cc immediately
or >200 cc/hour for >4 hours after placement of a chest tube should be taken directly to the operating
room for exploratory thoracotomy. The size of chest tubes has decreased over time and contemporary
data suggests that there is no difference in the ability of the 28-Fr versus the 36-Fr chest tube to
effectively drain a hemothorax. Some have advocated a 14-Fr pigtail catheter for drainage of a
hemothorax. In terms of chest tube position, there is little convincing evidence to suggest that the
position of the chest tube, anterior or posterior, makes a difference in the ability of the tube to drain a
hemothorax.20 This is likely a result of the pleura being a closed system and therefore, suction applied
to one area will apply equal amounts of pressure to other areas of the pleural space. The liquid
component of the hemothorax will be drained from any position. Clotted blood will not be effectively
drained even if the tube is in the middle of the clot. In general, patients with a moderate to large
volume hemothorax should be drained, approximately 300 cc when estimated using the following
formula: Estimated volume (cc) = d2 × l, where d equals the greatest dimension in centimeters from
the chest wall to the lung or mediastinum across the largest fluid pocket, and l is the craniocaudal
height (number of axial slices on the CT scan × the thickness of those slices in centimeter.21
Retained Hemothorax
Retained hemothoraces may occur in 30% of the patients.22 A retained hemothorax is defined as
hemothorax that persists despite an attempt at drainage. If the hemothorax is not adequately drained in
a 24-hour period it may be necessary to differentiate the hemothorax from atelectasis. A CT scan will
help the surgeon differentiate between the two and allow one to calculate the amount retained.
If the amount is moderate to large there are two options; (1) early video-assisted thoracostomy to
evacuate the clot or (2) tissue plasminogen activator (TPA) with or without DNAase. The key point is
that early intervention allows the clot to be evacuated and prevent a fibrothorax from forming. Ideally,
surgical drainage should be performed within 7 days to optimize the ability to successfully perform
thoracoscopy.
Aortic Injury
Those patients with evidence of mediastinal hematoma on CXR, as described above, or those with a
high-risk mechanism, that is, same-side motor vehicle collision (t-bone collision) should have a CT scan
of the chest with intravenous contrast. CT scan has become the standard of care for diagnosis and
classification of aortic injuries. Aortic injuries most commonly occur at points of fixation. These
locations in decreasing order of occurrence include; (1) ligamentum arteriosa (just distal to the left
subclavian artery), (2) diaphragmatic hiatus, and (3) root of the aorta (these usually die at the scene).
The current classification of aortic injuries divides the extent of injury into four grades; (1) small
intimal tear, (2) intramural hematoma (3) pseudoaneurysm (Fig. 24-8A,B), (4) periaortic rupture. The
treatment of these injuries has evolved.
5 Small injuries are placed on aspirin for 6 months. Types 2, 3, and 4 are treated with placement of
covered stent grafts via an endovascular approach. When compared to open clamp and sew repairs the
incidence of paraplegia is much lower in the endovascular treatment group, which has resulted in its
adoption as the contemporary standard of care (Fig. 24-9).23 These injuries do not need to be repaired
immediately as long as there is control of heart rate and blood pressure. The goal HR is <80 and goal
systolic blood pressure is <110 mm Hg. This control is achieved with the administration of short acting
beta-blocker (i.e., esmolol) followed by nitroprusside. The beta-blocker must precede the nitroprusside
because of the possible tachycardic side effects of nitroprusside. Patients should have an immediate
arterial line placed, esmolol begun and titrated carefully to achieve the target hemodynamic
parameters. This allows time for other associated injuries to be managed, that is, head injury, intra-
abdominal bleeding, severe pelvic fracture. Then in the following 24 to 48 hours as the initial
resuscitation and urgent treatments are achieved, repair of the aorta may follow. For those with high-
grade aortic injuries, repair should take a higher level of priority but remains balanced with other
conflicting priorities.
648
booksmedicos.org
Diaphragmatic Injuries
Injuries may be the result of either penetrating or blunt trauma. The average size of a diaphragmatic
injury for penetrating trauma is approximately 2 cm and the average size of the injury for blunt trauma
is 8 cm. In a 2015 review, there were 3,873 diaphragmatic injuries among the sample size of 833,309
giving an incidence of 0.46%.24 Initial imaging begins with CXR and is often followed by CT scan. The
sensitivity for diaphragmatic injuries on CT scan is approximately 70% (range is from 50% to 90%). For
penetrating trauma CXR and CT scan have very poor sensitivities and one must maintain a high index of
suspicion depending upon the trajectory of the knife or bullet. If there is a penetrating trauma to the
thoracoabdominal region (nipple line to costal margin) particularly on the left side one should perform
a diagnostic laparoscopy after a 24-hour window. This 24-hour window allows the surgeon to
effectively exclude an associated hollow viscus injury since these patients would manifest as peritonitis
prior to 24 hours.
Figure 24-8. A: Axial view of type III blunt aortic injury with pseudoaneurysm. B: Sagital view of type III blunt aortic injury with
pseudoaneurysm.
Treatment
Once the diagnosis is made the patient should be taken to the operating room for repair. In the case of
the penetrating trauma patient who is undergoing a diagnostic laparoscopy the repair can proceed
laparoscopically via the abdomen. For those with an acute rupture following blunt trauma the repair is
usually undertaken via the abdomen in order to inspect abdominal organs for injury. For chronic hernia
defects, one may consider repairing from the chest via a thoracotomy or via video-assisted
thoracoscopy.
Figure 24-9. Aortic stent graft for blunt rupture.
649
booksmedicos.org
The repair is with a nonabsorbable suture in either an interrupted or running fashion. The classic
repair is with an interrupted horizontal mattress but can be a figure of eight or running suture. The
repair must be air tight and a chest tube is usually placed at the time of the repair. It is important to
lavage the chest and ensure complete evacuation of any hemothorax via the hole in the diaphragm. In
patients where primary repair of the diaphragm is not possible due to tissue loss a mesh (synthetic or
biologic) may be used or the diaphragm can be sown to a lower rib, in essence transposing it to a
slightly lower position to achieve closure of the hemithorax.
Cardiac
Lacerations can occur with either penetrating or blunt mechanisms. The most common chamber affected
with penetrating injury is the right ventricle since it has the largest anterior surface area. The right
atrium is the most common chamber that ruptures from blunt mechanisms because of its thin wall. The
diagnosis of hemopericardium is usually made via the bedside FAST examination. The FAST examination
is 95% sensitive and specific for hemopericardium, and is an important adjunct in the trauma bay.
Hemopericardium is diagnosed by ultrasound but tamponade is diagnosed by the combination of
hemopericardium and hypotension. The presence of distended neck veins, hypotension, and
hemopericardium defines cardiac tamponade and should be treated emergently.
Treatment
If a patient is deteriorating (with loss of consciousness) or has lost vital signs then an ED thoracotomy is
indicated. This provides quick access to the pericardium and allows the surgeon to decompress the
tamponade, gain control of the hole and potentially repair the injury in the trauma bay. If the patient is
awake or vital signs are not quickly deteriorating then an emergent transport to the operating room is
preferred. There is very limited role for pericardiocentesis in the acute trauma scenario, given the
difficulties in evacuating clot from the pericardium. A pericardial window is a diagnostic test and is
restricted to those patients who have a possible confounding issue and are stable, that is, HIV-positive
patients with chronic pericardial effusions. Otherwise, a positive pericardial FAST mandates surgical
exploration via a sternotomy or thoracotomy.
It is important to understand that in cardiac tamponade when the patient is placed under general
anesthesia and placed on positive pressure ventilation the subsequent drop in preload may cause the
patient to lose vital signs. Therefore, the surgical team must be ready to quickly perform a median
sternotomy. The patient should be prepped and draped from the chin to the thighs, in case there is the
need to enter the neck or the abdomen. Once the patient is prepped and draped then anesthesia is
induced and the operation commences. This allows the team to be ready with the sternal saw and
equipment prior to induction just in case the patient loses vital signs.
Once in the chest via the preferred incision, median sternotomy, the pericardium is opened and the
injury identified. The injury can usually be controlled with a finger or two. Other adjuncts are then
employed to close the wound, that is, skin stapler, Foley catheter (careful not to rip the thin right
ventricle with the balloon), or two stay sutures on either side of the injury that are crossed to close the
wound. Once temporary control is obtained one may then place additional sutures which are usually 3-0
silk or prolene. It is helpful to ask for a suture with a large needle. The hole is then closed with or
without pledgets in an interrupted fashion. One must take note of the relationship of the injury to the
coronary vessels. If the injury is juxtaposed to a coronary vessel, one should perform a horizontal
mattress and pass the needle deep to the coronary artery. If the coronary vessel is injured by the trauma
it must be bypassed or repaired if it involves the proximal two-thirds. If the distal third of a coronary is
involved it is possible to simply ligate the artery.
Postoperative echocardiography should be performed to evaluate the function of the valves to ensure
there is no significant injury to valvular function.
Blunt Cardiac Contusion

There is a spectrum of blunt cardiac contusion, better named blunt cardiac injury. Injuries may cause
mild dysrhythmias or lead to wall rupture (Fig. 24-10) and death. Any patient that undergoes a rapid
deceleration is at risk of having a traumatic blunt cardiac contusion. These patients are screened with a
12-lead ECG and if completely normal one can rest assured that there is no significant contusion. If the
patient has any dysrhythmias including sinus tachycardia serial troponin levels will provide the
additional sensitivity to diagnose contusion.
Treatment
650
booksmedicos.org
These patients are placed on telemetry and observed. If ST segment changes occur a cardiac
catheterization is necessary to rule out coronary dissection. If the patient is unstable but with normal ST
segments an echo should be performed to identify structural injuries, that is, valve damage or septal
defects.
Open Pneumothorax
In circumstances where there is a loss of a portion of the chest wall the normal negative pressure
pleural space is lost. The chest wall defect is usually secondary to a high-velocity bullet or close range
shot-gun blast. Due to the intrinsic nature of the lung parenchyma to collapse, there must be negative
pressure in the chest wall to allow for reexpansion. In an open pneumothorax (sucking chest wound) the
lung collapses and the patient has difficulty with ventilation.
Treatment
As a temporary measure, perhaps during transport, a partially occluding dressing can be applied. This
dressing is sealed in a way that allows air to escape from a corner of the dressing while preventing
atmospheric air from entering the pleural space. However, if encountered in the trauma bay or the
operating room the trauma surgeon should close the defect and place a chest tube in a separate space.
The chest tube will create the negative pressure required to reexpand the lung with the defect closed. If
the defect is large a rotational flap may be necessary to close the defect or the chest wall may require
reconstruction with mesh.
Tracheobronchial Injury
Injury can occur from either blunt or penetrating mechanisms and usually presents with a large
pneumothorax and air leak. More proximal intrathoracic injuries can be easily visualized via
bronchoscopy. At times the patients may be difficult to ventilate due to large air leaks. In rare cases
there may be the need for selective lung ventilation with a bronchoscopically placed bronchial blocker
or may even require extracorporeal membrane oxygenation (ECMO).
Treatment
The majority of intrathoracic injuries are to the right mainstem bronchus and therefore a right
posteriolateral thoracotomy is the best approach. The location of the injury on bronchoscopy will
provide direction for surgical exposure. Once exposed the bronchus or trachea can be primarily repaired
using a 3-0 absorbable suture. Chest tubes are placed and extubation is guided by the underlying lung
contusion and hypoxia. Ideally, these patients should be taken off positive pressure ventilation as soon
as possible, even immediately postoperatively.
Figure 24-10. Blunt cardiac rupture/contusion.
Thoracic Esophageal Injury

Esophageal injuries are secondary to penetrating trauma. A blunt rupture of the esophagus is
exceedingly rare. The signs and symptoms of an acute injury are nonspecific and include hematemesis
and chest pain. If the trajectory of the knife or gun-shot wound is such that it crosses the midline, the
mediastinum must be evaluated. If the patient is unstable from a thoracic gun-shot wound a rapid trip to
the operating room is warranted for exploration and hemorrhage control. If the patient is stable one
may perform imaging studies to evaluate the esophagus.
651
booksmedicos.org
The initial imaging study is a CT scan of the chest with IV contrast to better delineate the track of the
missile (Fig. 24-11A). Secondary signs of an esophageal injury may be present including
pneumomediastinum, pleural effusion, or mediastinal hematoma. If the missile track is in close
proximity to the esophagus (<2 cm) then additional imaging with a water-soluble followed by a
barium-contrast study is warranted. The water-soluble contrast is used first in case there is a large leak
(Fig. 24-11B). If no obvious leak is identified then the water-soluble contrast should be followed up
with a barium study to increase the sensitivity for a small leak. If the barium esophageal imaging is
negative one can be assured there is no full-thickness injury to the esophagus. If an injury is identified
as an esophageal leak urgent exploration is necessary to minimize contamination of the chest. There is a
direct correlation between time to repair and morbidity/mortality, therefore any delay must be
minimized.
Figure 24-11. A: Tract of bullet coursing to posterior mediastinum. B: Contrast leaking from an injury to the esophagus.
If the distal one-thirds of the thoracic esophagus is injured a left thoracotomy is the approach of
choice. If the proximal two-thirds is involved then a right thoracotomy is performed, which allows one
to dissect the esophagus up to the thoracic outlet since the aortic arch is not obscuring the view. Once
the esophageal injury is identified, it should be debrided and repaired in a full-thickness single layer.
The repair should be buttressed with either a pedicled intercostal muscle flap or a pleural patch. Some
have used a tongue of omentum for distal esophageal repairs. Of note, single lung ventilation is
necessary to adequately visualize the injury and ensure a safe repair.
EMERGENCY DEPARTMENT THORACOTOMY VERSUS OPERATIVE

THORACOTOMY, TIPS/TRICKS
ED thoracotomy is a procedure done to gain primary vascular control of an injured vessel, it also allows
one to open the pericardium, perform internal massage, relieve cardiac tamponade, repair cardiac
injury, gain control of the pulmonary hilum, and clamp the aorta if necessary. The ED thoracotomy is a
652
booksmedicos.org
left anterolateral thoracotomy (Fig. 24-12). The survival from ED thoracotomy is as high as 60% in
victims of penetrating trauma that arrive in the trauma bay with a palpable pulse. The survival
decreases to about 4% if the patient arrives without a pulse, assuming a less than 15-minute cardiac
arrest time. In blunt trauma the odds of regaining a blood pressure in those who lose vital signs in the
trauma bay is about 4% but drops to 0.2% if lost in the field. For these reasons the generally accepted
indications for an ED thoracotomy in penetrating trauma is if the patient loses vital signs in the trauma
bay or within 15 minutes of arrival. For blunt trauma, the only accepted indication is patients who lose
vital signs in the trauma bay. ED thoracotomy is a futile maneuver (and should be avoided) in patients
who suffer cardiopulmonary arrest, although some advocate ED thoracotomy if the patient loses signs
within 10 minutes of arrival.
Figure 24-12. Left anterolateral thoracotomy incision.
The indications for a formal operative thoracotomy are if the initial chest tube drains >1,500 cc of
blood or >200 cc/hr × 4 hours. The other indication is if there is ongoing hemodynamic instability
with continued chest tube drainage.
Control of an intercostal artery can be difficult if low in the chest and posterior. At times it may be
necessary to encircle the rib proximal and distal to the bleeding vessel to compress the vessel indirectly.
This suture can be absorbable or even brought out through the full thickness of the chest wall and cut in
48 hours. At times one may be dealing with a deep hole from a gun-shot wound into the musculature of
the posterior chest wall. Under these circumstances aggressive and tight packing may suffice or a Foley
catheter may be placed in the tract and inflated to tamponade the bleeding. The Foley may even exit the
chest wall via a separate stab incision and be deflated 24 to 48 hours later and removed while the
patient is observed for recurrent bleeding.
The other common injury that may be found on exploration is a laceration of the lung. It is important
to understand that bleeding from the track of a penetrating trauma must not be closed superficially.
Closing the entrance or exit holes may simply cause more bleeding into the bronchi or allow air to
embolize from the bronchi to the pulmonary venous system. Patients will die from cardiac arrest from
air emboli that enter the coronary vessels. Instead the pulmonary tract should be opened (tractotomy)
with either clamps or GIA stapling devices. This opens the tract where the raw surface area can be
oversewn or stapled while saving lung tissue. Peripheral lesions can simply have wedge resections
performed.
CONCLUSION
Thoracic injuries are a common entity with rib fractures being the most common injury. A careful and
systematic approach to the trauma patient is key to uncovering significant thoracic injuries. Life-
threatening injuries, that is, massive hemorrhage, tension pneumothorax, or cardiac tamponade must be
identified within the trauma bay and treated without delay.
References
1. LoCiecero J III, Mattox KL. Epidemiology of chest trauma. Surg Clin North Am 1989;69(1):15–19.
653
booksmedicos.org
2. Bulger EM, Arneson MA, Mock CN, et al. Rib fractures in the elderly. J Trauma 2000;48(6):1040–
1046.
3. Wong YC, Ng CJ, Wang LJ, et al. Left mediastinal width and mediastinal width ratio are better
radiographic criteria than general mediastinal width for predicting blunt aortic injury. J Trauma
2004;57(1):88–94.
4. American College of Surgeons. ATLS Manual. 9th ed. Chicago, IL: American College of Surgeons;
2012.
5. Maenza RL, Seaberg D, D’Amico F. A meta-analysis of blunt cardiac trauma; ending mycardial
confusion. Am J Emerg Med 1996;14:237–241.
6. Rozycki G, Ballard R, Feliciano D, et al. Surgeon performed ultrasound for assessment of truncal
injuries. Ann Surg 1998;228:16–28.
7. Kirkpatrick AW, Sirois M, Laupland KB, et al. Hand-held thoracic sonography for detecting post-
traumatic pneumothoraces: the Extended Focused Assessment with Sonography for Trauma
(EFAST). J Trauma 2004;57(2):288–295.
8. Bulger EM, Edwards T, Klotz P, et al. Epidural analgesia improves outcome after multiple rib
fractures. Surgery 2004;136:426–430.
9. Moon MR, Luchette FA, Gibson SW, et al. Prospective, randomized comparison of epidural versus
parenteral opioid analgesia in thoracic trauma. Ann Surgery 1999;229:684–691.
10. Tanaka H, Yukioka T, Yamaguti Y, et al. Surgical stabilization of internal pneumatic stabilization?
A prospective randomized study of management of severe flail chest patients. J Trauma
2002;52:727–732.
11. Granetzny A, Abd El-Aal M, Emam E, et al. Surgical versus conservative treatment of flail chest:
evaluation of the pulmonary status. Interact Cardiovasc Thorac Surg 2005;4:583–587.
12. Ahmed Z, Mohyuddin Z. Management of flail chest injury: internal fixation versus endotracheal
intubation and ventilation. J Thorac Cardiovasc Surg 1995;110:1676–1680.
13. Nirula R, Allen B, Layman R, et al. Rib fracture stabilization in patients sustaining blunt chest
injury. Am Surg 2006;72:307–309.
14. Alrajab S, Youssef AM, Akkus NI, et al. Pleural ultrasonography versus chest radiography for the
diagnosis of pneumothorax: review of the literature and meta-analysis. Crit Care 2013;17(5):R208.
15. Inaba K, Branco BC, Eckstein M, et al. Optimal positioning for emergent needle thoracostomy: a
cadaver-based study. J Trauma 2011;71(5):1099–1103.
16. Inaba K, Lustenberger T, Recinos G, et al. Does size matter? A prospective analysis of 28–32 versus
36–40 French chest tube size in trauma. J Trauma Acute Care Surg 2012;72(2):422–427.
17. Kulvatunyou N, Erickson L, Vijayasekaran A, et al. Randomized clinical trial of pigtail catheter
versus chest tube in injured patients with uncomplicated traumatic pneumothorax. Br J Surg
2014;101:17–22.
18. Cropano C, Mesar T, Turay D, et al. Pneumothoraces on CT scan: Observation using the 35
millimeter rule is safe. Panamer J Trauma Acute Care Surg 2015; in press.
19. de Moya MA, Manolakaki D, Chang Y, et al. Blunt pulmonary contusion: admission computed
tomography scan predicts mechanical ventilation. J Trauma 2011;71(6):1543–1547.
20. Benns MV, Egger ME, Harbrecht BG, et al. Does chest tube location matter? An analysis of chest
tube position and the need for secondary interventions. J Trauma Acute Care Surg 2015;78(2):386–
390.
21. Mergo PJ, Helmberger T, Didovic J, et al. New formula for quantification of pleural effusions from
computed tomography. J Thorac Imaging 1999;14:122–125.
22. Dubose J, Inaba K, Demetriades D, et al. Management of post-traumatic retained hemothorax: a
prospective, observational, multicenter AAST study. J Trauma Acute Care Surg 2012;72(1):11–22.
23. Moainie SL, Neschis DG, Gammie JS, et al. Endovascular stenting for traumatic aortic injury:an
emerging new standard of care. Ann Thorac Surg 2008;85(5):1625–1629.
24. Fair KA, Gordon NT, Barbosa RR, et al. Traumatic diaphragmatic injury in the American Colleges of
Surgeons National Trauma Data Bank; a new examination of a rare diagnosis. Am J Surg
2015;209(5):864–868.
654
booksmedicos.org
Chapter 25
Abdominal Trauma
Kenji Inaba, Elizabeth R. Benjamin, and Demetrios Demetriades
Key Points
1 Clinical examination is the cornerstone of the diagnostic workup after blunt abdominal trauma and
any patient with peritonitis or instability with a positive FAST requires immediate laparotomy. CT is
a high-yield diagnostic modality for the intra-abdominal contents with high degree of sensitivity and
specificity for clinically significant injuries.
2 For stable, evaluable patients without peritonitis or evisceration after penetrating abdominal trauma,
selective non-operative management is an acceptable treatment option. For those undergoing non-
operative management of a gunshot wound, CT scanning is essential. For both stab wounds and
gunshot wounds, close clinical observation is utilized to detect those patients with an occult injury
that will ultimately require laparotomy and repair.
3 Rapid access to an operating room with immediate access to the instrumentation, consumables and
support services such as the blood bank and radiology are required for the successful treatment of
patients with abdominal trauma.
4 Standard positioning is supine, however, for injuries in stable patients where the rectum or perineum
is at risk, lithotomy may be utilized. The initial incision is usually a midline laparotomy. Extension
into the subcostal regions and across the inguinal ligament or into the thoracic cavity may be
required to facilitate exposure.
5 Damage control laparotomy, which consists of rapid bleeding and contamination control, followed
by temporary closure and resuscitation with delayed definitive repair of injuries should be
considered for any patient who is physiologically depleted, has a burden of injury which will result
in compromise if definitive repair is attempted, or has an injury profile beyond the scope of the
surgeon or facility skillset.
6 Abdominal compartment syndrome is after trauma laparotomy and all patients should be monitored
closely with bladder pressures in the recovery area. Any elevation in the intra-abdominal pressures
warrants consideration of decompressive laparotomy.
7 Angioembolization is an important adjunct for patients who are undergoing damage control surgery
and may be of particular benefit for patients with ongoing bleeding from complex hepatic trauma.
INTRODUCTION
For patients who have sustained a stab wound (SW), gunshot wound (GSW), or blunt multisystem
injury, the abdomen remains a high-risk cavity with the potential to hide occult but life-threatening
injuries. Unlike the extremity or neck for example, where bleeding occurs externally, for the abdomen,
significant bleeding and enteric spillage can occur with minimal symptoms until late. In patients
presenting after both blunt and penetrating traumas, injury to the abdominal contents is common. In the
National Trauma Data Bank, the largest repository of trauma registry data that exists in the United
States, from 2008 to 2012, of the approximately 3,146,401 patients entered, 10.6% had an abdominal
injury.
Broken down by regional abbreviated injury scale (AIS), 34.0% of these had an AIS 1, 31.4% an AIS
2, 21.8% an AIS 3, 9.9% an AIS 4, and 2.9% an AIS 5 injury. This injury severity breakdown for all
patients was consistent with the data seen for blunt trauma. In comparison, when penetrating injuries
were examined, whereas only 9.6% of blunt trauma patients had an abdominal injury with 33.5%
having an AIS ≥3, a full 25.2% of penetrating patients had an abdominal injury with 39.7% of these
having an AIS ≥3.
Abdominal injuries are therefore common and a systematic approach to the rapid diagnosis and
655
booksmedicos.org
treatment of these injuries is essential. This chapter will provide a pragmatic approach to the patient
with abdominal trauma, focusing on the acute resuscitation, diagnosis, and treatment of clinically
relevant injuries to the abdominal structures.
BLUNT INITIAL EVALUATION AND DIAGNOSTICS

Resuscitation
For the patient that sustains abdominal trauma, unlike the extremity, where a tourniquet can be placed,
there are currently no validated prehospital methods for direct or indirect hemorrhage control. With the
increasing interest in resuscitative endovascular balloon occlusion of the aorta,1 in the appropriate
clinical setting with trained personnel, this procedure could theoretically be performed in the
prehospital setting. Experimental work looking at the use of abdominal insufflation with air or foam
also shows some promise but is not yet ready for clinical implementation at this time. Rapid transport
to definitive care therefore remains the primary goal. The general principles of resuscitation that apply
to all trauma patients as outlined elsewhere in this textbook should be followed. Specific to patients
with abdominal trauma, whenever possible, venous access should be gained in the upper limbs or torso.
Resuscitation through a femoral central venous catheter is suboptimal as the return of blood products
into the systemic circulation is compromised if the patient has an injury to the iliac system or vena cava.
In the resuscitation area, once the diagnosis of an intra-abdominal injury requiring operative repair has
been made, travel to the OR should take precedence over continued resuscitative efforts which can be
continued concurrent to definitive hemorrhage control.
Diagnostics
1 The diagnostic workup of a blunt multisystem injury patient is often more difficult than for a
penetrating injury patient. The following discussion focuses on the isolated abdominal trauma patient
however, practically, for most patients the remainder of the torso must also be considered. In general,
the most practical approach to the patient in the resuscitation area depends on hemodynamic status.
Patients can be categorized into those that are arresting, unstable, or stable.
For any arresting patient, if the decision to intervene is made, airway control, venous access with
blood product infusion, and resuscitative thoracotomy with concurrent right chest tube insertion are the
immediate priorities. The outcomes for resuscitative thoracotomy performed for traumatic arrest due to
blunt trauma are poor,2 especially if the source of hemorrhage is in the abdomen, and at many centers,
would not even be considered. Survival to discharge and organ donation are possible however, and at
our center, thoracotomy is performed liberally. If a resuscitative thoracotomy is performed, and the
primary source of hemorrhage is in the abdomen, aortic cross-clamping is designed to mitigate intra-
abdominalblood loss. If the procedure is successful and a perfusing rhythm is regained, there is no role
for any imaging or further workup. The patient should be taken immediately to the OR for laparotomy
and definitive injury management.
For the unstable patient, aggressive resuscitation with blood products should be initiated
immediately, and the patient will either stabilize, in which case a complete workup can be performed as
described below, or they will arrest, as discussed above or they will remain unstable. If they remain
unstable despite resuscitative efforts, bilateral diagnostic chest tubes should be inserted if a chest x-ray
(CXR) is not immediately available. Concurrent with the ongoing resuscitation, a focused assessment
with sonography in trauma (FAST) should be performed. If free abdominal fluid is visualized, the
patient should immediately be taken to the OR and a laparotomy should be performed. If the FAST is
negative, a confirmatory diagnostic peritoneal aspirate (DPA) looking for gross blood should be
performed. If this is positive, the patient undergoes laparotomy. If negative, alternative sources for the
hemorrhage are sought. It is possible that the source of hemorrhage is a contained retroperitoneal
vascular injury which would be missed by both DPA and FAST however, for blunt trauma, in the
absence of a pelvic fracture, this would be extremely rare.
In the stable patient, a complete diagnostic workup can be completed. This begins with an external
examination for any soft tissue evidence of injury. A seatbelt sign for example has been associated with
an eightfold increase in the incidence of intra-abdominal injuries, impacting both the solid organs and
hollow viscus.3,4 While not sufficient to warrant mandatory laparotomy, a very low threshold for
imaging with CT should be maintained and the patient should undergo a mandatory period of
observation. With this mechanism, the seatbelt can cause a “bucket-handle” type injury (Fig. 25-1)
656
booksmedicos.org
where the mesentery is sheared away from the more elastic bowel wall causing ischemia. Clinical
evidence of the ischemic GI tract injury can take hours to manifest and close observation is warranted.
If on initial examination, the patient already has peritonitis, in the setting of trauma, immediate
laparotomy should be performed. This is a high-yield indication for operation. Although data were
accrued in penetrating trauma, the urgency of peritonitis was made clear in a study examining 139
patients who were hemodynamically stable with peritonitis as the sole indication for operation. Of
these, 97% had an intra-abdominal injury, with 11% having between 750 and 1,500 mL and 7% having
>1,500 mL of blood on opening with 25% sustaining intraoperative hypotension and 39% requiring
blood transfusions despite being hemodynamically normal at presentation.5
Figure 25-1. Bucket handle–type injury of small bowel.
For patients without peritonitis, the initial imaging modality is FAST. Because cardiac rupture causing
an effusion is so rare in blunt trauma patients presenting alive to the hospital,6 the abdominal windows
are of primary importance after blunt trauma. The presence of free fluid is assumed to be blood. The
presence of free fluid should trigger additional imaging with CT. For blunt trauma, there is no role for
plain radiographs of the abdomen. In unstable patients, a pelvic x-ray can identify a potential source of
ongoing blood loss and should be performed early in the resuscitation bay. For the stable patient, a
pelvic x-ray is unnecessary especially if the patient is to undergo CT as it is unlikely to impact
management. Although specific trauma protocols vary between institutions, CT scans should be
performed with IV contrast. PO contrast is not required for the initial CT. A baseline creatinine level for
all patients and a pregnancy test in females of child-bearing age should be obtained prior to the test. In
general, a CT should be considered in the stable patient when there is external evidence of significant
force transfer to the abdomen such as a seatbelt sign, or with free fluid on FAST or when there is
significant abdominal tenderness on examination. Mechanism as a sole criterion for deciding which
patients require CT scanning is unreliable, but a high-energy mechanism is often considered when
making this decision. For the asymptomatic patient with a negative FAST who is fully examinable,
cooperative, and can be observed, CT can be omitted. Based on the CT results, patients can be
categorized into three groups, those with no injury, those with an injury, and those with an equivocal
finding. If the patient has a fully adequate CT demonstrating no abnormalities, the likelihood of a
clinically significant injury is extremely low and the patient can be prepared for discharge once the
remainder of the body areas is cleared. For patients with a CT that demonstrates injury, the nature of
the injury will determine management. Any hollow viscus injury including the GI tract or bladder, will
require operative repair. For solid organ injuries, the indications for operative management will depend
on the extent of injury, the physiologic status of the patient including comorbidities, and their tolerance
for blood loss and associated injuries. In general, the majority of solid organ injuries can be successfully
managed non-operatively.7,8 In centers where there is access to interventional radiology, endovascular
solutions, such as stenting or embolization and percutaneous management of complications such as a
biloma can also be used as an adjunct to non-operative management. This will be further elucidated in
the following organ-specific sections. This then leaves the patient with equivocal findings of a hollow
viscus injury on CT. Equivocal findings would include subtle findings such as mesenteric fat stranding,
free fluid without solid organ injury, and bowel wall thickening. These patients should be observed
clinically, ideally by a single provider and collateral evidence of injury such as the WBC count, heart
rate, temperature, and abdominal examination are used to detect worsening, indicative of a hollow
viscus injury requiring operative intervention. The exact period of time required for observation is
657
booksmedicos.org
unknown, however, it is expected that a patient who is improving at 24 hours has a low likelihood of a
clinically significant missed injury.
PENETRATING INJURY – INITIAL EVALUATION AND DIAGNOSTICS

General Approach to Penetrating Abdominal Injury
Following the experience of World Wars I and II, with the high rates of destructive injuries, penetrating
abdominal trauma was historically treated with universal surgical exploration. Starting in the 1960s,
with SWs, followed by GSWs, this paradigm began to shift.9–11 Patient selection for operative versus
non-operative management based on the clinical picture and radiologic evidence began to evolve. With
improved access, and quality of the images and the growing body of evidence regarding the potential
morbidity of nontherapeutic operations, contemporary evidence now supports a non-operative approach
to the management of penetrating abdominal trauma in select circumstances.12
2 The balance between prompt surgical management of traumatic injury and avoiding unnecessary
operation remains a central diagnostic and management challenge in penetrating abdominal injury.
Patients who present in extremis, with hemodynamic instability, peritonitis, or are unevaluable mandate
immediate operation. For the remaining patients, the practice of universal exploration would result in a
high rate of nontherapeutic laparotomy. Although mortality after negative trauma laparotomy is low,
morbidity attributed to negative laparotomy is as high as 20%.13,14 In addition, late complications
including hernias and bowel obstructions are likely underreported given the challenges of long-term
follow-up. Finally, not only is there a decrease in patient-centered outcomes, from a trauma resource
utilization viewpoint, negative laparotomy is associated with an increase in unnecessary operative costs
and hospital length of stay.13,15–17 The introduction of selective non-operative management of
penetrating abdominal trauma has been shown to result in a tangible cost savings.18
Although a subset of patients with penetrating abdominal trauma will ultimately require exploration,
a significant number can be managed without operative intervention and thus be spared the potential
morbidity and mortality of a negative laparotomy. In a retrospective analysis of abdominal SWs,
mandatory exploration was associated with a negative laparotomy rate of 37%.13 A Western Trauma
Association Multicenter Study including 359 patients with anterior abdominal SWs found that 64% of
patients did not require laparotomy.19 The need for laparotomy is even lower after SWs to the back
with only 15% of patients noted to have clinically significant injury.20 GSWs to the abdomen are more
likely to require operative exploration, but the presence of gunshot injury alone does not necessitate
mandatory laparotomy. In an analysis of 1,856 patients with abdominal GSWs, had a policy of
mandatory laparotomy been employed, 47% of patients would have undergone an unnecessary
laparotomy.18 Similar to SWs, posterior and transpelvic injuries are less likely than anterior injuries to
require exploration.18,21–22
Indications and Contraindications to Selective Non-operative Management

In the modern era of selective non-operative management of abdominal trauma, several absolute
indications for operative intervention remain. Hemodynamic instability in the setting of penetrating
abdominal trauma requires laparotomy. In the hemodynamically stable patient, physical examination
remains critical to patient triage, and peritonitis is an absolute indication for laparotomy. Although soft
tissue injury can cause local tenderness, diffuse peritonitis after penetrating abdominal trauma is
associated with a 97% chance of intra-abdominal injury at laparotomy.5 Given the central role of
physical examination in patient triage, unevaluable patients including those with concomitant head or
spinal cord injury or those undergoing urgent nonabdominal operations are not candidates for selective
non-operative management. Although not an absolute contraindication to selective non-operative
management, patients with omental or visceral evisceration after penetrating abdominal trauma should
be strongly considered for operative intervention. Significant intra-abdominal injury is present in 46%
to 85% of patients with omental evisceration, and even higher rates with visceral evisceration.17,19,23,24
Peritoneal penetration alone after penetrating trauma is not an absolute indication for operative
exploration. For this reason, invasive evaluation including diagnostic laparoscopy for the sole purpose
of determining peritoneal violation is not indicated.
Diagnostics
658
booksmedicos.org
Radiologic imaging is a key component of the diagnostic workup of patients who have sustained
penetrating abdominal trauma, especially those undergoing a trial of non-operative management. In
hemodynamically stable evaluable patients without peritonitis, a detailed evaluation of the external
wounds and retained fragments using plain radiographs is imperative to plot missile trajectories.
External wounds do not always correspond to internal injury and, especially in the setting of multiple
missiles, trajectory may be misleading from external wounds alone. For example, an abdominal GSW
may have a cranial trajectory resulting in a mediastinal injury. Alternatively, paired lateral abdominal
wall bullet wounds may represent a superficial tangential trajectory or two separate transabdominal
injuries with retained missiles. In both scenarios, management will change significantly based on the
internal trajectory.
FAST examination is a central component of the early assessment after blunt trauma. The utility of
this imaging modality in penetrating trauma, however, is less uniformly accepted. The primary use of
the FAST examination in penetrating abdominal trauma is to evaluate for pericardial fluid as a marker
of cardiac injury. Especially in the setting of an unknown missile trajectory, the cardiac FAST is a
critical component of the initial trauma evaluation. A positive cardiac FAST after penetrating trauma
mandates immediate median sternotomy. For the intra-abdominal fluid windows, while the FAST
examination is highly specific for fluid, the sensitivity is poor ranging from 46% to 67%.25–27 In the
hemodynamically unstable patient with multiple cavitary sources of hypotension, a positive FAST can
still be helpful as a rapid tool for operative incision planning. For stable patients however, it rarely
impacts clinical decision-making as the patient either meets criteria for selective non-operative
management and will be undergoing CT, or will be going to the OR, irrespective of the FAST findings.
CT has become universally accepted as an integral component in the evaluation of the penetrating
trauma patient undergoing selective non-operative management. For patients undergoing exploration,
CT is unnecessary and should not be routinely obtained. For patients with a GSW who are stable,
evaluable, and without peritonitis and are undergoing a trial of non-operative management however,
CT is a requisite next step.
GSWs follow a linear path and have an associated air bubble tract that allows for trajectory
identification on CT scan. Understanding the missile trajectory provides critical information regarding
potentially injured structures and those to which injury is unlikely. CT scan imaging after abdominal
GSWs has been shown to be highly reliable for injury identification, with a sensitivity and specificity of
90.5% to 96% and 95% to 96%, respectively.28,29 The injury tract on CT scan is often more subtle after
SWs due to the lower velocity and smaller volume of air bubbles along the tract, and as a result, CT
scan has been shown to be a less useful30 adjunct in patient triage.30,31
Based on the CT scan findings, patients may be divided into four groups. (1) Patients with no
peritoneal violation on CT scan. In this population, it is exceedingly rare that operative intervention will
be required. (2) Patients with peritoneal violation but no obvious intra-abdominal injury on CT scan.
This is the ideal patient population for selective non-operative management with serial abdominal
examinations and observation. (3) Patients with peritoneal violation and evidence of vascular or hollow
viscus injury on CT scan. Although there are no strict criteria for diagnosing hollow viscus injury on CT
scan, findings concerning for injury include bowel wall edema, missile trajectory traversing bowel,
extraluminal fluid, air, or contrast. In this group, laparotomy is mandatory. (4) Patients with peritoneal
violation and solid organ injury. In the absence of hollow viscus injury, solid organ injury alone does
not mandate laparotomy.32,33 For patients meeting all other criteria for non-operative management, this
remains a treatment option with a high rate of success.
For patients with a GSW and an equivocal finding on CT or for patients with a SW undergoing non-
operative management, clinical observation becomes the next important step. This is the most time-
consuming aspect of non-operative management and one of the primary reasons it is not feasible in all
practice settings. This observation should be performed by a consistent team, ideally by the same
provider, who can carefully examine for changes in abdominal pain, collateral markers of occult injury
such as tachycardia or fever, and laboratory abnormalities such as an increasing white blood cell count.
During this observation period, it is expected that a certain percentage of patients initially selected for
non-operative management will progress to operative intervention based on imaging or changes in
clinical examination. Selective non-operative management hinges on the ability to perform frequent,
consistent physical examinations. Patients should receive no narcotics, anesthetics, or antibiotics and
undergo serial hemodynamic and laboratory testing including white blood cell count, lactate, and
hemoglobin levels. Strict adherence to a protocol is necessary to ensure early identification of patients
who fail non-operative management and require operative intervention.
659
booksmedicos.org
In patients selected for non-operative management after penetrating abdominal wounds, the duration
of observation is individualized based upon the clinical scenario. After abdominal GSWs, a review of
270 patients found that all injuries requiring laparotomy were apparent within 24 hours of
observation.34,35 Similar results have been described for abdominal SWs with injuries requiring
laparotomy detected within 12 hours of observation.36
Penetrating left thoracoabdominal injuries, bounded by the nipple, scapular tip, and costal margin,
present a unique challenge due to the risk of occult diaphragmatic injury. Diaphragmatic injuries are
notoriously difficult to diagnose on CT scan and are often asymptomatic in the early, postinjury setting.
Over time, as the injury expands, the patient will be at risk for visceral herniation and strangulation.
This complication is less likely after right-sided injuries due to buttressing of the injury by the liver but
is a serious consideration after left-sided injury. The incidence of diaphragmatic injury after
thoracoabdominal injury is as high as 17% to 40%.37–39 For this reason, patients treated non-operatively
for left thoracoabdominal penetrating injuries should undergo a period of clinical observation. If
peritonitis develops, the diaphragm can be directly examined at laparotomy. If the patient passes the
period of observation, the patient can be offered diagnostic laparoscopy to specifically evaluate the
diaphragm on the left side. As the patient has already been clinically evaluated and other intra-
abdominal injury excluded, laparoscopy can be focused on diaphragmatic evaluation and a full
exploration is not necessary. Insufflation for this procedure should be done carefully with close
monitoring of the vital signs. With any evidence of the development of tension physiology due to a
diaphragmatic injury, immediate release of pressure and insertion of a chest tube should be performed
before proceeding.
THE TRAUMA LAPAROTOMY

3 For any hospital that cares for trauma patients, the ability to emergently perform an operative
intervention is critical. Preparation before the critically ill patient arrives is key. An operating room that
is easily accessible from the resuscitation area as well as the ICU should be earmarked for use in these
situations. A plan for securing the room for high-profile patients should be in place and there should be
a designated waiting area for family members. A contingency plan for multiple casualty situations
should be available, with operating rooms located in close proximity to facilitate surgical, anesthesia,
and nursing cross-coverage. Transportation of critically ill patients is a high-risk situation, and
preplanned routes that minimize distance, elevator use, and public exposure should be well known to all
providers. Instruments and disposables should be centrally located and redundant so that multiple
casualty situations can be dealt with effectively. Having a dedicated trauma pack that allows for a
laparotomy and thoracotomy, with add on sets for a sternotomy, amputation, and peripheral vascular
injuries will facilitate circulator efficiency. With the high rate of retained foreign bodies after emergent
trauma cases, the use of radiofrequency detection device embedded fabric is recommended. In higher-
volume centers, access to a satellite blood bank with uncross-matched packed red blood cells and plasma
is ideal, otherwise a system for communication with the main blood bank and product delivery to the
OR should be developed and practiced. If a hybrid room is available, the operative team and nursing
team should be familiar with the indications for starting an emergent case in this room. For all rooms,
access to fluoroscopy and plain films is critical. Because of service line cross-coverage, ongoing in-
servicing of the nursing and support staff is important to ensure that practices such as massive
transfusion protocols, are universally understood.
4 For all emergent laparotomies, the patient should be placed in the supine position with arms
abducted at 90 degrees. Even with a concomitant thoracic injury, this is the preferred starting position.
Rarely, for patients with a penetrating injury with a transpelvic trajectory, where endoscopic evaluation
may be required, the lithotomy position may be used. Likewise, in the blunt trauma patient where there
is external perineal injury, this may be considered. At a minimum, the torso, neck, and upper half of the
lower extremities should be prepared into the field for maximum flexibility. With any concurrent limb
injuries, the entire extremity should be prepared. If there is any concern of a urethral or bladder injury,
the Foley catheter should be prepared into the field to allow manipulation by the surgeon. Forced air
warming on the lower half of the extremities, and other warming adjuncts should be utilized. All
preoperative patient preparation including venous and arterial access, catheterization, and confirmation
of patient identification should be a team effort with full participation by the surgical team.
The trauma laparotomy incision extends from the xiphoid process to the symphysis pubis.
660
booksmedicos.org
Traditionally made with a scalpel, unless emergent, electrocautery can be utilized to minimize bleeding.
This extensile midline incision can be extended across the right or left inguinal ligament for distal iliac
vascular injuries. Superiorly, a subcostal extension can be added to improve access to the liver on the
right, especially with retrohepatic venous injuries, or to the left for gastroesophageal (GE) junction
injuries. The incision can be extended into a sternotomy for concurrent thoracic cavity injuries or to
facilitate suprahepatic vena cava control for high-grade liver injuries not amenable to packing. If the
patient has a pre-existing right thoracotomy, this can be joined to the laparotomy with incision of the
diaphragm to afford the same view of the liver, retrohepatic venous structures, and intrapericardial
vena cava.
On entry to the abdomen, the falciform should be taken down so as to minimize traction damage to
the liver. Traditionally, blind four quadrant packing was advocated. In reality, this maneuver is not very
helpful. In order to prevent iatrogenic damage, it is preferable to remove large amounts of central
clotted blood, followed by selected packing of any areas with active bleeding. A rapid examination of
the retroperitoneum should also be performed. Focusing on an obvious bowel injury that is encountered
first while a retroperitoneal vascular injury remains unattended to is a pitfall. The goal of the initial
packing and survey of contents is to identify and temporize any major sources of bleeding. A plan for
surgical control can then be made. This includes notifying the circulator of any necessary additional
equipment and close communication with anesthesia to optimize the resuscitation needs of the patient.
Early consideration of damage control, addressed later in the chapter should be considered. The need
for adjunctive services such as angiography prior to proceeding to the SICU should be considered and
initiated early to allow lead-time for preparation. Once active hemorrhage has been temporized, a
careful and complete survey of all of the abdominal contents should be performed. In the
exsanguinating patient who is undergoing a damage control procedure, this may not be possible, but in
the stable patient, this is critical. The potential for a missed injury can be mitigated by a systematic
approach to the abdominal contents. We recommend that the entire abdomen be reviewed in the same
manner for every case, regardless of the mechanism. For example, even a patient with a clear
transpelvic GSW trajectory should have their upper abdomen inspected because a fragment undetected
on the preoperative imaging may have caused an unexpected colon injury or, a concurrent blunt splenic
injury may have been sustained by the patient and not elicited on the initial history. Specific areas
warrant extra care during the examination. For blunt injuries without preoperative imaging, duodenal
injuries may present with only a subtle hematoma in the retroperitoneum. For hematomas in this area, a
right visceral medial rotation should be performed. For penetrating injuries, especially those due to
shotguns, colonic, rectal, and small bowel injuries, especially on the mesenteric surface may only be
visible as a small bloodstain or hematoma in the overlying fat. These need to be inspected carefully. The
posterior surface of the stomach is also a common area for missed injuries and should be inspected
carefully.
While exceedingly uncommon for blunt injuries, for both SWs and GSWs, ureteric injuries can be
difficult to diagnose and for any trajectories in this region, care should be taken to inspect the at-risk
segment of the ureter without devascularizing the structure. Likewise, whereas blunt bladder injuries
are often large and located near the dome, penetrating injuries, even those that are intraperitoneal, can
be small and asymptomatic. Most small extraperitoneal injuries can be managed non-operatively with
urinary catheter drainage however, large injuries, especially those with an intact connection to the skin
can be problematic. If there is an intraperitoneal component of bladder injury, this can be extended and
the interior of the bladder visualized. If not, we recommend injection of methylene blue containing
sterile water into the bladder retrograde to look for any gross extravasation. If this is identified, the
bladder should be taken down and these injuries repaired.
For retroperitoneal hematomas, the abdomen is traditionally broken down into three zones. Zone I is
the central portion from the aortic hiatus to the sacral promontory encompassing the aorta, IVC, and
major branches. Zone II covers the lateral retroperitoneum which contains the kidneys. Zone III is the
pelvis, which encompasses the sacral venous plexus and iliac vessels. For penetrating injuries, all zones
undergo exploration. For blunt injuries, traditionally, all zone I hematomas would be explored with
zones II and III only warranting exploration if the hematoma was large, expanding or pulsatile. The
retrohepatic area is distinct from the remaining areas and we often refer to this as zone IV, containing
the retrohepatic IVC and major hepatic veins. This area is difficult to expose and control and as such, if
controllable with packing, should not be explored for either blunt or penetrating injuries.
661
booksmedicos.org
DAMAGE CONTROL LAPAROTOMY
5 Damage control40 has become a common practice in the management of patients with complex
abdominal trauma and has been credited with saving more lives than many of the other surgical
techniques developed over the last two decades. Abdominal damage control techniques should always
be combined with damage control resuscitation, which includes permissive hypotension, early empiric
balanced blood component therapy minimizing crystalloid usage, and the prevention and treatment of
hypothermia. Abdominal damage control includes three key components: (a) temporary rapid control of
bleeding and contamination with early termination of the operation, (b) postoperative resuscitation
with correction of coagulopathy, hypothermia, and acidosis, and (c) subsequent definitive repair of
injuries.
The standard indications for damage control include: (a) patients with severe physiologic compromise
with coagulopathy, hypothermia, or acidosis, (b) bleeding from difficult to control injuries or an injury
burden which will result in physiologic compromise if treated definitively at the index operation, and
(c) austere environments with limited resources or surgeon skillset, such as in a rural or combat setting.
There is evidence that early damage control, even prior to physiologic decompensation, may be
associated with better survival and as such, patients with a large injury burden at risk of becoming
physiologically depleted should also be considered as candidates for damage control surgery. The exact
timing of damage control should be determined by the complexity of the injuries, the physiologic
condition of the patient, the available resources, and the experience of the surgical team.
Effective temporary hemorrhage control can be achieved by mechanical compression or gauze
packing in most cases where there is bleeding from surfaces such as complex liver injuries, the
retroperitoneum, or the pelvis. However, packing is usually not effective for major vascular injuries and
surgical control with ligation or shunting41 may be necessary. For deep tracts, for example in the liver,
balloon tamponade42 can be very effective (Fig. 25-2). Angioembolization may be a useful adjunct for
abdominal damage control and should be considered early, immediately following the operation. A
hybrid operating room may be a valuable tool, facilitating simultaneous operation in the abdomen and
angioembolization of difficult bleeding sites.
Figure 25-2. Gunshot injury through the center of liver requiring balloon tamponade using Foley catheters for damage control.
Control of intestinal spillage is also an integral part of abdominal damage control. It has been
suggested that ligation or stapling of the injured bowel, without reestablishing continuity, should be
considered as part of damage control for intestinal injuries requiring resection. Definitive reconstruction
is performed at a later stage, once the patient is stabilized, often 24 to 36 hours after the initial
operation. There are concerns that this approach may create a complete intestinal obstruction, which
may promote bacterial and toxin translocations or aggravate bowel ischemia, especially in patients
requiring vasopressors. Although not always possible, reconstruction of the bowel or creation of an
ostomy for diversion should be considered at the index operation if tolerated by the patient.
Damage control should be performed in an organized and orderly fashion, making sure that no
significant injuries are missed and that there is effective control of hemorrhage and contamination. The
procedure should not be terminated if there is persistent bleeding.
6 Following damage control, the abdominal fascia or skin should never be closed because of the high
risk of intra-abdominal hypertension and abdominal compartment syndrome.43 The abdomen should be
temporarily closed. The ideal method of temporary abdominal closure should prevent evisceration,
preserve the fascia and abdominal wall domain, facilitate reoperation, allow effective removal of toxin-
loaded intraperitoneal fluid, reduce the risk of enteroatmospheric fistulas, and help achieve early
662
booksmedicos.org
definitive fascia closure (Fig. 25-3).
Numerous materials and techniques have been used for temporary abdominal closure over the last
decade. A widely used technique in the past was passive closure with simple materials, such as a sterile
x-ray cassette cover, which is stapled or sutured to the fascia or the skin. This method does not allow
effective removal of any contaminated or toxin and cytokine-rich intraperitoneal fluid, and does not
prevent the loss of abdominal wall domain. Most contemporary systems now include the addition of
negative pressure. This can be made using perforated plastic sheeting, adhesive drapes, drains and
laparotomy packs, or a commercially available device. There is evidence that these negative pressure
dressings may improve survival and increase the success rate of primary fascia closure.
Once the patient has had their initial abbreviated procedure and temporary abdominal wall closure,
they can then be taken to the ICU for continuation of the resuscitation which was started in the OR.
After physiologic status has normalized, the patient can then return to the OR for definitive exploration
and repair of all injuries. Even prior to normalization of the patient’s physiology, if significant bleeding
is noted in the negative pressure system, the pressure should be immediately discontinued and the
patient returned to the operating room for reexploration and bleeding control. Although rare, even with
a temporary abdominal wall closure in place, intra-abdominal hypertension may still occur. It is
important that bladder pressures are monitored routinely during the first few hours after laparotomy,
even if it was a damage control procedure with the abdomen left open.
Figure 25-3. Temporary abdominal closure after damage control laparotomy.
DIAPHRAGM
Anatomy
The diaphragm consists of a central aponeurotic portion which fuses with the pericardium and a
peripheral muscular portion which is attached to the lower sternum, the lower six ribs, and the lumbar
spine. During exhalation, the diaphragm rises to the level of the nipples at the fourth to fifth intercostal
space. Penetrating injuries of the lower chest or insertion of a thoracostomy tube below the nipple,
therefore has the potential to cause injury to the diaphragm.
Epidemiology
In a prospective study of 119 consecutive patients with penetrating injuries to the left thoracoabdominal
region (nipple and tip of the scapula superiorly, costal margin inferiorly), undergoing laparotomy or
laparoscopy,38 a diaphragmatic injury was identified in 59% of GSWs and 32% of SWs. There were no
differences between anterior, lateral, or posterior injuries. Blunt trauma may cause diaphragmatic injury
through three different mechanisms which include a sudden increase in intra-abdominal pressure causing
a bursting of the diaphragm, fractured ribs perforating the diaphragm, and deceleration injuries causing
detachment of the diaphragm from the ribs. For blunt trauma, a diaphragmatic injury is found in
approximately 7% of all laparotomies and in about 7.5% of autopsy studies. The left hemidiaphragm is
involved in approximately 70% of cases and the right in 30% presumably due to the protective presence
of the liver. Blunt tears (Fig. 25-4) are usually 7- to 10-cm long as compared with 2 to 3 cm for
penetrating trauma (Fig. 25-5). A right diaphragmatic rupture indicates a more severe traumatic insult
and in almost all cases there are associated intra-abdominal injuries, compared to 77% for left
diaphragmatic ruptures.
663
booksmedicos.org
Figure 25-4. Large blunt diaphragm injury.
Figure 25-5. Small diaphragm injury after a stab wound to the left thoracoabdominal region.
Diagnostics
Isolated and uncomplicated diaphragmatic injuries are difficult to diagnose as they may be completely
asymptomatic or present with minor, nonspecific abdominal signs. The classic signs and symptoms
normally associated with diaphragmatic injury such as shortness of breath, bowel sounds in the chest, GI
obstruction, or ischemia, are relatively rare, and require acute herniation of abdominal contents.
The natural history of unrecognized diaphragmatic injuries is unknown and although some small
injuries may heal, this is not uniform. For right hemidiaphragm injuries, the presence of the liver
generally protects against diaphragmatic herniation. However, for the left side, unrepaired diaphragm
injuries commonly result in a diaphragmatic hernia, which may present within hours, days, weeks,
months, or even years after the injury.
Due to the occult presentation and the risks of unrecognized diaphragmatic injuries, for penetrating
trauma, all patients with a wound to the left thoracoabdominal area, defined as the area between the
nipple and scapula superiorly and the costal margin inferiorly, should be aggressively evaluated for
diaphragm injury. Plain chest x-ray and CT are unreliable in detecting uncomplicated diaphragm injuries
as the injuries are often very small. For patients undergoing laparotomy, care should be taken to inspect
the diaphragm. If the patient is to be managed non-operatively, as mentioned earlier in the chapter,
delayed laparoscopic evaluation is warranted.
For larger blunt injuries, imaging can be more useful. Plain radiologic findings suspicious of
diaphragmatic injury include an elevated diaphragm, an irregular diaphragmatic contour, and
nonvisualization of the diaphragm. Classically, an NG tube may be seen in the thoracic cavity. Once GI
tract herniation has occurred, chest x-ray (Fig. 25-6) and CT (Fig. 25-7) have higher sensitivity. CT scan
is the highest-yield investigation because it also includes any associated intra-abdominal injuries and has
a higher sensitivity than plain radiographs, especially for newer multidetector CT scans.44
Treatment
For patients where there is suspicion of a diaphragmatic injury with herniation, care should be taken to
avoid perforation of any hollow viscus in the chest. All diaphragm injuries should ultimately have the
abdominal contents reduced and the defects repaired. Acutely, diaphragmatic injuries should be
664
booksmedicos.org
approached through a laparotomy to facilitate exploration of the remaining intra-abdominal contents. In
chronic, elective cases, access and repair of the hernia can be performed through a thoracotomy. The
repair should be performed using nonabsorbable sutures and if there is contamination of the pleural
cavity, extending the incision and washing the cavity out prior to closure are warranted. Tube
thoracostomy should be considered in most cases. In rare cases where there is loss of diaphragmatic
tissue, synthetic prosthetic reconstruction can be utilized. If the diaphragm has been avulsed from the
chest wall, careful reconstruction of the diaphragmatic architecture utilizing nonabsorbable sutures is
required. In some cases where there is significant tissue loss, apposition of the remaining diaphragm to
the chest wall several rib spaces up may be required to create a tension-free repair.
Figure 25-6. Chest x-ray demonstrating blunt left diaphragmatic injury with herniating gastrointestinal tract.
Figure 25-7. CT demonstrating left blunt diaphragmatic injury with herniating gastrointestinal tract contents.
LIVER AND BILIARY TRACT

Anatomy
The anatomical division of the liver into the eight classicCouinaud segments has no practical application
in trauma. Parenchymal resection should be minimized and does not follow any anatomical boundaries.
An understanding of the blood supply however is important. The retrohepatic IVC is approximately 8- to
10-cm long and in most patients is partially covered by the liver parenchyma. In approximately 7% of
individuals the IVC is completely embedded in the liver. For outflow, there are three major hepatic
veins (right, middle, and left), with numerous accessory veins. Only the proximal 1 to 2 cm of the major
hepatic veins are extrahepatic. In approximately 70% of individuals, the middle hepatic vein joins the
left hepatic vein, near the IVC. The portal vein provides approximately 70% of hepatic blood flow, and
50% of the hepatic oxygenation. It divides into right and left branches at the level of the liver
parenchyma. The common hepatic artery originates from the celiac artery. In most individuals it
665
booksmedicos.org
branches into the left and right hepatic arteries at the hilum of the liver. In some individuals the right
hepatic artery originates from the superior mesenteric artery. The left hepatic artery may originate
from the left gastric artery. The porta hepatis contains the hepatic artery to the left, and the common
bile duct to the right. The portal vein lies posteriorly and between the common bile duct and the hepatic
artery. The left hepatic bile duct, the left hepatic artery, and the left portal vein enter the undersurface
of the liver, near the falciform ligament.
Epidemiology
The liver is one of the most commonly injured intra-abdominal organs following blunt trauma. The
mechanisms of injury include direct blunt force compression, penetration by a fractured rib, and
deceleration with avulsion of the ligaments or the hepatic veins. In penetrating trauma the liver is the
most commonly injured solid organ. Low-velocity missiles cause limited tissue damage and are life-
threatening only if they cause injury to a major vessel. High-velocity missiles can cause massive tissue
destruction and are associated with high mortality. The AAST-OIS grading system (Table 25-1) ranges
from a mild grade I injury to a grade VI total hepatic avulsion which is lethal.45
Table 25-1 OIS-AAST Grading Scale for the Liver
Diagnostics
A FAST will detect free intraperitoneal bleeding, but it does not provide any information about the
source of this bleeding. A formal ultrasound performed by an experienced radiologist may provide
additional information regarding the grade of the hepatic injury but this is not practical for acutely
injured patients. An abdominal CT scan with intravenous contrast is the most widely used and highest-
yield modality. CT provides accurate information about the architecture of the injury, the amount of
intraperitoneal blood, the presence of active bleeding, pseudoaneurysms or arteriovenous fistulas, and
the presence of associated injuries. CT is a valuable tool in the selection of patients for operation,
angiographic embolization, or observation (Fig. 25-9).
Treatment
Selective non-operative management of blunt liver trauma is the only acceptable contemporary standard
of care. The selection of patients for non-operative management should incorporate clinical
examination, CT scan findings, and the presence or absence of associated injuries. Hemodynamic
stability and the absence of peritonitis are absolute requirements for non-operative management. The
success rate of non-operative management for blunt hepatic trauma, including those with high-grade
injuries, is high.46,47 In a recent National Trauma Data Bank study of 6,402 patients with grade IV or V
blunt liver injuries, 68% were managed non-operatively.48 For these high-grade injuries, especially with
evidence of contrast extravasation (Fig. 25-8), angiointervention has been shown to be an independent
predictor of survival and should be used liberally as a postoperative adjunct. Most failures of non-
operative management occur within the first 24 hours of admission. There is some evidence that
patients with high injury severity score (ISS), severe grade IV or V liver injuries, multiple transfusions,
666
booksmedicos.org
major associated injuries, and associated chronic conditions such as cirrhosis, are at an increased risk for
failure of non-operative management. Angiographic embolization may be a significant adjunctive
therapeutic modality which increases the success rate of non-operative management of high-grade
injuries.47,49 Although non-operative management of blunt liver trauma has become the standard of
care, many centers still treat penetrating injuries operatively. However, there is good evidence that at
experienced trauma centers, selected cases with penetrating trauma due to SWs or GSWs (Fig. 25-9), can
safely be managed non-operatively.32,33 For both blunt and penetrating injuries being managed non-
operatively, continuous close monitoring in an ICU environment and frequent serial clinical
examinations are critical for success.
Figure 25-8. High-grade blunt liver injury with active contrast extravasation.
For operative management, the initial incision should be a midline laparotomy because it provides
adequate exposure of the liver in the majority of cases and allows systematic exploration of the
abdomen. For improved access to posterolateral liver injuries, a right subcostal incision may be
required. In rare occasions, addition of a sternotomy may be required in order to obtain access to the
intrapericardial inferior vena cava for total vascular isolation of the liver (Fig. 25-10), or exposure of
the heart for placement of an atriocaval shunt (Fig. 25-11). Alternatively, as discussed earlier in the
chapter, if the patient has a right thoracotomy, usually in the setting of a gunshot injury which
presented with a massive hemothorax due to decompression of a high-grade liver injury through the
diaphragm, the thoracotomy and laparotomy can be joined with incision of the diaphragm for
unimpeded access to the posterior liver and suprahepatic segment of the IVC.
In this case a cuff of diaphragm should be left so that if the patient survives, reconstruction is
facilitated. In approximately 80% to 85% of patients undergoing operation, the liver injury can be
managed by relatively simple surgical techniques, such as application of local hemostatic agents,
electrocoagulation, or superficial suturing. Bleeding from deep liver lacerations can be controlled by
clipping or suture ligation of any major vessels, followed by deep, figure-of-eight sutures, on a large
blunt liver needle. Omental packing of large liver defects is useful in eliminating any dead space.
Significant bleeding from deep bullet or knife tracts in the liver may require a tractotomy for peripheral
wounds or balloon catheter tamponade and perihepatic packing for central wounds.
Figure 25-9. Gunshot injury to the liver successfully managed non-operatively.
667
booksmedicos.org
Figure 25-10. Laparotomy and sternotomy demonstrating excellent access to the liver and the intrapericardial segment of the
suprahepatic IVC.
7 Severe blunt trauma or high-velocity GSWs associated with extensive parenchymal damage are not
amendable to deep suturing. Bleeding control in these cases may be achieved with perihepatic packing,
with or without liver resection. Perihepatic packing and damage control is a significant advancement in
the management of complex liver injuries. In order to be effective it needs to be performed early,
before the patient becomes unstable. The presence of intact hepatic ligaments enhances the effectiveness
of the perihepatic packing and they should not routinely be divided. Laying a piece of absorbable mesh
on the raw surface of the liver prior to packing facilitates pack removal at the take back as the mesh
with its integrated clot can be left undisturbed once the packs are removed. Angioembolization
following perihepatic packing should be considered early postoperatively and ideally, intraoperatively,
if a hybrid operating room (Fig. 25-12) is available. The perihepatic packing should be removed after
correction of coagulopathy and other physiologic abnormalities, usually within 24 to 36 hours of the
index operation. Delaying the removal of the packs for more than 48 hours may be associated with an
increased risk of infection. Nonanatomic liver resection may be needed in cases where there is a
destructive injury, and perihepatic packing is not effective.50 In general however, packing is highly
effective and major anatomic hepatic resections are rarely indicated acutely. Once the patient has
stabilized, and the liver has demarcated and the patient is able to tolerate resection, any nonviable
parenchyma can be resected. If required acutely, the liver resection can be performed with finger
dissection of the parenchyma, with suture ligation of vessels and biliary branches, or with the use of an
electrothermal bipolar vessel sealing system. Selective hepatic artery ligation or clipping may be a
useful adjunct to packing in rare cases and should be considered if packing by itself is insufficient and
temporary occlusion results in reduction of the bleeding. The combination of hepatic artery occlusion,
extensive parenchymal injury, and hypotension increases the risk of hepatic necrosis.
Figure 25-11. Schematic demonstrating an atriocaval shunt. (From Demetriades D, Inaba K, Velmahos G, eds. Atlas of Surgical
Techniques in Trauma. New York, NY: Cambridge University Press; 2015, with permission.)
668
booksmedicos.org
Figure 25-12. Hybrid operating room.
In the rare situation where perihepatic packing is not effective, often due to major retrohepatic
venous injuries, total vascular isolation of the liver may be required to achieve temporary bleeding
control, allowing identification and ligation of the injured vessels. The procedure consists of cross-
clamping of the infradiaphragmatic aorta, the suprahepatic and infrahepatic inferior vena cava, and the
porta hepatis. Control of the suprahepatic IVC is extremely challenging in the intra-abdominal segment
as this is usually where the primary source of bleeding necessitating the procedure has occurred.
Consequently, it is recommended that the intrapericardial segment as described earlier is accessed for
control.
Injury to the retrohepatic venous structures should be suspected in the presence of retrohepatic
bleeding or hematoma, especially if the bleeding becomes worse when the liver is retracted anteriorly.
Characteristically, the bleeding is reduced with posterior compression of the liver. A noncontained
retrohepatic venous injury is highly lethal because of the difficult surgical exposure. As discussed
earlier, contained retrohepatic hematomas should not be explored because of the risk of uncontrollable
hemorrhage. This applies to both blunt and penetrating injuries. However, in the presence of active
bleeding not controlled by packing and posterior compression of the liver, exploration and repair or
ligation of the bleeding vessel are mandatory. Addition of a subcostal incision improves exposure of the
liver and the retrohepatic veins. Division of the falciform and coronary ligaments allows inferior-medial
rotation of the liver and direct visualization of the inferior vena cava and the right hepatic vein. As
described earlier, an alternative to the subcostal incision is a median sternotomy or if the patient
already has a right anterolateral thoracotomy, division of the diaphragm, straight down to the inferior
vena cava.
The use of an intracaval shunt may be considered in selected complex retrohepatic venous injuries
which cannot be controlled with simpler approaches. The procedure involves extension of the
laparotomy incision into a median sternotomy and opening of the pericardium. A tape tourniquet is then
applied around the intrapericardial IVC. A purse–string suture (2-0 silk) is placed in the right atrial
appendage and a size 8 endotracheal tube with a side hole cut at approximately 8 to 10 cm from the
clamped proximal end, is then inserted through the purse–string and guided into the IVC. The balloon of
the tube is then inflated just above the renal veins and the tape tourniquet around the intrapericardial
IVC is tightened.51 Alternatively, a 36-Fr chest tube, with fenestrations cut into the proximal segment of
the tube to allow blood flow from the IVC into the right atrium may be used. The intracaval shunt may
reduce bleeding but in reality, rarely achieves complete hemostasis. The reported results with atriocaval
shunts are generally poor, and should be considered if all other techniques have failed.
For completion, other techniques which have been used in the management of retrohepatic venous
injuries include intravascular balloons inserted through the femoral vein, extracorporeal venovenous
bypass, hypothermic circulatory arrest, and liver transplantation.52
The incidence of postoperative liver-related complications after high-grade liver injuries has been
reported to be as high as 50%.53 The clinical presentation of these complications may vary from a few
days to many months. Complications include early or late hemorrhage, pseudoaneurysm, arteriovenous
fistula, biloma, biliary fistula, liver necrosis, liver abscess, hemobilia, and intrahepatic biliary strictures.
Approximately 35% of patients with significant liver-related postoperative complications are
asymptomatic and have the complication diagnosed on CT.53 The majority of these complications can
safely be managed non-operatively, with percutaneous endovascular or endoluminal interventional
radiology-based or ERCP-guided solutions.
669
booksmedicos.org
Extrahepatic Biliary Tract Injury
Trauma to the extrahepatic biliary tree is rare and is usually due to a penetrating mechanism. Bile duct
injuries are usually diagnosed during laparotomy, although some cases may present late, occurring even
days after injury. The diagnosis may be confirmed with a hepatobiliary iminodiacetic acid (HIDA) scan,
MRCP, or ERCP. The management of injuries to the biliary tree is determined by the location and
extent of the biliary injury, the time of diagnosis, and the presence of associated intra-abdominal
injuries. Injuries to the gallbladder are treated by cholecystectomy. Complete duct transections are best
managed with a Roux-en-Y biliary-enteric anastomosis because primary repair is associated with a high
stricture rate.
Incomplete injuries to the extrahepatic ductal system discovered intraoperatively, can be managed
with primary repair, if the transection involves less than 50% of the duct circumference. Placement of a
T-tube through a separate choledochotomy facilitates the repair. Transections involving more than 50%
of the circumference of the duct, especially with questionable tissue viability, should be treated like a
complete transection. All repairs of the biliary tract should be drained externally with closed suction
drains.
In the damage control setting, the duct may be ligated or an external catheter may be placed into the
proximal duct and exteriorized through the skin. Definitive repair can be performed after physiologic
stabilization of the patient or once expert assistance becomes available.
SPLEEN
Anatomy
The spleen is held in place by four ligaments which include the splenogastric ligament medially, the
splenocolic ligament inferiorly, and the splenophrenic and splenorenal ligaments posterolaterally. The
splenogastric ligament is the only vascular ligament and contains five to seven short gastric vessels,
which originate from the distal splenic artery. The tail of the pancreas is in close proximity to the
splenic hilum and is at risk of injury during splenectomy or hilar clamping. The splenic artery courses
superior to the pancreas and near the splenic hilum it divides into upper and lower pole arteries. The
splenic vein is located posterior and inferior to the splenic artery, receives the inferior mesenteric vein
and joins the superior mesenteric vein to form the portal vein.
Epidemiology
The spleen is a commonly injured intra-abdominal organ following blunt trauma and the second most
commonly injured solid organ after penetrating trauma. The severity of splenic injury is graded by the
OIS-AAST spleen injury scale, which is based on CT, as well as operative findings (Table 25-2).
Generally, grades I and II are considered minor injuries, grade III a moderate injury, and grades IV and
V are severe injuries.
Diagnostics
The clinical presentation of a spleen injury depends on the volume of blood loss and the presence of
associated injuries. Many low-grade splenic injuries may be asymptomatic or have only minor local
tenderness and the diagnosis is made on CT. If associated with significant blood loss the patient may
present with tachycardia and hypotension. Classically, those with large splenic hematomas may
experience pain in the left upper quadrant, radiating to the left shoulder (Kehr sign), especially when
placed in the Trendelenburg position. Although plain chest x-rays are not diagnostic, the presence of
fractures of the left lower ribs or an elevated left hemidiaphragm can be associated with an increased
possibility of splenic injury. The FAST may show free fluid around the spleen. Abdominal CT scan with
intravenous contrast is the most widely used and highest-yield investigation (Figs. 25-13 and 25-14). It
provides accurate information about the grade of injury, the amount of intraperitoneal bleeding,
evidence of active bleeding, and associated injuries.
Table 25-2 OIS-AAST Grading Scale for the Spleen
670
booksmedicos.org
Figure 25-13. CT image of a high-grade spleen injury.
Treatment
Approximately 80% of blunt splenic injuries in adults and 90% to 95% in children can be safely
managed non-operatively.54 Recent studies suggest that approximately 10% of all penetrating splenic
injuries may also be managed non-operatively.55 The selection of patients for non-operative
management should be based on clinical examination and CT scan findings. The patient should be
hemodynamically stable and have no signs of peritonitis. Although associated head trauma is not an
absolute contraindication for non-operative management, it should lower the threshold for operative
intervention, because head trauma-related coagulopathy increases the risk of splenic bleeding and the
splenic bleeding may cause hypotension which would be detrimental to the injured brain.
Figure 25-14. Spleen after removal as seen on CT in Figure 25-13.
671
booksmedicos.org
Low-grade splenic injuries are much more likely to be successfully managed non-operatively, but
many high-grade injuries may still be managed non-operatively. Patients with higher-grade splenic
injuries selected for non-operative management should be observed in the ICU. Development of
hemodynamic instability, peritonitis or the need for blood transfusion should trigger operative
exploration. Most failures occur within the first few days, although in some cases, especially those with
subcapsular hematomas or pseudoaneurysms, delayed bleeding may occur days to weeks after the
injury. Patients with severe splenic injuries selected for non-operative management should receive
prophylactic vaccinations against Streptococcus pneumonia, Neisseria meningitidis, and Haemophilus
influenza, in case conservative management fails and the patient requires splenectomy.
A follow-up CT scan should be performed for all grade III to V splenic injuries within 2 to 3 days of
admission to rule out the development of a pseudoaneurysm or progression of the hematoma.
Subsequent follow-up CT scan evaluation should be considered in selected cases with high-grade
injuries, especially those with subcapsular hematomas.
The duration of avoidance of vigorous physical activities and contact sports should be individualized,
taking into account the severity of the spleen injury, the findings on follow-up CT scan, and patient’s
lifestyle. Most surgeons recommend a period of approximately 4 to 6 weeks before resumption of heavy
duties.
Angioembolization has been used as an adjunct to non-operative management in high-grade splenic
injuries. For patients with CT scan evidence of active contrast extravasation or pseudoaneurysm,
angioembolization should be considered. Proximal splenic artery embolization consists of coil occlusion
of the splenic artery distal to the dorsal pancreatic artery and promotes hemostasis by reducing blood
flow to the spleen. Distal selective embolization consists of coil or gelfoam deployment as close to the
bleeding site as possible. The available evidence is inconclusive and suggests that the two approaches
may be equally effective in preventing significant rebleeding. Both techniques are associated with the
same incidence of infarctions and infections requiring splenectomy. Distal embolization is associated
with a higher rate of asymptomatic segmental infarctions.56 A Western Trauma Association multicenter
trial which included 140 splenic artery embolizations reported an overall complication rate of 32%,
including splenic infarctions in 21% and splenic abscess in 4.3%.57
For operative management, midline laparotomy is the incision of choice for accessing the spleen.
After entering the peritoneal cavity any free blood is evacuated and the left upper quadrant is packed
for temporary bleeding control. This allows a rapid evaluation of the rest of the abdomen to rule out
any other major injuries which may require immediate attention. The next step is the assessment of the
type and severity of the splenic injury, in order to determine if the spleen is salvageable. After removal
of the temporary packing, the organ is rotated inferomedially. Several laparotomy pads are then placed
under the left diaphragm and behind the spleen, aiding in the exposure of the spleen. Excessive traction
on the stomach or the splenic flexure of the colon or excessive medial rotation of the spleen may cause
avulsion of the delicate splenic capsule, resulting in bleeding and decreasing the possibility of splenic
preservation.
Profuse bleeding from the spleen can temporarily be controlled with digital compression of the hilum
or direct digital compression of the splenic parenchyma. A vascular clamp can also be placed across the
hilum, taking care not to injure the tail of the pancreas.
The critical move for a quick and safe splenectomy is adequate mobilization and inferomedial rotation
of the spleen. This is achieved by sharp division of the splenophrenic and splenorenal ligaments
posterolaterally and medial rotation of the spleen. The next step is division and ligation of the vascular
gastrosplenic ligament, as far away from the stomach as possible, in order to avoid injury or ischemic
necrosis of the gastric wall. Likewise, the splenic artery and vein should be ligated as close to the hilum
as possible, in order to avoid injury to the tail of the pancreas. The final step is division of the
splenocolic ligament. Although this stepped approach to mobilization of the spleen is applicable to most
patients, the order of taking down the splenic ligaments should be determined by the anatomy and may
vary from patient to patient. In fact, for acutely injured spleens, many of these ligaments may already
be avulsed.
Preservation of the spleen should be considered in low-grade injuries if the patient is
hemodynamically stable with a low overall injury burden. In cases with avulsion of the splenic capsule
or minor lacerations, hemostasis can be achieved with electrocautery and local hemostatic agents.
Splenic lacerations may be repaired with absorbable figure-of-eight or horizontal mattress sutures, on a
blunt liver needle. The presence of an intact splenic capsule makes the placement of the sutures
technically easier. If the parenchyma is fragile and does not hold sutures, pledgets may be used. An
672
booksmedicos.org
absorbable splenic mesh can also be used (Fig. 25-15) as an adjunct to splenorrhaphy, especially in cases
with multiple stellate parenchymal injuries.
Early local postsplenectomy complications include recurrent bleeding, pancreatic complications
(pancreatitis, pseudocyst, and pancreatic fistula), gastric complications (gastroparesis, necrosis of the
greater curvature), subdiaphragmatic abscess, splenic vein thrombosis, splenic arteriovenous fistula, left
lower lobe atelectasis, or pleural effusion. Complications after splenorrhaphy include intrasplenic
hematoma or abscess, splenic infarcts, and pseudoaneurysms or arteriovenous fistulas. A follow-up CT
scan with intravenous contrast should be performed in all high-grade splenic injuries managed with
splenorrhaphy. Early postsplenectomy hematologic changes include leukocytosis and thrombocytosis.
The leukocytosis is usually moderate, rarely exceeding 16,000 to 18,000/mm3 and may last several
weeks. More severe leukocytosis may indicate an infectious complication, especially in the presence of
fever or tachycardia.58 Thrombocytosis is usually moderate, may last for a few weeks and in most cases
is clinically irrelevant.
Figure 25-15. Splenic preservation with use of an absorbably mesh bag. (With permission Demetriades D, Inaba K, Velmahos G,
eds. Atlas of Surgical Techniques in Trauma. New York, NY: Cambridge University Press; 2015.)
Postsplenectomy infections may occur early or late. There is evidence that splenectomy is associated
with an increased risk of early postsplenectomy infections. A recent prospective observational,
multicenter study of 269 patients with blunt splenic injury surviving at least 72 hours, reported that
splenectomy had a significantly higher incidence of infectious complications than splenic preservation.59
A regression analysis identified splenectomy as an independent risk factor for infectious complications.
Overwhelming postsplenectomy infection (OPSI) is a rare but life-threatening complication, especially
in children. The reported mortality varies from 10% to 80%. Encapsulated organisms, such as
Haemophilus influenza, Streptococcus pneumonia, and Neisseria meningococcus are the most common
pathogens. Although the majority of infections occur within the first 3 to 4 years, OPSI may occur at
any time after splenectomy. The Surgical Infection Society recommends that all splenectomized patients
2 to 64 years old receive the 23-valent pneumococcal vaccine.60 In addition, high-risk patients should
receive Haemophilus influenza and Meningococcal vaccines. The timing of administration of the vaccines
after trauma may be optimal at 14 days after splenectomy.61 There is no evidence to support routine
long-term prophylactic antibiotic administration in splenectomized patients. Patients should be educated
on postsplenectomy sepsis, wear a medical alert bracelet, inform caregivers of their asplenic state, and
be advised to seek medical care with the onset of any signs of infection.
PANCREAS
Anatomy
673
booksmedicos.org
The pancreas is a retroperitoneal organ with its head directly situated over the inferior vena cava and
its neck over the superior mesenteric vessels and the proximal portal vein. The body extends over the
suprarenal aorta and the left renal vessels, closely related to the splenic artery and vein. The uncinate
process wraps around the superior mesenteric vessels. As described for the spleen, the splenic vein
courses inferior to the splenic artery and joins the superior mesenteric vein at a right angle to form the
portal vein behind the neck of the pancreas. The inferior mesenteric vein drains into the splenic vein
behind the body of the pancreas (Figs. 25-16 and 25-17).
The major pancreatic duct of Wirsung travels down the entire length of the pancreas and drains into
the ampulla of Vater, approximately 8 cm downstream from the pylorus. The lesser duct of Santorini
branches off the superior aspect of the major duct, at the level of the neck of the pancreas. This drains
into the duodenum, approximately 2 to 3 cm proximal to the ampulla of Vater. The pancreatic head and
the proximal duodenum receive their blood supply from the anterior and posterior pancreaticoduodenal
arcades. Because these arcades lie on the surface of the pancreas, close to the duodenal loop, separating
these can result in ischemic damage to the duodenum.
Figure 25-16. Pancreatic anatomy demonstrating relationship to vascular structures and spleen. (With permission Demetriades D,
Inaba K, Velmahos G, eds. Atlas of Surgical Techniques in Trauma. New York, NY: Cambridge University Press; 2015.)
Figure 25-17. Pancreatic anatomy demonstrating relationship to stomach. (With permission Demetriades D, Inaba K, Velmahos G,
eds. Atlas of Surgical Techniques in Trauma. New York, NY: Cambridge University Press; 2015.)
Epidemiology
Pancreatic trauma is seen in approximately 0.2% of blunt trauma and about 1% of penetrating trauma
patients. Overall, about 60% of patients with blunt trauma and about 90% with penetrating trauma will
674
booksmedicos.org
have associated intra-abdominal injuries. The most commonly associated injury in blunt trauma is the
spleen. Duodenal injuries are found in less than 10% of the patients. In penetrating trauma, the most
commonly associated injuries are the stomach, closely followed by the liver. Associated intra-abdominal
vascular injuries are common in penetrating injuries and are found in more than 75% of penetrating
injuries to the head of the pancreas. A concomitant major vascular injury increases the likelihood of a
poor outcome. The most widely used grading system (Table 25-3) is the OIS-AAST.45 The classification
is based on CT and operative findings.
Table 25-3 OIS-AAST Grading Scale for the Pancreas
Diagnostics
The diagnosis of penetrating pancreatic injury is usually made intraoperatively. The diagnosis in blunt
trauma, especially for isolated injuries, may be difficult because the initial symptoms may be occult.
Clinical signs may take hours or even days to manifest. Serial serum amylase and lipase levels may be
useful as a screening test for pancreatic trauma but isolated values have poor sensitivity and specificity.
Contrast-enhanced CT scan (Fig. 25-18) is the investigation of choice in suspected pancreatic
trauma.62,63 Its accuracy increases with time from injury and in cases with an equivocal initial test, a
repeat CT scan 6 to 8 hours after the initial investigation should be considered. MRCP or ERCP can be
considered in selected cases with pancreatic trauma to establish the integrity of the pancreatic duct.64,65
Figure 25-18. CT image of pancreatic transection after blunt trauma. Oval demonstrates the pancreatic transection.
Treatment
The management of pancreatic trauma is determined by the mechanism of injury and the presence or
absence of pancreatic duct injury. All penetrating injuries require operative management. However,
most patients with isolated blunt trauma to the pancreas with an intact pancreatic duct can safely be
managed non-operatively. A National Pediatric Trauma Registry study of pancreatic injuries in 154
children, reported that non-operative management was successful in approximately half of high-grade
injuries and in approximately 80% of low-grade injuries.66 Other studies have confirmed the safety and
675
booksmedicos.org
high success rate of non-operative management in children.67,68 The success rate of non-operative
managment in adults however is significantly lower, in part due to the higher incidence of pancreatic
duct injury which is less than 1% in children, but approximately 15% in adults. The safety of selective
non-operative managment in adults has been confirmed in many studies.69,70
Non-operative management is safe for low-grade injuries and many selected higher-grade injuries,
especially in children. For higher-grade injuries, the integrity of the pancreatic duct should be evaluated
with ERCP or MRCP. ERCP can also be therapeutic with pancreatic duct stent placement, as definitive
treatment. Complications associated with non-operative management include pancreatic pseudocyst and
pancreatitis. There is no evidence that the use of somatostatin analogs increases the success rate of non-
operative management and they should not be used routinely.
For patients undergoing operative management, the pancreas is exposed through the lesser sac. This
allows access to the anterior, superior, and inferior surfaces of the body and tail of the pancreas. The
posterior aspect of the pancreas can be mobilized by incising the peritoneum over the inferior border of
the pancreas and retracting upward. If more extensive mobilization is required for the distal pancreas,
this can be achieved by en-block mobilization and medial rotation of the spleen and tail of the pancreas.
For the head and uncinate processes, exposure is achieved with an extended Kocher maneuver.
As a general rule, all peripancreatic hematomas should be explored to examine for any underlying
ductal injuries. However, hematomas localized to the head of the pancreas may be left undisturbed,
because the duct in this area is deep in the parenchyma and exploration is difficult and potentially
dangerous. These injuries should be drained externally with closed drains and postoperatively the
integrity of the duct can be evaluated using MRCP or ERCP and treated with stenting.65,71
Low-grade injuries without obvious ductal disruption should be treated with the debridement of
nonviable tissue, hemostasis, and wide external drainage. For severe parenchymal injuries with known
or suspected ductal disruption, the optimal procedure will depend on the condition of the patient and
the site of the pancreatic injury (head and neck vs. tail). Severe pancreatic injuries involving the body
to the left of the superior mesenteric vessels are best treated by distal pancreatectomy, with or without
splenic preservation (Fig. 25-19). For destructive injuries to the head of the pancreas, especially with
concurrent duodenal injury, if the operative procedure is to undergo damage control, or if this is beyond
the skill set of the operating surgeon, the safest option is hemostasis and external drainage. Damage
control packing and temporary abdominal closure with delayed resection and reconstruction can be
performed. If however, a pancreaticoduodenectomy is to be performed, even for hemodynamically
stable patients with an experienced surgeon, a two-stage procedure is highly recommended. The initial
operation includes temporary control of bleeding by means of packing and in the appropriate cases,
arterial shunting or if there is a concomitant venous injury, ligation. The duodenal and pancreatic head
resection is performed and the common bile duct is ligated or drained externally. The definitive
reconstruction should be performed only after normalization of the patient’s physiology. The
reconstruction, which includes pancreaticojejunostomy, choledochojejunostomy, and gastroenterostomy,
is similar to that in elective cases and should be performed with expert assistance in an optimized
patient.
Figure 25-19. Distal pancreatectomy specimen with splenectomy specimen after blunt trauma.
Pancreas-related local complications occur in about 25% of patients and include pancreatic fistulas,
pseudocysts, pancreatitis, and perihepatic infection. Most of these complications can successfully be
managed non-operatively or with percutaneous drainage and endoscopic stenting of the duct.71
Endocrine and exocrine pancreatic insufficiencies may occur after major pancreatic resections, but the
true incidence of this remains unknown. Patients undergoing major pancreatic resections should be
676
booksmedicos.org
monitored on a regular basis, at least during the first few months after the operation. For those who
underwent a pancreaticoduodenectomy and survived, late stricture of the choledochojejunostomy is not
uncommon, because of the small size of the common bile duct. The stricture may manifest many months
after the operation and thus it is recommended that these patients are followed regularly, especially
during the first few months after the injury.
STOMACH
Anatomy
The stomach is a hollow viscus organ located in the left upper quadrant of the abdomen with the
fundus, GE junction, and often a significant portion of the body lying above the costal margin. The
stomach has a robust blood supply including the left and right gastric arteries, the right and left
gastroepiploic arteries, and the short gastric arteries. This level of vascularity can result in significant
bleeding after injury but also provides redundancy, making devascularization and necrosis of the
stomach relatively rare after trauma.
Diagnostics
Gastric injury usually results from either significant blunt force trauma or after penetrating trauma to
the left upper abdomen or lower chest. Presence of blood upon placement of an NG tube is concerning
for gastric injury. The majority of patients with full-thickness gastric injury after trauma will present
with spillage of gastric contents and peritonitis resulting in direct transfer to the operating room. Blunt
injury to the stomach can cause local contusion with gastric wall hematoma or hollow viscus rupture,
similar to bladder rupture, with a large full-thickness defect.
After blunt or penetrating trauma, in the absence of peritonitis or hemodynamic instability, additional
diagnostic workup with CT imaging is appropriate. CT scan findings concerning gastric injury include
extraluminal contrast, air, blood, or fluid, or localized thickening, or enhancement and discontinuity of
the gastric wall.72–74
Treatment
Gastric repair is generally well tolerated due to the redundancy of tissue and blood supply of the
stomach. After penetrating injury, if a single gastric injury is identified, the operating surgeon must
assume there is an additional injury corresponding to the entry or exit site. A single gastric injury is
exceedingly rare and even a linear laceration should not be mistaken for a tangential wound unless
meticulous inspection has ruled out an additional enterotomy. The anterior border of the stomach is
fully inspected from the esophagus to the pylorus. The left lobe of the liver may need to be retracted or
mobilized for better visualization of the proximal third of the stomach. The posterior aspect of the
stomach is evaluated by accessing the lesser sac below the gastroepiploic vessels. The posterior gastric
wall must be fully evaluated and visualized all the way up to the GE junction to avoid missed injury.
Blood or fluid upon entry into the lesser sac should alert the surgeon to a likely gastric and/or
pancreatic injury. Care must be taken when inspecting the GE junction and greater curvature not to
apply excess tension on the gastric fundus as this may result in iatrogenic splenic capsular tear or
laceration.
Low-grade injuries including hematomas and contusions should be evaluated and evacuated as
appropriate. After hematoma evacuation and hemostasis is achieved, the area may be reinforced with
Lembert sutures. Full-thickness injuries can be repaired in one or two layers. A two-layered repair
includes an inner layer of running absorbable suture and an outer layer of Lembert sutures. Injuries of
the greater curvature or larger injuries of the body can be controlled with a stapling device and wedge
resection. In gunshot injuries, it is important to debride the devitalized tissue surrounding the injury
prior to repair. Given the tissue redundancy of the stomach, stapling devices may be used liberally for
wedge resection. Care must be taken, however, to avoid narrowing the GE junction or pylorus. Injuries
involving the pylorus may be incorporated into a pyloroplasty for repair.
Significant destructive injuries or those involving the GE junction or pylorus may require a proximal
or distal gastrectomy with reconstruction. In rare cases, a total gastrectomy with esophagojejunostomy
is required. Proximal gastric injuries or those at the GE junction may present a technical challenge for
surgeons not accustomed to these operations. Attempts to repair these complex injuries without
appropriate experience can lead to significant morbidity and mortality for the patient. In such cases, a
677
booksmedicos.org
two-staged procedure should be considered. At the initial operation, the distal esophagus or proximal
stomach may be stapled and internally drained with a nasogastric tube thus controlling the injury in a
damage control manner. An additional staple line distal to the injury will prevent reflux contamination.
The area may be drained and the patient stabilized with a delayed reconstruction performed under
optimal conditions with all of the requisite expertise present.
DUODENUM
Anatomy
The duodenum is the first portion of the small intestine and forms a C-loop around the head of the
pancreas. The duodenum is divided into four parts, an anatomic distinction that can help guide
management of traumatic injury. The first portion is intraperitoneal and associated with the portal
structures and the gastroduodenal artery. The second and third portions are retroperitoneal and curve
around the head of the pancreas. The common bile and pancreatic ducts drain into the ampulla in the
second portion of the duodenum. The fourth portion of the duodenum ascends to the ligament of Treitz
to join the jejunum.
Figure 25-20. Gunshot injury to duodenum just proximal to the ligament of Treitz.
Epidemiology
Duodenal trauma is rare, occurring in less than 5% of all trauma patients, and is associated with a high
morbidity and mortality.75–77 Patients with duodenal trauma frequently have additional intra-abdominal
injury, most commonly of the liver, pancreas, and small bowel.
Treatment
Most low-grade duodenal hematomas secondary to blunt trauma without perforation can be managed
conservatively with NG tube decompression and supplemental nutrition. The majority of duodenal
trauma, however, is secondary to penetrating injury (Fig. 25-20) and is identified during operative
exploration. Duodenal hematomas encountered intraoperatively require exploration to evaluate for
underlying perforation.
Mobilization of the duodenum is most commonly achieved with a Kocher maneuver. This allows for
medialization of the second and third portions of the duodenum, evaluation of the posterior wall, and
exposure of the underlying vascular structures to examine for injury. Separation of the second portion of
the duodenum from the head of the pancreas is not advised as disruption of the blood supply puts the
duodenum at high risk of ischemia.
Most duodenal injuries can be repaired primarily in one or two layers with a transverse closure to
avoid luminal narrowing. Segmental resection is rarely needed but, in the event of injury >50% of the
duodenal circumference, resection with primary, end-to-end anastomosis may be performed when
appropriate. Segmental resection is not recommended for the second portion of the duodenum due to
the presence of the ampulla and inability to mobilize the medial wall. In complex injuries, pyloric
exclusion with gastrojejunostomy may be utilized to protect the repair, however, routine exclusion
should not be used for all duodenal injuries. In an analysis of 193 consecutive patients with duodenal
injuries, pyloric exclusion offered no morbidity or mortality benefit over primary repair.78 If performed,
678
booksmedicos.org
external stapling of the pylorus with a TA stapler and internal cerclage with a suture are both acceptable
techniques for pyloric exclusion. Most frequently, a gastrojejunostomy to restore continuity is
performed. Additional surgical adjuncts include a serosal patch and duodenojejunostomy. In the unstable
patient, damage control techniques may be safely applied to duodenal injury with delayed repair or
diversion.79 The traumatic Whipple is rarely indicated and carries a high mortality.80,81 This should be
considered only in patients with complex destructive injuries to the duodenum and pancreas. In these
cases, the provider should focus on a damage control procedure with control of contamination and
associated hemorrhage as the goals of the index operation. The subsequent reconstruction should be
performed in a stabilized patient, most commonly in a staged manner, with expert assistance available.
Liberal use of closed suction drainage is recommended after duodenal injury and/or repair.
One of the major complications after duodenal injury repair is fistula formation, occurring in 4% to
33% of patients.76,79,82 These are managed, when possible, with percutaneous drainage. In rare cases,
reoperation and repair or diversion is required.
COLON
Epidemiology
Colon injuries occur in approximately 30% of abdominal GSWs and 20% of SWs undergoing laparotomy.
In blunt trauma, approximately 10% of patients undergoing laparotomy will have a colon injury. Many
of the blunt trauma injuries are superficial with only 3% of patients undergoing laparotomy having a
full-thickness perforation. The presence of an external seatbelt mark sign is associated with an increased
risk of colon injury.
Diagnostics
The definitive diagnosis of colon injury is almost always made intraoperatively. Preoperative diagnosis
of colon injury following blunt trauma is difficult, especially in unevaluable patients. If a CT is
obtained, mesenteric stranding, bowel wall thickening, and unexplained fluid can be seen, increasing the
level of suspicion for a bowel perforation. Free extraluminal air is rare. Intraoperatively, all colonic
hematomas should be explored to rule out any underlying colon injury without devascularizing the wall.
Particular care should be taken for penetrating injuries, especially due to shotgun wounds, where the
injury can be hidden within the fat.
The severity of colon injury can be graded by the OIS-AAST colon injury scale (Table 25-4), which is
based on the operative findings.45 A practical classification used by many surgeons breaks injuries down
into two severity groups, nondestructive injuries involving <50% of the bowel wall without
devascularization versus destructive injuries which involve >50% of the bowel wall or demonstrate
devascularization.
Treatment
The management of colon injuries has undergone major changes over the last two decades.83–85 For
nondestructive injuries there is sufficient class I and class II evidence supporting primary repair
irrespective of risk factors, such as the site of colon injury, associated injuries, or physiologic status.86–88
For destructive colon injuries, defined as those with loss of >50% of the bowel wall circumference or
with devascularization, segmental colonic resection is required. The management of these cases is
controversial. These injuries were traditionally managed with diversion because of the perceived high
risk for anastomotic leak and intra-abdominal sepsis. Although the safety of primary anastomosis was
demonstrated in several small studies,86–88 for specific circumstances such as a penetrating abdominal
trauma index ≥25 or hypotension or large-volume blood transfusions or patient comorbidities, the
potential benefit of diversion remains unclear.88,89
Table 25-4 OIS-AAST Grading Scale for the Colon
679
booksmedicos.org
The Eastern Association for the Surgery of Trauma (EAST) guidelines based largely on class III
evidence recommended that diversion be considered in patients with shock, significant associated
injuries, peritonitis, or underlying disease.90 Since these were published, a more recent American
Association for the Surgery of Trauma prospective multicenter study examined 297 patients with
penetrating colon injuries requiring resection.91 This was a prospective observational study examining
the outcomes associated with diversion versus primary anastomosis without diversion. The overall
colon-related mortality was 1.3% and all deaths occurred in the diversion group. The incidence of
anastomotic leaks was 6.6%. Multivariate analysis identified severe fecal contamination, >4 units of
blood transfusions within the first 24 hours, and antibiotic choice as independent risk factors for
abdominal complications. The method of colon management, anastomosis, or diversion did not impact
outcomes. In addition, delay of operation >6 hours, shock at admission, site of colon injury,
penetrating abdominal trauma index >25, ISS >20, or associated intra-abdominal injuries were also
found to have no association with a negative outcome. Based on the available data, for both blunt and
penetrating destructive injuries, if the patient meets criteria for a damage control procedure,
contamination control with stapling of the colon should be performed. Whenever possible, an
anastomosis should be performed at the index operation, but this is only if the patient is able to tolerate
the additional operative burden. For stable patients not requiring damage control, the anastomosis
should be performed without diversion. The choice of a stapled versus hand-sewn anastomosis has been
shown not to make a difference.92 In a prospective study of 207 patients undergoing resection and
anastomosis, the leak rate was 7.8% for hand-sewn and 6.3% for stapled anastomoses. For edematous
bowel, often seen at the take back after an initial damage control resection, a hand-sewn anastomosis
may be preferred.
Abdominal complications after colon injuries are common, with an abdominal sepsis rate of
approximately 20%. Independent risk factors associated with an increased incidence of abdominal sepsis
include fecal spillage, blood transfusions exceeding four units of blood within the first 24 hours, and the
presence of chronic comorbid conditions. Retained bullets that have passed through the colon are not
associated with an increased risk of infection and therefore their routine removal is not required.93
Colonic leaks causing abdominal sepsis after repair or resection and anastomosis have been examined
in detail. For primary repairs, in a review of 35 prospective or retrospective studies including 2,964
primary repairs, a leak rate of 2.2% was seen.94 For patients undergoing resection and anastomosis,
which are more likely to leak, the rate was 5.5%.94 In the multicenter AAST study of 197 patients
undergoing resection and primary anastomosis, the leak rate was 6.6%.91 Anastomotic leaks occur more
commonly with a colon–colon anastomosis when compared to an ileocolic anastomosis. In the AAST
study the leak rate was 4.2% for ileocolostomies and 8.9% for colocolostomies.91
The majority of leaks can be managed non-operatively with percutaneous drainage. They are usually
small and seal off on their own. CT imaging should be obtained to examine for the presence of any
intra-abdominal collections and to guide drainage. Reexploration of the abdomen for drainage and
either fecal diversion or resection and reanastomosis is only required if the patient fails percutaneous
drainage or develops evidence of generalized peritonitis.
For patients who require a colostomy, there is a significant complication burden associated with the
colostomy itself as well as the subsequent closure. In a large series of 528 stomas performed in the
trauma setting, approximately 22% of patients sustained an early complication and 3% a late
complication.95 In another study of 110 colostomy closures, a local complication rate of 14.5% was
noted.96
680
booksmedicos.org
RECTUM
Anatomy
As the colon continues downstream, the rectum begins where the tenia coli coalesce as the terminal part
of the large intestine. The rectum is approximately 12- to 15-cm long and is both intra- and
extraperitoneal. Anteriorly, the upper two-thirds and laterally the upper one-third are intraperitoneal,
with the lower third being completely extraperitoneal. The blood supply is derived from the superior
rectal artery branching from the inferior mesenteric artery, the middle rectal artery from the internal
iliac artery, and the inferior rectal artery which is from the internal pudendal artery.
Epidemiology
Most rectal injuries result from a penetrating mechanism, usually secondary to GSWs although anally
inserted foreign body trauma and endoscopic trauma are also seen. Because of its protected location,
blunt injury is only seen in approximately 5% to 10% of injuries, and is often associated with a pelvic
fracture.
Diagnostics
The clinical presentation of rectal injuries that are intraperitoneal does not differ from that of colon
injuries. For extraperitoneal injuries, the clinical symptomatology can be masked by containment of the
perforation in the retroperitoneal tissues. As a direct consequence, operative exploration, direct
visualization on anoscopy and sigmoidoscopy, or CT rather than clinical examination is used to make
the diagnosis.
For blunt trauma patients, because the majority of injuries are in the intraperitoneal segment, the
same diagnostic principles for colonic injuries apply. For penetrating injuries, both intraperitoneal and
extraperitoneal injuries can occur. The diagnostic approach depends on the patient’s clinical
presentation. Patients with peritonitis, instability, or who are unexaminable should proceed directly to
the operating room. For unstable patients, positioning should be supine with an emphasis on the
laparotomy and hemorrhage control. Intraoperative sigmoidoscopy and anoscopy can be performed to
examine the extraperitoneal segment of the rectum. For those that have peritonitis or instability, the
patient may be placed in lithotomy to facilitate sigmoidoscopy and anoscopy. For those who are stable
and who meet the criteria for a trial of non-operative management, the highest-yield initial examination
is CT (Fig. 25-21). On the CT, the bullet trajectory is tracked. If the trajectory appears to traverse the
rectum, the patient can be brought to the operating room, placed in lithotomy and a laparotomy
performed. Preoperative or intraoperative sigmoidoscopy and anoscopy can be performed to examine
the extraperitoneal segment of the rectum. If the tract is clear of the rectum on CT, no further
investigations or treatment is required. For the equivocal CT scan where there is a questionable rectal
injury, several options exist. The patient can be brought to the operating room for a laparotomy,
sigmoidoscopy, and anoscopy. Another option is to perform diagnostic laparoscopy to look for
intraperitoneal breach as well as a sigmoidoscopy and anoscopy. Any entry into the peritoneal cavity
can then trigger a laparotomy and closer evaluation.
Figure 25-21. CT demonstrating a gunshot wound tract traversing the rectum, arrow demonstrates bullet tract.
681
booksmedicos.org
For intraperitoneal injuries, the management principles are the same as those that apply to colon
injuries. The vast majority undergo primary repair without the need for diversion. For extraperitoneal
injuries, the management has evolved over the last decade. The classic approach to rectal injuries which
included diversion, presacral drainage, and distal rectal washout is no longer performed.97–106
For distal extraperitoneal injuries that are accessible through a transanal approach, local repair can be
performed without colostomy.99,105,106 For higher extraperitoneal injuries inaccessible in this manner,
the primary treatment is fecal diversion without taking down the rectum and repairing the injury.103,104
This can even be done laparoscopically with a low rate of morbidity. In fact, the absolute need for
colostomy has not even been demonstrated. Theoretically, diversion allows for decreasing the fecal flow
past the unrepaired injury augmenting the healing process. Even after diversion, as there is some fecal
flow past the injury at least initially during the early phases of healing, the true value of colostomy is
questionable.
If there is an associated bladder injury, a tissue barrier using omentum should be placed between the
suture lines as a method of decreasing rectovesical fistula formation, a complication seen in upward of a
quarter of patients with combined injuries.107 In the rare case where there is a combined destructive
anorectal injury (Fig. 25-22), acutely, hemostasis and diversion are recommended. Once the patient has
been stabilized, assessment of the anal sphincter function should be performed, and semielective
reconstruction should be performed by a colorectal specialist.
Figure 25-22. Large perineal and groin avulsion injury after pedestrian struck by train.
References
1. Stannard A, Eliason JL, Rasmussen TE. Resuscitative endovascular balloon occlusion of the aorta
(REBOA) as an adjunct for hemorrhagic shock. J Trauma 2011;71(6):1869–1872.
2. Rhee PM, Acosta J, Bridgeman A, et al. Survival after emergency department thoracotomy: review
of published data from the past 25 years. J Am Coll Surg 2000;190(3):288–298.
3. Velmahos GC, Tatevossian R, Demetriades D. The “seat belt mark” sign: a call for increased
vigilance among physicians treating victims of motor vehicle accidents. Am Surg 1999;65(2):181–
185.
4. Sharma OP, Oswanski MF, Kaminski BP, et al. Clinical implications of the seat belt sign in blunt
trauma. Am Surg 2009;75(9):822–827.
5. Brown CV, Velmahos GC, Neville AL, et al. Hemodynamically “stable” patients with peritonitis
after penetrating abdominal trauma: identifying those who are bleeding. Arch Surg
2005;140(8):767–772.
6. Teixeira PG, Inaba K, Oncel D, et al. Blunt cardiac rupture: a 5-year NTDB analysis. J Trauma
2009;67(4):788–791.
7. Gaines BA. Intra-abdominal solid organ injury in children: diagnosis and treatment. J Trauma
2009;67(2 suppl):S135–S139.
8. Schroeppel TJ, Croce MA. Diagnosis and management of blunt abdominal solid organ injury. Curr
Opin Crit Care 2007;13(4):399–404.
9. Shaftan GW. Selective conservatism in penetrating abdominal trauma. J Trauma 1969;9(12):1026–
682
booksmedicos.org
1028.
10. Jansen JO, Inaba K, Resnick S, et al. Selective non-operative management of abdominal gunshot
wounds: survey of practise. Injury 2013;44(5):639–644.
11. Navsaria PH, Nicol AJ, Edu S, et al. Selective nonoperative management in 1106 patients with
abdominal gunshot wounds: conclusions on safety, efficacy, and the role of selective CT imaging in
a prospective single-center study. Ann Surg 2015;261(4):760–764.
12. Inaba K, Demetriades D. The nonoperative management of penetrating abdominal trauma. Adv Surg
2007;41:51–62.
13. Leppaniemi A, Salo J, Haapiainen R. Complications of negative laparotomy for truncal stab
wounds. J Trauma 1995;38(1):54–58.
14. Renz BM, Feliciano DV. Unnecessary laparotomies for trauma: a prospective study of morbidity. J
Trauma 1995;38(3):350–356.
15. Renz BM, Feliciano DV. The length of hospital stay after an unnecessary laparotomy for trauma: a
prospective study. J Trauma 1996;40(2):187–190.
16. Hasaniya N, Demetriades D, Stephens A, et al. Early morbidity and mortality of non-therapeutic
operations for penetrating trauma. Am Surg 1994;60(10):744–747.
17. Arikan S, Kocakusak A, Yucel AF, et al. A prospective comparison of the selective observation and
routine exploration methods for penetrating abdominal stab wounds with organ or omentum
evisceration. J Trauma 2005;58(3):526–532.
18. Velmahos GC, Demetriades D, Toutouzas KG, et al. Selective nonoperative management in 1,856
patients with abdominal gunshot wounds: should routine laparotomy still be the standard of care?
Ann Surg 2001;234(3):395–402; discussion 402–403.
19. Biffl WL, Kaups KL, Pham TN, et al. Validating the Western Trauma Association algorithm for
managing patients with anterior abdominal stab wounds: a Western Trauma Association multicenter
trial. J Trauma 2011;71(6):1494–1502.
20. Demetriades D, Rabinowitz B, Sofianos C, et al. The management of penetrating injuries of the
back. A prospective study of 230 patients. Ann Surg 1988;207(1):72–74.
21. Velmahos GC, Demetriades D, Foianini E, et al. A selective approach to the management of gunshot
wounds to the back. Am J Surg 1997;174(3):342–346.
22. Velmahos GC, Demetriades D, Cornwell EE 3rd. Transpelvic gunshot wounds: routine laparotomy
or selective management? World J Surg 1998;22(10):1034–1038.
23. Burnweit CA, Thal ER. Significance of omental evisceration in abdominal stab wounds. Am J Surg
1986;152(6):670–673.
24. Nagy K, Roberts R, Joseph K, et al. Evisceration after abdominal stab wounds: is laparotomy
required? J Trauma 1999;47(4):622–624; discussion 624–626.
25. Soffer D, McKenney MG, Cohn S, et al. A prospective evaluation of ultrasonography for the
diagnosis of penetrating torso injury. J Trauma 2004;56(5):953–957; discussion 957–959.
26. Udobi KF, Rodriguez A, Chiu WC, et al. Role of ultrasonography in penetrating abdominal trauma:
a prospective clinical study. J Trauma 2001;50(3):475–479.
27. Boulanger BR, Kearney PA, Tsuei B, et al. The routine use of sonography in penetrating torso injury
is beneficial. J Trauma 2001;51(2):320–325.
28. Velmahos GC, Constantinou C, Tillou A, et al. Abdominal computed tomographic scan for patients
with gunshot wounds to the abdomen selected for nonoperative management. J Trauma
2005;59(5):1155–1160; discussion 1160–1161.
29. Munera F, Morales C, Soto JA, et al. Gunshot wounds of abdomen: evaluation of stable patients
with triple-contrast helical CT. Radiology 2004;231(2):399–405.
30. Inaba K, Okoye OT, Rosenheck R, et al. Prospective evaluation of the role of computed tomography
in the assessment of abdominal stab wounds. JAMA Surg 2013;148(9):810–816.
31. Salim A, Sangthong B, Martin M, et al. Use of computed tomography in anterior abdominal stab
wounds: results of a prospective study. Arch Surg 2006;141(8):745–750; discussion 750–752.
32. Demetriades D, Hadjizacharia P, Constantinou C, et al. Selective nonoperative management of
penetrating abdominal solid organ injuries. Ann Surg 2006;244(4):620–628.
33. DuBose J, Inaba K, Teixeira PG, et al. Selective non-operative management of solid organ injury
683
booksmedicos.org
following abdominal gunshot wounds. Injury 2007;38(9):1084–1090.
34. Inaba K, Branco BC, Moe D, et al. Prospective evaluation of selective nonoperative management of
torso gunshot wounds: when is it safe to discharge? J Trauma Acute Care Surg 2012;72(4):884–891.
35. Inaba K, Barmparas G, Foster A, et al. Selective nonoperative management of torso gunshot
wounds: when is it safe to discharge? J Trauma 2010;68(6):1301–1304.
36. Alzamel HA, Cohn SM. When is it safe to discharge asymptomatic patients with abdominal stab
wounds? J Trauma 2005;58(3):523–525.
37. Murray JA, Demetriades D, Asensio JA, et al. Occult injuries to the diaphragm: prospective
evaluation of laparoscopy in penetrating injuries to the left lower chest. J Am Coll Surg
1998;187(6):626–630.
38. Murray JA, Demetriades D, Cornwell EE 3rd, et al. Penetrating left thoracoabdominal trauma: the
incidence and clinical presentation of diaphragm injuries. J Trauma 1997;43(4):624–626.
39. Leppaniemi A, Haapiainen R. Occult diaphragmatic injuries caused by stab wounds. J Trauma
2003;55(4):646–650.
40. Rotondo MF, Schwab CW, McGonigal MD, et al. ‘Damage control’: an approach for improved
survival in exsanguinating penetrating abdominal injury. J Trauma 1993;35(3):375–382; discussion
382–383.
41. Subramanian A, Vercruysse G, Dente C, et al. A decade’s experience with temporary intravascular
shunts at a civilian level I trauma center. J Trauma 2008;65(2):316–324; discussion 324–326.
42. Demetriades D. Balloon tamponade for bleeding control in penetrating liver injuries. J Trauma
1998;44(3):538–539.
43. Raeburn CD, Moore EE, Biffl WL, et al. The abdominal compartment syndrome is a morbid
complication of postinjury damage control surgery. Am J Surg 2001;182(6):542–546.
44. Bocchini G, Guida F, Sica G, et al. Diaphragmatic injuries after blunt trauma: are they still a
challenge? Reviewing CT findings and integrated imaging. Emerg Radiol 2012;19(3):225–235.
45. Moore EE, Moore FA. American Association for the Surgery of Trauma Organ Injury Scaling: 50th
anniversary review article of the Journal of Trauma. J Trauma 2010;69(6):1600–1601.
46. Pachter HL, Knudson MM, Esrig B, et al. Status of nonoperative management of blunt hepatic
injuries in 1995: a multicenter experience with 404 patients. J Trauma 1996;40(1):31–38.
47. Velmahos GC, Toutouzas KG, Radin R, et al. Nonoperative treatment of blunt injury to solid
abdominal organs: a prospective study. Arch Surg 2003;138(8):844–851.
48. Sivrikoz E, Teixeira PG, Resnick S, et al. Angiointervention: an independent predictor of survival in
high-grade blunt liver injuries. Am J Surg 2015;209(4):742–746.
49. Wahl WL, Ahrns KS, Brandt MM, et al. The need for early angiographic embolization in blunt liver
injuries. J Trauma 2002;52(6):1097–1101.
50. Strong RW, Lynch SV, Wall DR, et al. Anatomic resection for severe liver trauma. Surgery
1998;123(3):251–257.
51. Khaneja SC, Pizzi WF, Barie PS et al. Management of penetrating juxtahepatic inferior vena cava
injuries under total vascular occlusion. J Am Coll Surg 1997;184(5):469–474.
52. Plackett TP, Barmparas G, Inaba K, et al. Transplantation for severe hepatic trauma. J Trauma
2011;71(6):1880–1884.
53. Demetriades D, Karaiskakis M, Alo K, et al. Role of postoperative computed tomography in patients
with severe liver injury. Br J Surg 2003;90(11):1398–1400.
54. Peitzman AB, Heil B, Rivera L, et al. Blunt splenic injury in adults: multi-institutional study of the
Eastern Association for the Surgery of Trauma. J Trauma 2000;49(2):177–187; discussion 187–189.
55. Berg RJ, Inaba K, Okoye O, et al. The contemporary management of penetrating splenic injury.
Injury 2014;45(9):1394–1400.
56. Schnuriger B, Inaba K, Konstantinidis A, et al. Outcomes of proximal versus distal splenic artery
embolization after trauma: a systematic review and meta-analysis. J Trauma 2011;70(1):252–260.
57. Haan JM, Biffl W, Knudson MM, et al. Splenic embolization revisited: a multicenter review. J
Trauma 2004;56(3):542–547.
58. Toutouzas KG, Velmahos GC, Kaminski A, et al. Leukocytosis after posttraumatic splenectomy: a
physiologic event or sign of sepsis? Arch Surg 2002;137(8):924–928; discussion 928–929.
684
booksmedicos.org
59. Demetriades D, Scalea TM, Degiannis E, et al. Blunt splenic trauma: splenectomy increases early
infectious complications: a prospective multicenter study. J Trauma Acute Care Surg
2012;72(1):229–234.
60. Howdieshell TR, Heffernan D, Dipiro JT. Surgical infection society guidelines for vaccination after
traumatic injury. Surg Infect (Larchmt) 2006;7(3):275–303.
61. Shatz DV, Romero-Steiner S, Elie CM, et al. Antibody responses in postsplenectomy trauma patients
receiving the 23-valent pneumococcal polysaccharide vaccine at 14 versus 28 days postoperatively.
J Trauma 2002;53(6):1037–1042.
62. Teh SH, Sheppard BC, Mullins RJ, et al. Diagnosis and management of blunt pancreatic ductal
injury in the era of high-resolution computed axial tomography. Am J Surg 2007;193(5):641–643;
discussion 643.
63. Bradley EL 3rd, Young PR Jr, Chang MC, et al. Diagnosis and initial management of blunt
pancreatic trauma: guidelines from a multiinstitutional review. Ann Surg 1998;227(6):861–869.
64. Ragozzino A, Manfredi R, Scaglione M, et al. The use of MRCP in the detection of pancreatic
injuries after blunt trauma. Emerg Radiol 2003; 10(1):14–18.
65. Kim HS, Lee DK, Kim IW, et al. The role of endoscopic retrograde pancreatography in the
treatment of traumatic pancreatic duct injury. Gastrointest Endosc 2001;54(1):49–55.
66. Keller MS, Stafford PW, Vane DW. Conservative management of pancreatic trauma in children. J
Trauma 1997;42(6):1097–1100.
67. Stringer MD. Pancreatic trauma in children. Br J Surg 2005;92(4):467–470.
68. Canty TG Sr, Weinman D. Management of major pancreatic duct injuries in children. J Trauma
2001;50(6):1001–1007.
69. Duchesne JC, Schmieg R, Islam S, et al. Selective nonoperative management of low-grade blunt
pancreatic injury: are we there yet? J Trauma 2008;65(1):49–53.
70. Subramanian A, Dente CJ, Feliciano DV. The management of pancreatic trauma in the modern era.
Surg Clin North Am 2007;87(6):1515–1532, x.
71. Recinos G, DuBose JJ, Teixeira PG, et al. Local complications following pancreatic trauma. Injury
2009;40(5):516–520.
72. Khan I, Bew D, Elias DA, et al. Mechanisms of injury and CT findings in bowel and mesenteric
trauma. Clin Radiol 2014;69(6):639–647.
73. Brofman N, Atri M, Hanson JM, et al. Evaluation of bowel and mesenteric blunt trauma with
multidetector CT. Radiographics 2006;26(4):1119–1131.
74. Kim HC, Yang DM, Kim SW, et al. Gastrointestinal tract perforation: evaluation of MDCT according
to perforation site and elapsed time. Eur Radiol 2014;24(6):1386–1393.
75. Asensio JA, Demetriades D Berne JD, et al. A unified approach to the surgical exposure of
pancreatic and duodenal injuries. Am J Surg 1997;174(1):54–60.
76. Velmahos GC, Kamel E, Chan LS, et al. Complex repair for the management of duodenal injuries.
Am Surg 1999;65(10):972–975.
77. Talving P, Nicol AJ, Navsaria PH. Civilian duodenal gunshot wounds: surgical management made
simpler. World J Surg 2006;30(4):488–494.
78. Velmahos GC, Constantinou C, Kasotakis G. Safety of repair for severe duodenal injuries. World J
Surg 2008;32(1):7–12.
79. Ordonez C, Garcia A, Parra MW, et al. Complex penetrating duodenal injuries: less is better. J
80. van der Wilden GM, Yeh D, Hwabejire JO, et al. Trauma Whipple: do or don’t after severe
pancreaticoduodenal injuries? An analysis of the National Trauma Data Bank (NTDB). World J Surg
2014;38(2):335–340.
81. Asensio JA, Petrone P, Roldan G, et al. Pancreaticoduodenectomy: a rare procedure for the
management of complex pancreaticoduodenal injuries. J Am Coll Surg 2003;197(6):937–942.
82. Cogbill TH, Moore EE, Feliciano DV, et al. Conservative management of duodenal trauma: a
multicenter perspective. J Trauma 1990;30(12):1469–1475.
83. Demetriades D. Colon injuries: new perspectives. Injury 2004;35(3):217–222.
84. Greer LT, Gillern SM, Vertrees AE. Evolving colon injury management: a review. Am Surg
685
booksmedicos.org
2013;79(2):119–127.
85. Steele SR, Maykel JA, Johnson EK. Traumatic injury of the colon and rectum: the evidence vs
dogma. Dis Colon Rectum 2011;54(9):1184–1201.
86. Sasaki LS, Allaben RD, Golwala R, et al. Primary repair of colon injuries: a prospective randomized
study. J Trauma 1995;39(5):895–901.
87. Chappuis CW, Frey DJ, Dietzen CD, et al. Management of penetrating colon injuries. A prospective
randomized trial. Ann Surg 1991;213(5):492–497; discussion 497–498.
88. Stewart RM, Fabian TC, Croce MA, et al. Is resection with primary anastomosis following
destructive colon wounds always safe? Am J Surg 1994;168(4):316–319.
89. Murray JA, Demetriades D, Colson M, et al. Colonic resection in trauma: colostomy versus
anastomosis. J Trauma 1999;46(2):250–254.
90. Pasquale M, Fabian TC. Practice management guidelines for trauma from the Eastern Association
for the Surgery of Trauma. J Trauma 1998;44(6):941–956; discussion 956–957.
91. Demetriades D, Murray JA, Chan L, et al. Penetrating colon injuries requiring resection: diversion
or primary anastomosis? An AAST prospective multicenter study. J Trauma 2001;50(5):765–775.
92. Demetriades D, Murray JA, Chan LS, et al. Handsewn versus stapled anastomosis in penetrating
colon injuries requiring resection: a multicenter study. J Trauma 2002;52(1):117–121.
93. Demetriades D, Charalambides D. Gunshot wounds of the colon: role of retained bullets in sepsis. Br
J Surg 1993;80(6):772–773.
94. Curran TJ, Borzotta AP. Complications of primary repair of colon injury: literature review of 2,964
cases. Am J Surg 1999;177(1):42–47.
95. Park JJ, Del Pino A, Orsay CP, et al. Stoma complications: the Cook County Hospital experience.
Dis Colon Rectum 1999;42(12):1575–1580.
96. Berne JD, Velmahos GC, Chan LS, et al. The high morbidity of colostomy closure after trauma:
further support for the primary repair of colon injuries. Surgery 1998;123(2):157–164.
97. Herzig DO. Care of the patient with anorectal trauma. Clin Colon Rectal Surg 2012;25(4):210–213.
98. Johnson EK, Steele SR. Evidence-based management of colorectal trauma. J Gastrointest Surg
2013;17(9):1712–1719.
99. Velmahos GC, Gomez H, Falabella A, et al. Operative management of civilian rectal gunshot
wounds: simpler is better. World J Surg 2000;24(1):114–118.
100. Steinig JP, Boyd CR. Presacral drainage in penetrating extraperitoneal rectal injuries: is it
necessary? Am Surg 1996;62(9):765–767.
101. Gonzalez RP, Falimirski ME, Holevar MR. The role of presacral drainage in the management of
penetrating rectal injuries. J Trauma 1998;45(4):656–661.
102. Navsaria PH, Graham R, Nicol A. A new approach to extraperitoneal rectal injuries: laparoscopy
and diverting loop sigmoid colostomy. J Trauma 2001;51(3):532–535.
103. Navsaria PH, Shaw JM, Zellweger R, et al. Diagnostic laparoscopy and diverting sigmoid loop
colostomy in the management of civilian extraperitoneal rectal gunshot injuries. Br J Surg
2004;91(4):460–464.
104. Navsaria PH, Edu S, Nicol AJ. Civilian extraperitoneal rectal gunshot wounds: surgical management
made simpler. World J Surg 2007;31(6):1345–1351.
105. Levine JH, Longo WE, Pruitt C, et al. Management of selected rectal injuries by primary repair. Am
J Surg 1996;172(5):575–578; discussion 578–579.
106. McGrath V, Fabian TC, Croce MA, et al. Rectal trauma: management based on anatomic
distinctions. Am Surg 1998;64(12):1136–1141.
107. Franko ER, Ivatury RR, Schwalb DM. Combined penetrating rectal and genitourinary injuries: a
challenge in management. J Trauma 1993;34(3):347–353.
686
booksmedicos.org
Chapter 26
Genitourinary Trauma
Hunter Wessells
Key Points
1 Upper urinary tract injury is an infrequent result of trauma and the majority result from blunt
mechanism.
2 Renal injury after blunt trauma requires further evaluation for all cases of gross hematuria; cases of
microscopic hematuria associated with an episode of hypotension in adults; significant microscopic
hematuria in children.
3 Renal imaging is required with any degree of hematuria after penetrating trauma.
4 Most renal injuries are managed nonoperatively, with indications for exploration being symptomatic
renal hemorrhage causing hypotension, expanding or pulsatile retroperitoneal hematoma at
laparotomy, and grade V injury.
5 Ureteral injuries due to external violence are rare and require CT imaging or direct exploration;
missed injuries are common due to lack of consistent physical findings.
6 Injuries to the bladder require prompt diagnosis and catheter drainage, with intraperitoneal and
complicated extraperitoneal injuries necessitating surgical repair.
7 Initial management of urethral injuries varies based on location (anterior vs. posterior) and severity,
the most severe requiring urinary diversion with suprapubic cystostomy.
8 Immediate repair of urethral injuries in patients with complex pelvic fractures is not standard of
care, and early endoscopic realignment should be undertaken only by a surgeon experienced with
this technique.
The incidence of trauma is rising and the World Health Organization estimates that without change or
intervention, road traffic injuries will be the sixth leading cause of death by the year 2020 worldwide.1
Based on U.S. Census data, we estimate that 15,000 persons would sustain renal injuries requiring
hospital evaluation annually. The number of bladder and urethral injuries is estimated between 5,000
and 10,000. While injuries to the genitourinary system as a whole are rarely life threatening, the
potential morbidity is high and resultant effects on quality of life are marked. Genitourinary injuries
have predictable clinical presentations, and imaging modalities have improved our ability to identify
and treat these injuries. We review the fundamental principles guiding the evaluation and treatment of
genitourinary trauma, including the American Urological Association Practice Guidelines on Urotrauma.2
This recent publication incorporates a rigorous evidence review and standardized approach to guideline
development.
UPPER URINARY TRACT INJURY

Kidney
Injury to the upper urinary tract (kidney, ureter) is rare following trauma, with an incidence of renal
injury of 4.89 per 100,000 persons.3 Recognizing the factors that predispose to urinary tract injury
facilitates early diagnosis and management, which is associated with improved outcomes. The majority
of blunt traumatic injury is the result of motor vehicle collision, with fall and motor vehicle–pedestrian
collision being second and third, respectively. Penetrating injury predominantly is due to firearm and
less often stab wound.3 Findings on physical examination concerning significant renal injury include rib
fracture, significant flank ecchymosis, and penetrating wounds of the abdomen, flank, or lower chest.2
Anatomically, the kidneys lie in the retroperitoneum, surrounded by the ribcage, retroperitoneal fat,
perirenal fat within Gerota capsule, and overlying viscera (right: liver, colon, duodenum, and adrenal;
687
booksmedicos.org
left: spleen, colon, adrenal, and pancreas). Injury may occur as a result of interaction of the surrounding
“protective” bony and soft tissue structures with the kidney.4 The collecting system begins within the
kidney, forms the renal pelvis and concentrically narrows at the ureteropelvic junction (UPJ) to become
the ureter. The ureter then traverses the retroperitoneum inferiorly, protected by retroperitoneal fat
and the psoas muscle. After crossing over the common iliac vessels, the ureter descends into the pelvis,
coursing caudad to the base of the bladder, entering the trigone obliquely at the ureterovesical junction
(UVJ).
1 Hematuria is the most sensitive clinical sign of renal injury, yet the degree does not predict injury
severity (an algorithm for the evaluation and management of renal trauma is shown in Algorithm 26-1).
Clinicians should perform diagnostic imaging with intravenous (IV) contrast-enhanced computed
tomography (CT) to identify significant renal injuries in blunt trauma patients with (1) gross hematuria
or (2) microscopic hematuria, and any recorded systolic blood pressure <90 mm Hg.2 Penetrating
injuries with any degree of hematuria or a trajectory in proximity to the kidney also require imaging if
the patient is hemodynamically stable. Imaging decisions in hemodynamically unstable patients require
close coordination with the trauma surgery team and are beyond the scope of this chapter (see similar
chapter on GSW to abdomen). CT provides the most accurate staging of upper urinary tract injuries and
corresponds closely with the American Association for the Surgery of Trauma (AAST) Organ Injury Scale
(OIS) (Table 26-1, Fig. 26-1).5 The scan consists of early venous phase contrast-enhanced images,
detecting intravascular contrast extravasation (ICE), renal parenchymal perfusion and integrity, and
perinephric and retroperitoneal hematoma. Delayed (5 to 10 minutes) imaging is essential for
identifying the collecting system injury (urinary extravasation, hydronephrosis) and ureteral continuity
to the bladder. The use of intravenous urography to stage injuries is limited because of lower accuracy
for clinical staging.2,6 Focused abdominal ultrasound for trauma (FAST) is used primarily to detect
intraperitoneal bleeding in unstable blunt trauma patients; its use for detecting urologic injury is
inferior to CT.7–9 Renal arterial angiography should not be used diagnostically, but therapeutically is
indicated to treat isolated, symptomatic (early or late) renal bleeding, arteriovenous fistula, or
pseudoaneurysm using embolization.10
688
booksmedicos.org
Algorithm 26-1. Algorithm for the evaluation and management of renal injury.
2 Grade I and II injuries rarely require further management. The bulk of blunt grade III and
nonvascular grade IV injuries should be managed nonoperatively, whereas only selected penetrating
injuries in hemodynamically stable patients can be managed on observation protocols.11,12 Lacerations
with associated collecting system injury (i.e., grade IV) can initially be managed with observation,
although a subset of patients will require ureteral stenting due to persistent urinary extravasation. A
proposed modification to the AAST OIS stratifies major renal lacerations into “high risk” and “low risk”
based on the likelihood of intervention for hemodynamic instability.13 The CT imaging criteria of ICE,
medial parenchymal laceration, and perirenal hematoma rim distance >3.5 cm have been validated to
predict the need for intervention and may lead to further refinement in nonoperative management.14
3 The surgical team must perform immediate intervention (surgery or angioembolization in selected
situations) in hemodynamically unstable patients with no or transient response to resuscitation.2
Unstable patients will usually be found to have an expanding or pulsatile retroperitoneal hematoma at
laparotomy, and occasionally have hilar injury or pedicle avulsion. In patients undergoing laparotomy
for concomitant intraperitoneal injuries, exploration should only be considered judiciously for grade III
or IV renal injury due to higher rates of nephrectomy under such circumstances.15 If renal exploration is
contemplated or necessary, demonstration of contralateral renal function is important in the event of
ipsilateral nephrectomy. This can be achieved by manual palpation or preferably by intraoperative
single-shot intravenous urogram (KUB 10 minutes following intravenous injection of 2 mL/kg
contrast).6 Reasons for failure to demonstrate contrast excretion from the contralateral kidney may
indicate solitary kidney, hilar injury, hypoperfusion, or global renal insufficiency secondary to chronic
renal disease. Exploration of a solitary kidney should be performed only when absolute indications
exist.
689
booksmedicos.org
Table 26-1 American Association for the Surgery of Trauma Organ Injury Scale
The kidney and upper urinary tract are accessed through a midline abdominal incision, and the author
obtains preliminary isolation of the renal vessels before renal exploration. Using the inferior mesenteric
vein (IMV) as a landmark, a posterior peritoneal window is created medial to the IMV overlying the
aorta, which allows access, dissection, and control of the proximal renal vasculature.16 When immediate
nephrectomy is required, reflection of the right or left colon provides rapid access to the renal hilum.17
If this method is employed, manual compression followed by vascular clamping may be required. Renal
cooling is not routinely employed due to time constraints and potential for worsening hypothermia.
Once Gerota fascia is exposed and open, the kidney can be freed of its associated perinephric fat. The
capsule of the kidney is routinely preserved for closure following renal reconstruction. During renal
exploration, sharp debridement, hemostasis, collecting system repair, and bolstered closure of the renal
capsule using absorbable suture is performed. A perinephric suction drain is placed away from the repair
in the retroperitoneum and removed when drainage subsides, usually less than 50 mL/day. If concern
exists as the nature of the drainage, an aliquot of fluid can be sent for creatinine concentration to
evaluate for the presence of urine.
In the case of renal artery thrombosis, surgical revascularization is rarely helpful because of the time
delay from injury to revascularization. Intervention is commonly limited to patients with solitary
kidney or bilateral injuries.5 An emerging therapy is vascular stent placement across the injury or
thrombosis; however, most series are limited and results mixed.18 Venous injuries often result in
massive bleeding and may require nephrectomy. Isolated proximal left renal vein injuries can
potentially be managed by ligation of the renal vein because collateral drainage is present via the
gonadal, adrenal, and lumbar veins. Right renal venous injury requires repair, if feasible, or
nephrectomy due to lack of collateral circulation.
Clinicians should perform follow-up imaging for renal trauma patients with deep lacerations (AAST
grades III, IV, and V) and clinical signs of complications (e.g., fever, worsening flank pain, ongoing
blood loss, and abdominal distention).2 CT best delineates delayed bleeding, persistent urinary
extravasation, urinoma, and infection.5 Secondary bleeding after nonoperative or surgical repair, which
usually is caused by a pseudoaneurysm, should be managed angiographically. Ureteral stenting or
percutaneous drainage is indicated for persistent leak or abscess. Late complications are uncommon and
include renin-mediated hypertension from chronic renal ischemia, arteriovenous malformations, and
690
booksmedicos.org
segmental arteriolar pseudoaneurysm.
Ureter
Ureteral injuries are rare (1%), with fewer than 10 presenting annually in busy trauma centers.19 These
injuries often present without clear signs or symptoms, and many are missed at the initial assessment
(an algorithm for the evaluation and management of ureteral trauma is shown in Algorithm 26-2).
Clinicians should perform IV contrast-enhanced abdominal/pelvic CT with delayed imaging for stable
trauma patients with suspected ureteral injuries.2 In the adult population, gunshot wounds followed
distantly by stab wounds are the most frequent source of injury associated with external violence.20,21
4 Injury should be suspected when organs anatomically related to the ureter sustain injury: iliac vessels,
bladder, colon, and lumbar spine or transverse processes. Significant deceleration and hyperextension
mechanisms can result in ureteral avulsion as well. In children, the avulsion injury occurs at the UPJ
due to increased hyperextensibility of the spine.
Figure 26-1. Grading of renal injury by computed tomography. A: Grade I, contusion; B: Grade II; C: Grade III; D: Grade IV,
contrast extravasation; E: Grade V, devascularized.
Anatomically, the ureters begin posterior to the renal hilum at the UPJ. They course inferiorly
through the retroperitoneum, along the anterior aspect of the psoas muscle. Upon entering the pelvis,
the ureters run behind the gonadal vessels before crossing over the iliac vessels. Finally, the ureters
continue caudally, and enter the inferior aspect of the bladder obliquely. The blood supply is segmental
691
booksmedicos.org
and arises from the adjacent anatomic structures within the retroperitoneum and pelvis (proximal-
lateral, mid/true pelvis-medial, and inferior-posteriolateral).
Often, patients with penetrating ureteral injuries undergo surgical exploration for associated injuries.
Surgeons should directly inspect the ureters during laparotomy in patients with suspected ureteral injury
who have not had preoperative imaging.2 Traumatic ureteral contusions are best managed at the time of
laparotomy with ureteral stenting or resection and primary repair depending on ureteral viability and
clinical scenario.2
Algorithm 26-2. Algorithm for the evaluation and management of ureteral injury.
Surgeons should repair traumatic ureteral lacerations at the time of laparotomy in stable patients.2
Debridement as indicated precedes ureter reconstruction, and the level and length of ureteral defect
dictates the type of repair (Fig. 26-2). UPJ disruptions require formal reconstruction by reanastomosis
or ureteropyelostomy. For injuries occurring in the proximal to midureter without associated renal
injury, simple mobilization of the colon without hilar control can be used to expose the ureters. Short
upper and midureteral injuries are repaired by primary repair or spatulated reanastomosis over a stent,
whereas low pelvic ureteric injuries are repaired by ureteroneocystostomy (Fig. 26-3). A refluxing
implant is acceptable in children and adults.
When patients are hemodynamically unstable, surgeons should elect temporary urinary drainage
followed by delayed definitive management.2 Damage control techniques for urinary diversion include
debridement, drainage of the bladder and retroperitoneum, cutaneous ureterostomy diversion with a
feeding tube, or ligation of the ureter with percutaneous nephrostomy tube placement.
Patients presenting with a delay in diagnosis often have symptoms of fever, flank pain, fullness,
tenderness, atelectasis, or oliguria as a result of urinoma, hematoma, or abscess.19 Operative
intervention at the time of delayed diagnosis can result in nephrectomy. Therefore, management
options include ureteral stenting, nephrostomy tube placement, percutaneous urinoma drainage, and
Foley catheter insertion. Reconstruction is planned at 3 to 6 months to allow for resolution of
periureteral inflammation. Long-term complications of unrecognized ureteral injury include fistula, fluid
collections, ureteral stricture, and obstructive uropathy.
692
booksmedicos.org
Figure 26-2. Ureteral reconstruction by location of injury.
693
booksmedicos.org
Figure 26-3. Techniques of ureteral repair. A: End-to-end ureteroureterostomy; B: Vesicopsoas hitch reconstruction with
reimplantation performed by suturing of the bladder to psoas tendon after mobilization; C: Boari flap performed using a
tubularized bladder flap based on the ipsilateral superior vesical artery; D: Transureterureterostomy (TUU). For all repairs the
principles include tension free, watertight, stented, spatulated, mucosa-to-mucosa anastomosis using absorbable suture with drain
placement.
Individuals who have sustained major injury to the ureter require follow-up imaging in the form of
renal ultrasonography, radionuclide scanning or CT urography to evaluate for development of stricture
or fistula.19 Interval ultrasound to evaluate for urinoma or abscess is an acceptable imaging modality
and limits radiation exposure.
LOWER URINARY TRACT INJURY

Bladder
Blunt trauma accounts for the majority of bladder injuries, with penetrating mechanisms comprising the
remainder.22 Pelvic fractures are frequently associated with lower urinary tract injuries, although only 5
to 10% of pelvic fractures result in bladder injury.23 In pelvic fracture two mechanisms predominate as
causes of bladder injury, usually resulting in extraperitoneal rupture. The first involves shearing forces
at deceleration resulting in injury at the fixed sites of pelvic fascial attachment. The second mechanism
involves direct injury from pelvic bone fragments causing laceration of the bladder. Intraperitoneal
blunt injury is due to rapid deceleration creating a rapid rise in intravesical pressure resulting in a
“burst”-type injury. Extraperitoneal injuries account for 54% to 55% of bladder injuries, intraperitoneal
injuries are 38% to 40%, and combined injuries account for 5% to 8%.24 In the pediatric population, a
larger proportion of injuries are intraperitoneal because of the relative intra-abdominal location of the
bladder. However, the overall incidence is lower. The incidence of pelvic fracture is also lower in
children, but, in contradistinction to adults, bladder neck injuries are more common in boys with a
pelvic crush injury rather than urethral injuries as seen in adults.25
Gross hematuria is a reliable sign occurring in 95% of patients with bladder injury. Imaging must be
performed in the setting of gross hematuria and pelvic fracture, and should be performed when
mechanism suggests injury or in the face of pelvic ring fractures and clinical indicators of bladder
rupture (i.e. >30 RBC/hpf on urinalysis or physical findings).2,26 Isolated acetabular fractures without
pelvic ring involvement do not need cystography without other indications.26
Acutely, patients presenting with bladder injury may complain of inability to void or suprapubic pain,
although these symptoms may be masked by pain from more significant injuries.22 With delayed
presentation, frequent symptoms are abdominal distension, ileus, fever, or urinary ascites as a result of
persistent leakage, pelvic urinoma, or abscess formation. Laboratory analysis demonstrates acidosis,
hyperkalemia, hyperchloremia, hypernatremia, and uremia with intraperitoneal bladder injuries.
Particular attention is paid to thorough evaluation of the lower urinary tract for concurrent injury,
because of the frequency of these injuries with pelvic fracture. Penetrating and iatrogenic trauma to the
pelvis or perineum generally results in associated visceral, urethral, or genital injuries, but without
bony disruption.27
Imaging of the bladder, if indicated, consists of retrograde cystography, and is performed in the
clinically stable patient. For CT cystography, the bladder is filled retrograde with contrast and the scan
is performed after 300- to 400-mL contrast is instilled. Static cystography remains an acceptable means
of assessing for bladder rupture. Extraperitoneal contrast extravasation is confined to the pelvis on CT
and appears as a “flame-shaped” opacity on static cystography (Fig. 26-4). Characteristic patterns of
intraperitoneal contrast extravasation include pooling in the cul-de-sac, paracolic gutter, or retrohepatic
space on CT or outlining of bowel loops on static cystography (Fig. 26-5).
694
booksmedicos.org
Figure 26-4. CT cystography for intraperitoneal bladder injury.
Figure 26-5. CT cystography for extraperitoneal bladder injury.
5, 6 Surgeons must perform surgical repair of intraperitoneal bladder rupture in the setting of blunt
or penetrating external trauma.2 The size of these ruptures generally precludes nonoperative
approaches. Uncomplicated extraperitoneal bladder injuries should be managed with catheter drainage.
Surgeons should perform surgical repair in patients with complicated extraperitoneal bladder injury.
These are considered complex in the following circumstances2: exposed bone spicules in the bladder
lumen; rectal or vaginal lacerations; and bladder neck injuries. In the case of open reduction internal
fixation of pelvic fracture or repair of abdominal injuries, clinicians should perform bladder repair.
Bladder exploration includes assessment of the bladder wall, bladder neck, and ureteral orifices,
which are inspected through an anterior cystotomy or the laceration/injury itself. Sites of injury are
closed in a two-layer running fashion using 2-0 synthetic absorbable suture. Urethral catheter drainage
is sufficient in most cases.2 Suprapubic catheter diversion is reserved for extensive bladder injuries in
which ongoing bleeding or complex repairs require additional drainage. Closed suction drains are placed
away from the site of repair and can be removed in 48 hours unless the drainage fluid demonstrates a
creatinine level higher than serum. The urethral catheter is left in place for 7 to 10 days and removed
following cystogram demonstrating a healed, watertight repair.
Urethra
The anatomy of the urethra varies throughout its course and is divided for practical purposes into the
anterior and posterior segments (Fig. 26-6). The type of injury varies depending on the segment, but
most commonly is due to blunt mechanism. Anterior urethral injuries are the result of straddle-type falls
or blows to the perineum. Posterior urethral injuries are often associated with pelvic fracture and
involve varying degrees of prostatomembranous distraction.28 Female urethral injuries are uncommon
and are usually associated with pelvic fracture.29 Gross blood at the urethral meatus in males is the most
reliable sign and warrants evaluation for injury (an algorithm for the evaluation and management of
urethral trauma is shown in Algorithm 26-3). Further examination includes digital rectal examination
evaluating for hematoma, bony spicules, hemoccult blood, or a “high-riding prostate.” These findings on
examination and the presence of perineal ecchymosis or scrotal hematoma suggest anterior pelvic
disruption and urethral injury. Females with vaginal bleeding and pelvic fracture should be evaluated
for gynecologic as well as urethral injuries.
7 Clinicians should perform retrograde urethrography (RUG) in patients with blood at the urethral
meatus after pelvic trauma.2,30 RUG is readily performed using portable fluoroscopy in the emergency
695
booksmedicos.org
department or operating room. The fossa navicularis is occluded with the partially filled (2- to 3-mL)
balloon tip of a Foley catheter, the penis is stretched, and contrast is gently injected to opacify the
urethra. Oblique images are taken, when possible, to establish the absence of or the presence and
location of extravasation, which is indicative of injury. If no extravasation is present, the catheter is
advanced into the bladder. Clinicians should establish prompt urinary drainage in patients with pelvic
fracture urethral injury.2 Initial management involves urinary diversion with suprapubic cystostomy.
Figure 26-6. Urethral Injury. Normal retrograde urethrogram and urethral injury management by segment and mechanism of
injury.
Clinicians may perform primary realignment in hemodynamically stable patients with pelvic fracture
urethral injury.2 Techniques of early endoscopic realignment show promise in potentially decreasing
rates of stricture formation while providing equivalent results with regard to continence and erectile
dysfunction.31,32 Early realignment is achieved employing endoscopes and fluoroscopy, then placing a
catheter, by Seldinger technique, over a guidewire. Clinicians should not perform prolonged attempts at
endoscopic realignment in patients with pelvic fracture urethral injury.2 Whether a patient receives a
suprapubic cystostomy or a urethral catheter as drainage, an appropriate plan of follow-up for tube
changes, removals, and definitive reconstructive efforts is imperative, due to potential morbidities
including infection, encrustation, hematuria, stricture and obstructive uropathy.
8 Anterior urethral injuries can be divided into blunt straddle-type injury and penetrating
mechanisms. Surgeons should perform prompt surgical repair in patients with uncomplicated
penetrating trauma of the anterior urethra.2 In contrast, clinicians should establish prompt urinary
drainage, usually via suprapubic cystostomy in patients with straddle injury to the anterior urethra.2
Similarly, high-velocity injuries should be managed with suprapubic cystostomy and delayed
reconstruction.30
696
booksmedicos.org
Algorithm 26-3. Algorithm for the evaluation and management of urethral injury.
References
1. Peden M, et al. World Report on Road Traffic Injury Prevention. Geneva, Switzerland: World Health
Organization; 2004.
2. Morey AF, Brandes S, Dugi DD 3rd, et al. Urotrauma: AUA Guidelines. J Urol 2014;192(2):327–335.
3. Wessells H, Suh D, Porter JR, et al. Renal injury and operative management in the United States:
results of a population-based study. J Trauma 2003;54(3):423–430.
4. Snedeker JG, Barnstuble BB, Iaizzo PA, et al. A comprehensive renal injury concept based on a
validated finite element model of the human abdomen. J Trauma 2007;62(5):1240–1249.
5. Santucci RA, Wessells H, Bartsch G, et al. Evaluation and management of renal injuries: consensus
statement of the renal trauma subcommittee. BJU Int 2004;93(7):937–954.
6. Morey AF, McAninch JW, Tiller BK, et al. Single shot intraoperative excretory urography for the
immediate evaluation of renal trauma. J Urol 1999; 161(4):1088–1092.
7. McGahan JP, Richards JR, Jones CD, et al. Use of ultrasonography in the patient with acute renal
trauma. J Ultrasound Med 1999;18(3):207–213; quiz 215–216.
8. Perry MJ, Porte ME, Urwin GH. Limitations of ultrasound evaluation in acute closed renal trauma.
J R Coll Surg Edinb 1997;42(6):420–422.
9. Körner M, Krötz MM, Degenhart C, et al. Current role of emergency US in patients with major
trauma. Radiographics 2008;28(1):225–242.
10. Hotaling JM, Sorensen MD, Smith TG 3rd, et al. Analysis of diagnostic angiography and
angioembolization in the acute management of renal trauma using a national data set. J Urol
2011;185(4):1316–1320.
11. Hammer CC, Santucci RA. Effect of an institutional policy of nonoperative treatment of grades I to
IV renal injuries. J Urol 2003;169(5):1751–1753.
12. Wessells H, McAninch JW, Meyer A, et al. Criteria for nonoperative treatment of significant
penetrating renal lacerations. J Urol 1997;157(1):24–27.
697
booksmedicos.org
13. Dugi DD 3rd, Morey AF, Gupta A, et al. American Association for the Surgery of Trauma grade 4
renal injury substratification into grades 4a (low risk) and 4b (high risk). J Urol 2010;183(2):592–
597.
14. Figler B, Malaeb BS, Voelzke B, et al. External validation of a sub-stratification of the American
Association for the Surgery of Trauma renal injury scale for grade IV injuries. J Am Coll Surg
2013;217(5):924–928.
15. Wright J, Nathens AB, Rivara FP, et al. Renal and extrarenal predictors of nephrectomy from the
national trauma data bank. J Urol 2006;175(3 Pt 1):970–975; discussion 975.
16. Carroll PR, Klosterman P, McAninch JW. Early vascular control for renal trauma: a critical review.
J Urol 1989;141(4):826–829.
17. Gonzalez RP, Falimirski M, Holevar MR, et al. Surgical management of renal trauma: is vascular
control necessary? J Trauma 1999;47(6):1039–1042; discussion 1042–1044.
18. Lopera JE, Suri R, Kroma G, et al. Traumatic occlusion and dissection of the main renal artery:
endovascular treatment. J Vasc Interv Radiol 2011;22(11):1570–1574.
19. Brandes S, Coburn M, Armenakas N, et al. Diagnosis and management of ureteric injury: an
evidence-based analysis. BJU Int 2004;94(3):277–289.
20. Elliott SP, McAninch JW. Ureteral injuries from external violence: the 25-year experience at San
Francisco General Hospital. J Urol 2003;170(4 Pt 1):1213–1216.
21. Perez-Brayfield MR, Keane TE, Krishnan A, et al. Gunshot wounds to the ureter: a 40-year
experience at Grady Memorial Hospital. J Urol 2001; 166(1):119–121.
22. Gomez RG, Ceballos L, Coburn M, et al. Consensus statement on bladder injuries. BJU Int
2004;94(1):27–32.
23. Brandes S, Borrelli J Jr. Pelvic fracture and associated urologic injuries. World J Surg
2001;25(12):1578–1587.
24. Corriere JN Jr, Sandler CM. Diagnosis and management of bladder injuries. Urol Clin North Am
2006;33(1):67–71, vi.
25. Tarman GJ, Kaplan GW, Lerman SL, et al. Lower genitourinary injury and pelvic fractures in
pediatric patients. Urology 2002;59(1):123–126; discussion 126.
26. Avey G, Blackmore CC, Wessells H, et al. Radiographic and clinical predictors of bladder rupture in
blunt trauma patients with pelvic fracture. Acad Radiol 2006;13(5):573–579.
27. Franko ER, Ivatury RR, Schwalb DM. Combined penetrating rectal and genitourinary injuries: a
challenge in management. J Trauma 1993;34(3):347–353.
28. Basta AM, Blackmore CC, Wessells H. Predicting urethral injury from pelvic fracture patterns in
male patients with blunt trauma. J Urol 2007;177(2):571–575.
29. Black PC, Miller EA, Porter JR, et al. Urethral and bladder neck injury associated with pelvic
fracture in 25 female patients. J Urol 2006;175(6):2140–2144; discussion 2144.
30. Chapple C, Barbagli G, Jordan G, et al. Consensus statement on urethral trauma. BJU Int 2004;
93(9):1195–1202.
31. Mouraviev VB, Coburn M, Santucci RA. The treatment of posterior urethral disruption associated
with pelvic fractures: comparative experience of early realignment versus delayed urethroplasty. J
Urol 2005;173(3):873–876.
32. Leddy L, Dhakad U. Outcomes of endoscopic realignment of pelvic fracture associated urethral
injuries at a level 1 trauma center. J Urol 2012;188(1):174–178.
698
booksmedicos.org
Chapter 27
Vascular Trauma
Adriana Laser, Shahab Toursavadkohi, and Todd E. Rasmussen
Key Points
1 Vascular disruption and hemorrhage is a leading cause of mortality and morbidity in the civilian and
military setting.
2 Vascular injuries are categorized as occurring from either blunt or penetrating mechanisms.
3 Motor vehicle crashes are the main cause of blunt vascular trauma in the civilian setting.
4 Examining the patient is the most important step in evaluation of suspected vascular injury.
5 Hard signs of vascular injury suggest near or complete disruption of the vessel in question and
include pulsatile bleeding, expanding hematoma, palpable thrill, audible bruit, and or evidence of
acute ischemia distal to the injury site.
6 Contrast-enhanced computed tomography angiography (CTA) is the most available and common
imaging modality used in the emergency setting including the evaluation of patients suspected of
having vascular trauma.
7 In the trauma patient, hemorrhage leads to both the overall metabolic consequences of total-body
ischemia and end-organ ischemia of the specific injured vessel.
8 Damage control resuscitation involves allowing permissive hypotension with a goal of a palpable
radial pulse (in patients without head injury).
9 Elevated fascial compartment pressures can be due to reperfusion, hematoma, swelling from crush
injury, or major fractures.
10 When discussing neck trauma, there are three regions classically used to describe anatomic location.
Zone I is below the cricoid cartilage, zone II is between the cricoid cartilage and the angle of the
mandible, whereas zone III is above the angle of the mandible.
11 Control of bleeding from vascular disruption within the torso is not readily amenable to control with
direct pressure and is therefore referred to as noncompressible torso hemorrhage.
12 Proximal and distal control is essential when managing suspected vascular injury.
BACKGROUND
1 Vascular disruption and hemorrhage is a leading cause of mortality and morbidity in the civilian and
military setting.1–3 Because of their proximate anatomic nature, arterial and venous injuries often occur
in conjunction with one another and are often associated with injury to other vital structures. To
optimally manage scenarios in which there is suspicion for vascular injury or cases in which clear
evidence of vascular disruption exists, it is necessary to possess an understanding of the epidemiology
and anatomic distribution of this injury pattern, considerations associated with different mechanisms
and key tenants of diagnosis and management. The objective of this chapter is to familiarize the reader
with current knowledge pertaining to the topic of vascular trauma including commonality of the
problem, circumstances in which vascular injury occurs, and different approaches to diagnosis.
Additionally, this chapter will provide guidance on the management of different patterns of vascular
injury focusing on the categories of extremity, torso, and cervical.
EPIDEMIOLOGY AND MECHANISMS OF VASCULAR TRAUMA

The epidemiology of vascular trauma can be broadly categorized into contextual circumstances (military
and civilian), mechanism of injury (iatrogenic, blunt, penetrating, blast, and combination injuries), and
anatomical site or location of injury (extremity, torso, and junctional).
699
booksmedicos.org
Wartime Vascular Injury
Contemporary data confirm that exsanguination is the major cause of death in wounded service
personnel and that the prevalence of wartime vascular trauma seems to have increased markedly over
the past century (Figs. 27-1 and 27-2).1–3 Estimates from allied surgeons in World War I (WWI)
suggested overall vascular trauma rates of 0.4% to 1.3%.4 DeBakey characterized vascular injury burden
in World War II (WWII) as affecting 0.96% of all patients and for the Korean and Vietnam wars the rate
of vascular injury was judged to be slightly higher at 2% to 3%.4–6
Coalition militaries engaged in recent combat operations in Afghanistan and Iraq have reported rates
of vascular trauma higher than in the previously mentioned military campaigns.2,7–9 In a study reporting
US military experience, White and colleagues analyzed vascular cases entered in to the United States
Joint Theater Trauma Registry (JTTR) from 2002 to 2009 (Fig. 27-2).2 Defining the denominator as
battle-related injuries sufficiently severe to prevent return to duty in the combat theater, the specific
incidence of vascular injury (defined as the total incidence injury) was found to be 12% (1,570 of 13,076
cases). The incidence of injuries requiring an operation (defined as the operative incidence) was found to
be 9% (1,212 of 13,076 cases). Injuries were most common in the extremities (79%) followed by those
in the torso (12%) and cervical regions (8%). Of extremity vascular injuries two-thirds were
documented in the lower extremities (most commonly femoral artery) while one-third occurred in the
upper extremities (most commonly brachial artery).2 In the torso, the most frequently injured vessels
were the iliacs (3.8%) followed by the aorta (2.9%) and subclavian arteries (2.3%), and inferior vena
cava (IVC) (1.4%). In the neck, 109 carotid injuries accounted for 7% of the total.
Figure 27-1. The rate of vascular injury reported from the wars of the previous two centuries. (From White J, Stannard A,
Burkhardt GE, et al. The epidemiology of vascular injury in the wars in Iraq and Afghanistan. Ann Surg 2011;253(6):1184–1189.)
In the study by White and colleagues, it was noted that the vascular injury burden in the extremities
in Iraq and Afghanistan was similar to that noted in World War II, although the higher modern rate of
cervical and aortic injury was attributed to increased survivability and shortened medical evacuation
(MEDEVAC) times.2,8 Overall, the authors concluded that the rate of vascular injury in these modern
wars was five times that previously reported from Vietnam and Korea (Figs. 27-1 and 27-2). It is
important to note that many of these reports from the wars in Afghanistan and Iraq did not include
nonoperative cases and were generally confined to descriptions of vascular cases identified in the
theater of war. Other studies, including one by Fox and colleagues, document the rate of wartime
vascular injury from the perspective of military hospitals back in the United States, which also account
for injuries that were diagnosed in a delayed fashion (i.e., delayed presentation or diagnosis of fistula,
pseudoaneurysm or occlusion). In characterizing rates among patients having been evacuated to the
United States, Fox and colleagues9 described a 7% prevalence of vascular injury.
In a similar but smaller British study, Stannard and colleagues scrutinized records of 1,203 injured UK
servicemen between 2003 and 2008.7 Unlike the US JTTR, the British dataset also included patients who
were killed in action (KIA), that is those who died prior to reaching a treatment facility.7 In this study, it
was reported that 110 (9%) of the cohort sustained injuries to named vessels, of which more than two-
thirds had extremity vascular injuries. Blast wounds accounted for 54% and 76% of patients sustaining
torsocervical and extremity wounds, respectively. Some 66 of the 110 died before surgical intervention
could be undertaken, indicating the highly lethal nature of this wounding pattern. In particular, no
patient with a combination of vascular injuries affecting more than one body region (torso, extremity,
and cervical) survived to an operation.7 Cervical vascular injuries also proved lethal, with 13 of 17
patients succumbing. On the other hand, of 76 patients with extremity injuries, 37 survived to surgery
with one postoperative death. Interventions on 38 limbs included 19 damage control procedures (15
700
booksmedicos.org
primary amputations, 4 vessel ligations in a group with a median mangled extremity score of 9) and 19
definitive limb revascularization procedures (11 interposition vein grafts, 8 direct repairs), with a limb
salvage rate of 84%. This study concluded that while limb salvage is achievable in casualties able to
withstand revascularization, torso vascular injury is often not amenable to successful intervention.7
Figure 27-2. The rate of vascular injury reported during the wars in Afghanistan and Iraq. This specific rate refers to the 1,570 US
service personnel identified within the Department of Defence Joint Theater Trauma Registry (JTTR) as having sustained vascular
injury during the wars (between 2002 and 2009). Note that the overall rate of 12% is several-fold higher than the rate of vascular
injury reported in previous wars. (From White J, Stannard A, Burkhardt GE, et al. The epidemiology of vascular injury in the wars
in Iraq and Afghanistan. Ann Surg 2011;253(6):1184–1189.)
Civilian Population Vascular Trauma

The impact of vascular trauma in the civilian setting is less well characterized than that which occurs in
conjunction with combat-related activities. Most societies are not afforded large trauma-specific data
repositories or registries which allow characterization of this injury pattern. Even in the United States,
which is served by the National Trauma Data Bank® (NTDB®) large-scale studies are limited in number
and mostly retrospective. According to data from the National Center for Injury and Prevention, in 2011
in the United States, injuries accounted for 51.3% of all deaths among persons ages 1–44 years of age
which is more deaths than those caused by noncommunicable and infectious diseases combined.10 There
is a significant increase in the number of admissions for both general and vascular trauma as the number
of motor vehicle accidents increases and traffic density grows. Fatalities stem mainly from motor
vehicle accidents (32%), gunshot wounds (22%), and falls (9%). Vascular injuries represent 1% to 2% of
total trauma patients but they account for more than 20% of all trauma-related deaths and have the
highest utilization of resources among the trauma population.3
In 2010, Demetriades and colleagues characterized vascular injury in 22,089 patients, including
children, drawn from a population of more than 1.8 million in the NTDB®.11 Accepting reporting bias
that accompanies analysis of such retrospective data, it was determined that the incidence of vascular
injury (2002 to 2006) was 1.6%. Four-fifths of the injured were male and the average age was 34 years.
Half of the patients (51%) sustained a penetrating mechanism; the top 4 mechanisms of injury were
motor vehicle collisions, firearms, stab wounds, and falls. Just under a quarter of patients presented in
hemorrhagic shock and over half had an Injury Severity Score of more than 15.11 Abdominal and chest
injuries accounted for more than 25% and 24% of the injury burden, respectively, with arm and leg
injuries contributing 26% and 18%. Mortality among those with vascular trauma was 23% and vessels
associated with the highest rates of amputation were the axillary (upper limb amputation rate of 6%)
and popliteal arteries (lower limb amputation rate of 15%).11
In other reports of vascular trauma from civilian centers in New York and El Paso, the rates of injury,
in the context of all presenting to each trauma center, were 2.3% and 3.4%, respectively.12,13 These
reports confirm the “at-risk demographic” to be young and male and demonstrate that mortality in
those with vascular trauma is twice that of patients without this injury pattern. Not surprisingly,
penetrating mechanisms seem to be overrepresented in patients with vascular injury. The El Paso
authors reported that of patients with vascular injury, 40% had a penetrating mechanism whereas only
10% of those with nonvascular trauma were injured in such a manner.13 The largest single center study
of vascular trauma in the United States was published from Houston in 1988.3 This study encompassed a
30-year period, describing 5,760 injuries in 4,459 patients and confirmed that the burden of vascular
trauma was borne by young men (86% male gender of average age 30 years), 90% of whom had been
injured by firearms (gunshot 52%; shotgun 7%) or knives (31%).3 The Houston study also showed that
701
booksmedicos.org
the wounding pattern in civilian circumstances, even where ballistic penetrating injury is common, does
not follow that seen in wartime. Torso and neck injuries accounted for two-thirds of all injuries, while
lower extremity injuries (including the groin) comprised only 20%. Whereas very few soldiers with
injuries to the large vessels of the abdomen are seen by military surgeons, trauma to the abdominal
vasculature accounted for 34% of the injury cohort seen in Houston, a fact attributed to the maturation
of the city’s Emergency Medical Services.3
Mechanism of Vascular Trauma

2, 3 Vascular injuries are categorized as occurring from either blunt or penetrating mechanisms either
of which can disrupt, to varying degrees of severity, the normal integrity of the layers of the blood
vessel wall (intima, media, and adventitia). Blunt vascular trauma is produced by local tissue
compression and/or acceleration–deceleration resulting in disruptive shear forces. Motor vehicle crashes
are the main cause of blunt vascular trauma in the civilian setting and these patients usually have
injuries to other areas of the body including extremity fracture or dislocation, brain injury, and injury to
structures in the abdomen or thorax. Although a blunt mechanism is more commonly associated with
torso vascular injury (i.e., aortic disruption), this mechanism is also recognized to be associated with a
few specific extremity fracture or dislocation patterns near (e.g., posterior knee dislocation, tibial
plateau fracture and supracondylar fracture of humerus) is a common location for vascular disruption.
Penetrating mechanisms typically result in direct injury of the vessel(s) causing either laceration or
contusion of the wall as well as separation or destruction of soft tissues along the path of the object and
those directly surrounding the vessel. Penetrating vascular injury may result from simple, low-velocity
sharp objects (i.e., knife or glass), irregular fragments from explosives mechanism or higher velocity,
and uniform munitions fired from a weapon. For the later of these, damage to the vessel and
surrounding soft tissue often results from a concussive shockwave that is conducted through the tissues
as the object moves through the body dissipating energy. Unlike closed blunt injuries, which more
commonly affect torso vascular structures, penetrating injuries more commonly affect the extremity
vasculature, and this mechanism mandates management of the associated soft tissue wound.
DIAGNOSIS OF VASCULAR INJURY

Physical Examination
4 Examining the patient is the most important step in evaluation of suspected vascular injury.14,15 Most
vascular injuries can be diagnosed with this step if it is performed in an intentional manner, being
cognizant of the mechanism and while making use of a few enabling tools such as blood pressure
measurement, basic radiography, continuous wave Doppler, and ultrasound. The physical examination
should include exposing and palpating the extremities assessing for evidence of extremity fracture or
dislocation, penetrating soft tissue wound and/or hematoma. The extremity vascular examination
should also include assessment of distal perfusion, examining the appearance of the extremities, and
palpating for the presence of pulses. In addition to assessing for penetrating wounds, examination of the
abdomen and thorax (front and back) is important to identifying blood or fluid in these cavities with
palpation and auscultation. Similarly, the neck and cervical region should be examined for signs of
penetrating wounds, the presence of carotid pulses and/or bruising or hematoma.14,15
5 When considering physical evidence of vascular trauma, especially during in the extremities, it is
useful to categorize it into hard and soft signs. Hard signs of vascular injury suggest near or complete
disruption of the vessel in question and include pulsatile bleeding, expanding hematoma, palpable thrill,
audible bruit, and or evidence of acute ischemia distal to the injury site. Depending on the degree of
extremity ischemia, a patient may exhibit one or more of the classic six “P’s” including pulselessness,
pain, pallor, paresthesia, paralysis, and poikilothermia. Soft signs of vascular injury suggest only partial
disruption of the vessel in question and include the history or evidence of moderate hemorrhage that
has stopped, trauma in proximity to a named vessel (i.e., certain fracture or dislocation patterns) (Figs.
27-3 and 27-4), diminished pulse distal to the site of injury, nonexpanding hematoma or severe bruising,
and a peripheral neurologic deficit. Although torso vascular injury is more difficult to diagnose with just
the physical examination, it should be suspected in patients with asymmetric arm pulses or pressures
and those with severe hypotension and evidence of fluid in the peritoneum or thoracic cavity. As
mentioned, patients having survived a high-speed motor vehicle crash or lengthy fall should be
considered for a blunt aortic injury.14,15
702
booksmedicos.org
Adjuncts to the Physical Examination
Several simple, noninvasive tools exist which can greatly enhance one’s ability to diagnose vascular
injury starting with the blood pressure cuff and measurement of pressure in both arms. A persistent
discrepancy of more than 20 mm Hg between arm pressures suggests a proximal vascular injury to the
subclavian or axillary arteries. A plain chest radiograph is also quick and useful as an adjunct in the
diagnosis of blunt aortic injury. The classic signs of this injury pattern include a widened mediastinum
(greater than 8 to 10 cm), an apical cap, loss of the characteristic aortic nob, downward displacement of
the left mainstem bronchus, and a pleural effusion. Although multiple rib fractures are not a sign of
aortic injury itself, it is a marker of severe blunt injury with significant shear and should raise one’s
index of suspicion for injury to the thoracic aorta.
Figure 27-3. A,B: Radiographic images of a Gartland type III fracture of the right supracondylar humerus which is commonly
associated with brachial artery injury.
Figure 27-4. Radiograph of right upper extremity showing open humerus fracture and a temporary vascular shunt in the brachial
artery which was severed by the fracture. The temporary vascular shunt was placed as a damage control adjunct to restore
perfusion prior placement of the external fixator and patient evacuation to a higher echelon of care.
Continuous wave Doppler – with or without a manual blood pressure cuff – is another adjunct to the
physical examination of patients in whom there is a concern for vascular injury. Doppler signals in the
703
booksmedicos.org
distal extremity should be recorded as present or absent and, if present, graded as strong and bi- or
triphasic or weak and monophasic.16,17 In the lower extremity, signals should be assessed in the dorsalis
pedis and posterior tibial arteries while in the upper extremity, signals should be examined over the
radial, ulnar, and brachial arteries. While describing the quality of Doppler signals can be somewhat
subjective, identifying the presence of extremity perfusion by noting even the presence of an arterial
signal is an important step that is typically less subjective than palpation for a pulse with one’s finger.
The best use of continuous wave Doppler in the evaluation of the extremity is in conjunction with a
manual blood pressure cuff, which allows one to record an arterial occlusion pressure adding a degree
of sensitivity and objectivity to the process. In these instances, the blood pressure cuff is positioned on
the distal portion of the lower or upper extremity (leg or forearm, respectively) proximal to the arteries
which are to be examined. The Doppler probe is placed over a distal artery in the injured extremity
until the arterial signal is audible. At this point, the blood pressure cuff is inflated to the point at which
the signal is no longer present. The pressure at which the Doppler signal disappears is recorded as the
arterial pressure in that extremity. This ankle or wrist pressure is then compared with the occlusion
pressure of the arterial signal in another, noninjured extremity and the ratio of the occlusion pressure in
the injured compared to that in the noninjured extremity is recorded as the injured extremity index or
IEI. When comparison of arterial occlusion pressures is performed for a lower extremity injury –
comparison of the lower to the upper extremity – it can also be referred to as the ankle-brachial index
(ABI). The normal ABI or IEI is 0.9 or greater although caution should be used in interpreting the ratio
in patients who are hypotensive, in severe pain, or hypothermic.15–17 Peripheral vasoconstriction is a
normal response to significant trauma and shock and may result in a transiently decreased ABI or IEI in
the absence of an injured axial vessel. In this context, assessment of the Doppler occlusion pressures and
measurement of ratios should be viewed as dynamic and repeated after resuscitation, administration of
pain control, and/or rewarming.
Ultrasound is another noninvasive modality that can be used in the evaluation of patients for vascular
trauma. Brightness or B-mode ultrasound is ubiquitous in most emergency departments and critical care
settings and allows one to make basic assessments that provide insight into the presence and severity of
some patterns of vascular injury.14,15 The focused assessment with sonography for trauma or FAST
examination of the abdomen is based on B-mode ultrasound and is commonly used to determine the
presence or absence of fluid in the peritoneum following severe injury. Although not specific for
vascular injury, if the FAST examination is positive in a patient who is severely hypotensive following
trauma, one can deduce that the fluid is blood. In these cases, ultrasound is identifying the result of
vascular disruption from within the parenchyma of a solid organ (liver, kidney, or spleen), a larger
named vessel or some other source within the abdomen.
Duplex ultrasound combines B-mode imaging with pulsed Doppler and provides a more sensitive and
specific method of assessment for vascular trauma. Duplex is less practical in the immediate or initial
physical examination as these machines are typically less prevalent than basic Doppler or ultrasound and
they traditionally require more technical support to perform (i.e., vascular technician). Increasingly,
small and mobile ultrasound machines in the acute care setting are incorporating duplex into their
platforms allowing for more widespread use of this diagnostic modality without the restrictions that
traditionally limited its application. If available, duplex is particularly useful in evaluating the extremity
and cervical vasculature and provides not only a B-mode image of the vessel lumen but also an
assessment of the direction and velocity of flow. A full description of the capability and performance of
Duplex ultrasound is beyond the scope of this chapter. However, it is an incrementally more powerful
diagnostic, surveillance, and follow-up tool as it relates to vascular trauma and gaining familiarity with
its use is recommended.
Computed Tomography and Magnetic Resonance Imaging for Vascular Trauma

Contrast-enhanced computed tomography angiography (CTA) and magnetic resonance imaging (MRI) or
angiography (MRA) are sensitive tools used in the diagnosis of vascular trauma.18 The relative
ubiquitous nature of these modalities means that they are often performed in severely injured patients
as a matter of routine or screening (i.e., “pan-scan”) and not for the specific diagnosis of suspected
vascular injury. In this context, practitioners must be aware of incidental CTA findings not correlated
with the clinical case or mechanism of injury. In these cases, the incidental finding must be
acknowledged but should also be put in context of the mechanism and pattern of injury, the history and
physical examination, and the surgeon’s overall clinical experience. From the standpoint of diagnosis of
suspected vascular injury, CTA and MRA are most useful in patients with soft signs on physical
704
booksmedicos.org
examination or those who have a high-risk mechanism or patterns of trauma.18
6 Contrast-enhanced CTA is the most available and common imaging modality used in the emergency
setting including the evaluation of patients suspected of having vascular trauma. Multidetector CTA
with high-speed helical scanning has reduced the time required to conduct the imaging and improved
image quality. CTA has a high degree of sensitivity in identifying vessel dissection (i.e., separation of
layers of the vessel wall), occlusion (i.e., thrombosis), and/or extravasation of blood into a contained
space (i.e., pseudoaneurysm) or into an open space or cavity. CTA is particularly useful in the
assessment of anatomic regions where physical and Doppler examination of the vasculature is limited
(i.e., the torso, cervical and junctional regions). There is growing experience with CTA in the
assessment of the peripheral vasculature and several clinical reports now demonstrate this modality’s
sensitivity and specificity in the diagnosis of extremity vascular injury.19 Extremity CTA is appealing for
the polytrauma patient who has soft signs of vascular injury as it can be accomplished concurrent with
imaging of other body regions (i.e., head, neck, abdomen, and pelvis).19
MRI or MRA also possesses a high degree of sensitivity as it relates to the diagnosis of vascular
trauma. However, the more cumbersome nature of MRA, including the slower acquisition and
interpretation of images makes it less well suited for use in the acute and early phases of trauma care.
Currently, MRA is mostly reserved for select cases of cervical vascular injury (i.e., carotid and
vertebral) in which CTA is equivocal or in which there is a significant intracranial component of the
injury or its sequela (i.e., stroke). Although contrast-enhanced MRA of the extremity vasculature has
excellent definition, it thus far offers no significant practical advantage over other proven modalities
such as duplex ultrasound, CTA, or conventional contrast arteriography.
Contrast Angiography
Angiography is the direct imaging of any vascular structure using a contrast agent with fluoroscopy
while arteriography and venography refer specifically to imaging of arteries or veins, respectively. Like
CTA, angiography is often most useful in patients with soft signs of vascular injury or those having
sustained a particularly high-risk injury mechanism. Angiography can be useful in patients with hard
signs of vascular injury and in this scenario is often used as an intraoperative technique in those taken
immediately to the operating room for surgical repair. Unlike CTA, this imaging modality is more
invasive and requires a higher level of technical expertise to accomplish. However, contrast
arteriography has the advantage of being able to be performed in the operating room at the time during
which resuscitation can be accomplished and other injuries addressed.20 Contrast angiography also has
the advantage of being a precursor for endovascular therapies such as embolization and placement of
covered stents or stent grafts.
Intravascular injection of contrast agents allows visualization of anatomy and can be accomplished
after direct vascular puncture and placement of a needle or an endovascular catheter. Basic angiographic
techniques should be a standard part of any general, trauma, and vascular surgical practice and are
typically applied in the resuscitation or operating room. Diagnostic studies and interventions are also
performed by radiologists in specialized imaging suites. Transcatheter or catheter-based arteriography
provides the highest-resolution imaging of most vascular beds including anatomic definition and a road
map for surgical planning or intervention (open or endovascular). Vascular injury can be demonstrated
as extravasation of contrast if bleeding from the vessel(s) is brisk and ongoing. However, extravasation
may not be visualized if the bleeding is slow or under tamponade. Bleeding may also be missed if the
contrast bolus is too small, if it is injected into a different vessel, or if image acquisition is terminated
too soon. Angiographic interruption of vessel continuity usually indicates disruption or occlusion (i.e.,
thrombosis). With sufficient contrast, distal reconstitution of flow (i.e., beyond the disrupted segment)
from collateral vessels can typically be demonstrated. Imaging of distal arterial beds can be
compromised by hypoperfusion and vasoconstriction, typical manifestations of shock. Vasospasm, with
tapering of arteries (sometimes to occlusion) and slow flow, can be more prominent in young patients
who have a greater degree of vasomotor reactivity.18,20
Early venous filling after intra-arterial contrast injection indicates the presence of an arteriovenous
fistula. Traumatic pseudoaneurysms result from focal disruption of arterial-wall integrity, with blood
flow contained by adventitia or surrounding tissues. A pseudoaneurysm appears as a focal outpouching
of contrast beyond the normal artery wall. Intimal flaps and focal segments of nonocclusive thrombosis
may be detected as filling defects or lucencies within the contrast column, sometimes with a delay in
distal contrast flow.
705
booksmedicos.org
MANAGEMENT OF THE PATIENT WITH VASCULAR TRAUMA
Trauma Patient Pathophysiology
7 In the trauma patient, hemorrhage leads to both the overall metabolic consequences of total-body
ischemia and end-organ ischemia of the specific injured vessel. Ischemia of both types results in anoxic
cell death. Resuscitation is directed toward minimizing ischemia and the “lethal triad” of acidosis,
hypothermia, and coagulopathy. Hypoperfusion, or ischemia, leads to acidosis, which causes platelet
morphology changes and dysfunction and declining coagulation factor activity leading to decreased
thrombin generation and the degradation of fibrinogen. Resuscitation with 0.9% NaCl also leads down a
similar path of acidosis. Hypothermia likewise causes platelet dysfunction, less coagulation factor
activity, and the induction of fibrinolysis. Both of these pathways lead to coagulopathy and endothelial
damage. Nonbalanced massive blood transfusions can also lead to tissue injury, hypoperfused vascular
beds, hemo dilution, and depletion/dilution of clotting factors and platelets, which can all contribute to
a coagulopathic state.
Counterintuitively, the goal of resuscitation and repair, reperfusion, can precipitate another slew of
metabolic insults on the trauma patient. Reperfusing ischemic tissues releases reactive oxygen species
and sets off multiple proinflammatory processes including lipid peroxidation. This causes injury to the
microvasculature which increases cell permeability and edema. An increase in interstitial pressure in
turn leads to more stasis in microvasculature and therefore worsened ischemia, Ensuing cell lysis (e.g.,
rhabdomyolysis) leads to hyperkalemia, metabolic acidosis, and eventually myoglobin-induced renal
failure.
Resuscitation of the Trauma Patient

After the usual ABCD is completed and an inventory of injuries is initially acquired, priorities of injury
management can be set. Physical examination should include assessment for hard and soft signs of
vascular injury. Examination can be performed almost simultaneously with plain radiographs when
needed. General hard signs include active pulsatile bleeding or shock from blood loss,
expanding/pulsatile hematoma, pulselessness, audible bruit over an artery, and palpable thrill. Hard
signs mandate immediate trip to the OR for hemorrhage control and/or restoration of flow to the
ischemic limb. These patients should not have CT/CTA done except in special cases. Unnecessary
imaging delays definitive care and worsens outcome. If needed, on-table angiography can be used. Soft
signs can include history of hemorrhage prearrival, venous ooze, nonexpanding/nonpulsatile hematoma,
neurologic abnormality or decreased pulse as compared to contralateral limb, delayed capillary refill,
and other additional site-specific signs. Venous access is also part of the initial management of the
trauma patient. Large-bore catheters in peripheral veins of uninjured extremities are ideal, and
preferred over central access in the emergent setting. Vein cutdowns, including veins otherwise ideal for
later use as venous conduit, are sometimes necessary. Radial or femoral arterial lines are also often
accessed for hemodynamic monitoring.21
8 Damage control resuscitation, a term coined in 2005, involves allowing permissive hypotension
with a goal of a palpable radial pulse (in patients without head injury).22 It also includes limiting
crystalloid infusion and an early institution of massive transfusion protocol with higher rates of plasma
and platelets to prevent/reverse coagulopathy.23
General Intraoperative Considerations and Pearls

Often the theory of “damage control” and “life over limb” takes precedence in the chaotic trauma bay
and operating room. But there are basic tenants to follow when thinking beyond: control hemorrhage,
restore blood flow, and prevent further injury.
1. Prep widely, considering any possible procedure including the need to obtain vascular conduit (i.e.,
saphenous vein). With leg injuries, prep circumferentially, and include the shoulders, chest, and
abdomen. With chest or abdominal injuries, prep both groins. With neck or upper extremity wounds,
prep the chest.
2. Patients should receive preoperative antibiotics, based on local guidelines.
3. Longitudinal incisions that are parallel with neurovascular bundles should be used for the widest
exposure and best control. They may need to be S shaped over joint spaces. Minimization of the
devitalization of intervening tissues can improve arterial and venous collateral flow, and provide
coverage after repair.
706
booksmedicos.org
4. Proximal and distal control for any vascular injury is critical. This may be obtained with a digit,
vessel loop, vascular clamps, or a Foley or Fogarty balloon. Consider remote proximal control when
hematomas or open blast wounds impede visualization. Shunts should also be considered to decrease
ischemic time when orthopedic stabilization or other life-saving procedures must occur first.
Nonbleeding wounds should not be disturbed including removing debris or foreign objects until
surgical control is possible. Temporary application of a lower extremity tourniquet may be helpful
with multiple wounds or before control is attained. An inappropriately applied tourniquet inflated to
venous pressure can increase exsanguinating hemorrhage; it may need to be increased to stop
bleeding that may recommence once resuscitation is underway and systemic blood pressure increases.
5. Injury may require orthopedic surgeons to perform fracture reduction and limb stabilization prior to
vascular, nerve, or soft tissue repair. This will often improve vessel spasm and vascular examination
should be repeated.
6. Systemic heparin use is individualized and depends on multiple factors: preoperative blood loss,
hemodynamic stability, amount of ongoing bleeding, presence of brain injury, and status of patient
with regard to acidosis, hypothermia, and coagulopathy. Local administration of heparin and
papaverine can also be used in the wound and as vessel flushes. In general, systemic heparin is not
indicated in young patients with good vascular repairs who otherwise have healthy vessels (no
chronic atherosclerotic disease).
7. Exposure of the injury and vessels depends on the location, and can involve aggressive debridement
of devitalized tissue for adequate visualization and postoperative healing (Table 27-1).
Table 27-1 Exposures in Vascular Trauma Surgery
8. Inflow and outflow must be assessed before beginning an anastomosis; thrombectomy with a Fogarty
embolectomy catheter may be required.
9. Ensure bleeding has stopped, reassess hemodynamic status of patient, and complete repairs with
correct prioritization (including artery before veins in most situations).
10. Decision is made on which tension free repair to execute (Table 27-2).
11. Appropriate conduit is obtained, if applicable. Reversed greater saphenous vein of the uninvolved
leg is an ideal conduit.
12. Repair is performed with nonabsorbable, monofilament running suture in most cases, and
hemostasis is obtained. Hemostatic agents can be parenteral (e.g., tranexamic acid for
hyperfibrinolysis;) or topical (Table 27-3).
13. Repair should be assessed in the operating room with Doppler and possible arteriogram.
14. Muscle and/or soft tissue coverage over repairs should be utilized when feasible to decrease
contamination, dessication, and disruption.
15. Compartment syndrome must be considered, and fasciotomies performed as needed.
16. Wound care, physical and occupational therapy must be robust and intensive postoperatively.
Table 27-2 Options for Treatment of Vascular Injuries
707
booksmedicos.org
MANAGEMENT OF SPECIFIC INJURY PATTERNS—EXTREMITY
For all extremity trauma, management algorithms follow as listed in a previous section starting with
advanced trauma life support protocols, controlling hemorrhage, alleviating ischemia, and limb
stabilization to minimize future disability, in that order.24 Injuries with hard signs of vascular injury will
be taken immediately to the operating room for open and/or endoluminal diagnosis and interventions
once life supporting measures allow, without further workup. Presence of hard signs has an almost
100% sensitivity of existing vascular injury. Whereas soft signs, with only a 5% specificity for detecting
arterial injuries, allow time for further workup, imaging, and decisions into operative, endovascular, or
nonsurgical observation categories.25
Generally, the sequence should be stabilization of the extremity with or without the use of a
temporary vascular shunt, revascularization, and then as patient condition allows debridement, nerve
repair, and soft tissue coverage. Temporary vascular shunts have been shown in many military studies
as a successful adjunct in damage control situations with reduced rate of amputations (Figs. 27-4 and 27-
5).
An additional issue relevant to all extremity trauma is whether to repair venous injuries. It depends
on resources, comorbidities, other injuries, and of course, stability of patient. Ligation of veins is better
tolerated in upper extremities than lower. When harvesting the greater saphenous vein for conduit, it
should be from the uninjured leg when feasible to allow full venous drainage of injured leg (Fig. 27-6).
Table 27-3 Topical Hemostatic Agents
Figure 27-5. Operative photograph showing temporary vascular shunts placed as a damage control maneuver in the proximal
popliteal artery and vein of the left lower extremity. The shunts had been secured with silk suture ties, and both were patent with
Doppler flow several hours after the injury. Note also the operative approach to the left above-knee popliteal fossa that includes a
proximal Wietlaner retractor and a distal Henly popliteal retractor, and short handheld Wylie renal vein retractor.
708
booksmedicos.org
9 A critical issue in all extremity trauma management is evaluation of compartment syndrome.
Elevated fascial compartment pressures can be due to reperfusion, hematoma, swelling from crush
injury or major fractures. There must be a low threshold for performing fasciotomy, based on clinical
suspicion of present or pending compartment syndrome. Diagnosis is based on a high index of suspicion
suggested by any of the following: >4 to 6 hours of ischemia, crush injuries, combined arterial and
venous injuries, vessel ligation, tense compartments, pain out of proportion and on passive motion,
poikilothermy, pallor, paralysis, paresthesia, and finally, pulselessness. Compartment pressures can be
measured as an adjunctive aid in diagnosis. A commonly used cutoff is 30 mm Hg, but normal pressures
with a concerning examination should not deter from pursuing treatment with fasciotomy.
Postoperative considerations include starting aspirin as soon as possible, DVT prophylaxis, elevation
of the injured extremity, 24 hour of antibiotics, and starting rehabilitation as soon as appropriate in
patient’s condition. Systemic heparinization is usually not required postoperatively, and DVT
prophylaxis and/or antiplatelet agents can suffice.
Figure 27-6. Operative photograph showing interposition vein graft repair of the left proximal popliteal artery and vein. The
interposition grafts were performed after removal of the temporary vascular shunts and consisted of greater saphenous vein from
the right (contralateral) lower extremity.
Upper Extremity
Anatomically, the axillary artery is defined proximally by the lateral margin of the first rib and distally
by the lateral edge of the teres major muscle. The artery is protected proximally within the shoulder
from penetrating injury, but susceptible to forceful blunt trauma due to its fixation. It is difficult to
expose proximally due to the artery’s location under the clavicle and may require either infra- and
supraclavicular incisions to gain control, or a more proximal intrathoracic or mediastinal approach of
the subclavian artery. The mid- and distal axillary artery can be approached through a traditional
infraclavicular incision. The complications with more distal exposure are due to increasing branches and
associated nerves leading to the shoulder and arm. Employing endovascular techniques for temporary
balloon occlusion or placement of stent grafts may be advantageous in either of these locations.26
The axillary artery becomes the brachial artery, which runs in the anterior compartment of the arm
with the median nerve. Two veins accompany, and often cross over, the artery – the basilic and brachial
veins. Exposure of the brachial artery is simple compared to the axillary, in the medial grove between
the biceps and triceps muscles. The brachial artery is most often injured during penetrating trauma, but
should be considered with any humerus fracture, especially posterior or lateral fractures. The brachial
artery’s main proximal branch, the profunda brachii, can provide significant perfusion to the distal
upper extremity if it remains intact.
The radial artery is a terminal branch of the brachial just distal to the elbow and travels in the
anterior compartment to become the deep palmar arch. The ulnar artery is the larger terminal branch of
the brachial artery and runs to the wrist to form the superficial palmar arch and joins the deep arch. If
temporary control of bleeding is needed, a blood pressure cuff can be used as a tourniquet; clamps
should never be placed blindly into a bleeding wound due to the high risk of nerve injury. Evaluation
should include the previously described neurovascular examination with addition of the Allen test to
determine patency of the palmar arch. Some believe a single vessel injury with no ischemic changes can
be ligated if the palmar arch is intact. If both forearm arteries are injured, the usually dominant ulnar
repair is preferred, primarily or with vein from ipsilateral arm or dorsal foot vein. There is limited to no
role for acute management of traumatic forearm injuries by endovascular means.
709
booksmedicos.org
Lower Extremity
Femoral trauma constitutes 20% of all traumatic arterial injuries. Supracondylar femur and tibial
plateau fractures are associated with distal superficial femoral artery and popliteal artery injuries. Acute
ligation of the femoral artery leads to 50% amputation rate.27 Previously stated management principles
should be followed for the lower extremity as well with some site-specific caveats. Some situations may
require control of hemorrhage via an assistant’s digit prepped into field, a temporary balloon catheter
or tourniquet, or exposure of the distal external iliac artery in the preperitoneal space with compression
against iliac fossa for femoral triangle injuries. Incision should be longitudinal just distal to the inguinal
ligament. Primary repair or interposition grafts are the mainstay of therapy. Although vein conduit is
always preferred, prosthetic graft can be used when necessary, in larger vessels with good muscle
coverage. Heavy contamination (such as a bowel injury) may make an extra-anatomic bypass necessary,
at least temporarily. Endovascular techniques can be employed in certain circumstances in the femoral
and popliteal region including coiling arteriovenous fistulae or pseudoaneurysms, stenting
pseudoaneurysms or transections that can be crossed.
Popliteal trauma is classically due to posterior knee dislocation. Historically, amputation rates were
20% for both penetrating and blunt popliteal injuries.28 While failure to repair a popliteal occlusion
results in over 60% amputation rate. Incision should be medial, employ the use of a bump under the
slightly flexed leg, and utilize deep self-retaining retractors (Figs. 27-5 and 27-6). Repair is primary,
interposition graft, or with a stent. Primary repair should be attempted only if defect is <1 cm.
Completion angiography is recommended in most situations.
Reportedly, a single terminal vessel can be ligated in the lower extremity in a patient with no signs of
ischemia and no peripheral vascular disease. Whenever possible, preserving three artery perfusion to
the foot is preferred. When all three arteries are damaged, repair should focus on the posterior tibial via
a medial incision or anterior tibial via a lateral incision.
MANAGEMENT OF SPECIFIC INJURY PATTERNS – CERVICAL

The carotid artery travels in the anterior cervical triangle of the neck, specifically the carotid triangle
bordered by the sternocleidomastoid muscle, the superior belly of the omohyoid muscle, and the
posterior belly of the digastric muscle. Of course, besides hemorrhage from carotid artery, jugular veins
and branches, injury to nerves (vagus, hypoglossal), trachea, and esophagus must also be considered.
The vertebral artery, which supplies blood to the posterior brain, travels first in the transverse foramina
of the cervical vertebrae and then in the vertebral canal.
10 When discussing neck trauma, there are three regions classically used to describe anatomic
location. Zone I is below the cricoid cartilage, zone II is between the cricoid cartilage, and the angle of
the mandible, whereas zone III is above the angle of the mandible. The carotid and vertebral arteries
are at risk in all three zones.29
Neck trauma is also divided into penetrating and blunt injuries. Zone II of the neck is the most
commonly injured region at 47% of penetrating neck injuries. The most commonly injured structure
within the neck is blood vessel, with a 20% incidence of major vascular injury in penetrating neck
trauma. These injuries lead to a 7% to 27% stroke rate and 7% to 50% mortality rate; 80% of deaths
due to penetrating neck injuries are attributed to stroke.30 Evaluation of these injuries used to include a
mantra “operate if penetrated the platysma” but this is no longer the rule as it has been shown to lead
to a 50% to 90% negative exploration rate. Currently, CTA is used whenever the patient is deemed
stable enough to travel to CT scan. The CTA should include the neck and head, with extension through
the aortic arch if a zone I injury is suspected. CTA has a 90% sensitivity and 100% specificity rate for
vascular injuries that require treatment.31
As stated, treatment of injuries with hard signs in zone II is emergent operative exploration. This can
be undertaken often via a cervical incision. Stab wounds can often be repaired primarily or with a
patch, while ballistic injuries typically require segmental resection with interposition graft. Greater
saphenous vein should be used as conduit whenever possible. Internal jugular can be ligated in an
emergent setting, but otherwise should be repaired, especially if injury is bilateral. External jugular and
facial veins can be ligated without significant consequence, as can the external carotid artery. Internal
carotid artery should be repaired as there is a high mortality with ligation (45%).30 Heparinization with
or without shunting is employed during these repairs unless major contraindications exist in the multi-
injured trauma patient.
710
booksmedicos.org
Zone I and III injuries are much more difficult to expose using an open approach. Thus, they are often
managed with open surgery, endovascular intervention, or a hybrid combined approach depending on
location, comorbid conditions, other injuries, stability of patient, and availability of resources.
Endovascular approaches have become particularly appealing for injuries at the thoracic outlet and skull
base, which are especially difficult to access during open surgery.
Zone I injuries with hard signs of vascular injury typically involve the great vessels. These need to be
managed with either an endovascular approach (cover stents and endografts) or open clamp for
proximal control via median sternotomy, high anterior thoracotomy, or clavicular resection. Common
carotid can be controlled via a sternotomy, and portends a lower risk of stroke than clamping the
internal carotid due to collateral flow via external carotid and the circle of Willis.
Open control of zone III injuries can require subluxation of the mandible (jaw dislocation),
mandibulotomy, and other morbid exposures so endoluminal control is appealing in this region as well.
A temporary occlusive balloon while exposure and hemostasis is obtained, coil embolization, and a
covered stent placement over the injury are strategies that have been used. Covered stent have been
described in the treatment of traumatic carotid injuries. The results are inconsistent and based on small
studies. One study placed stents in 10 patients with carotid dissections, neurologic changes and
contraindication for or failure of anticoagulation with good overall results. Whereas a contemporary
study of 23 patients who underwent carotid stent placement for traumatic pseudoaneurysm documented
a 21% complication rate and 45% occlusion rate, both higher rates than the patients treated with
antithrombotic therapy alone.29,32
Vertebral artery injuries are less common, and more difficult to expose and control operatively, than
carotid artery injuries. Vertebral artery injuries are most often associated with cervical spine transverse
process fractures, subluxations, or penetrating injuries to the back of the neck. Only medical
management is needed if the injury is not bleeding. Endovascular means of embolization has been
employed for pseudoaneurysms and intimal disruption (and is technically a better option whenever
possible), if the vessel is not already thrombosed. Open access to the vertebral artery may be necessary
to control bleeding if endovascular approach cannot be used for any reason (not available or not enough
time, etc.). This involves an exposure similar to that for the carotid artery, and after the
sternocleidomastoid and anterior scalene muscles are mobilized, vertebral artery can be isolated and
ligated. In this procedure, care must be taken to avoid injury to the phrenic nerve and thoracic duct. To
obtain proximal and distal control of a more distal vertebral artery injury may require employing
similar techniques as with a zone III carotid injury. The expected stroke rate of ligation of the vertebral
artery in the spine literature is 0% to 8%. However, whenever possible, medical therapy with
antithrombotics is still the primary treatment modality.
Blunt vascular trauma to the neck is usually considered as blunt cerebrovascular injury (BCVI) and
encompasses both carotid and vertebral injuries (often discussed as one). BCVI represents <1% of
admissions for blunt trauma, but the impact is great when considering these injuries lead to a 12% to
58% stroke rate and 31% to 59% mortality rate when untreated.33 The goal of management is
thrombosis prevention, therefore treatment with antithrombotic therapy is recommended. Two such
examples reported a reduction in stroke rate from 64% to 6.8%, and 46% to 0% in blunt carotid injury
patients treated with any antithrombotic agent.34 However, the optimal drug(s) and duration for each
injury grade has not yet been determined by prospective data. This could include aspirin, clopidogrel,
anticoagulation, for a set time versus life long. Retrospective data have shown equivalence in injury
outcomes with antiplatelet and anticoagulation treatment regimens.
MANAGEMENT OF SPECIFIC INJURY PATTERNS – TORSO

11 Control of bleeding from vascular disruption within the torso is not readily amenable to control with
direct pressure and is therefore referred to as noncompressible torso hemorrhage (NCTH). Civilian
studies demonstrating that NCTH accounts for 60% to 70% of mortality following otherwise survivable
injuries clearly emphasize the lethality of this injury pattern. Hemorrhage is also a significant problem
in the wartime setting, accounting for up to 60% of deaths in potentially survivable injury scenario. The
distinction between compressible extremity hemorrhage and NCTH is notable. There has been a
demonstrable reduction in mortality from extremity injury with a better understanding of its
epidemiology and the need to rapidly control hemorrhage with tourniquets and/or topical hemostatic
agents. To date, there has been no such reduction in mortality in the setting of NCTH.35 Vascular
disruption with bleeding can arise from an array of anatomic sites:
711
booksmedicos.org
Large axial vessels
Solid organ injuries
Pulmonary parenchymal injuries
Complex pelvic fractures
As such, the definition of NCTH begins with the presence of vascular disruption from one or more of
four anatomic categories listed above.
Management of Torso Hemorrhage

12 Despite advances in surgical understanding, technique, and technology, one fundamental tenet
remains: Proximal and distal control is essential when managing suspected vascular injury. The majority
of patients with these types of injuries qualify for management in a damage-control fashion and the
appropriate surgical maneuvers depend primarily on the location of hemorrhage within the torso.
Thoracic Cavity
Vascular trauma to the aortic arch and its major branch vessels is rare and the majority of patients
present in shock, requiring immediate surgical intervention in the form of tube thoracostomy,
resuscitative thoracotomy (RT), or median sternotomy. Aortic arch injuries are often associated with
multiple other vascular injuries, including vena cava, innominate vein, and pulmonary artery injuries
and a median sternotomy is the operative exposure of choice. Sternotomy followed by division of the
innominate vein allows the pericardium to be opened for release of any associated cardiac tamponade.
Exposure of aortic branches can be facilitated by extending the sternotomy incision proximally as a
supraclavicular incision with division of the sternocleidomastoid muscle.
For hemorrhage control within the thoracic cavity, access to the ipsilateral side is best via an
anterolateral thoracotomy, through the fourth interspace, with the patient in the supine position, tilted
up on a roll. This approach also allows extension of this incision across the sternum into the right
hemithorax or the clam-shell incision, permitting access to either of the other two compartments in the
chest (mediastinum and contralateral thoracic cavity) if required. It is important that a surgeon
performing this maneuver must also have the ability to concomitantly explore the abdomen, so this
must be included when preparing the surgical field.
Once within the chest, hemorrhage control is the priority. Pulmonary bleeding can be controlled
using several techniques, depending on location. Injury to the periphery of the lung can be stapled off in
a nonanatomic fashion using a linear stapler. If hemorrhage from the lung is from the deeper hilar
structures, the lung itself (after mobilization) can be compressed or even twisted on itself to occlude the
hilar vessel. In cases where the injury significantly compromises a patient’s pulmonary reserve,
extracorporeal life support (ECLS) may also be a useful adjunct.
Abdominal Cavity
The abdomen should be opened through a midline incision from the xiphoid process to the pubic
symphysis to permit access to all 4 quadrants. Initial packing remains the best method of initial
hemostasis, allowing for the resuscitation to restore the circulating volume. An additional useful adjunct
for patients in extremis is resuscitative aortic occlusion of the aorta at the diaphragmatic hiatus. The
next key steps are sequential evaluation of the abdomen, decisions regarding local control of
hemorrhage and contamination and the type of reconstruction required for any large vessel injury (Fig.
27-7).
712
booksmedicos.org
Figure 27-7. End-to-end interposition graft repair of mid-superior mesenteric artery injury with great saphenous vein.
Hemorrhage from the solid organs of the abdomen is managed differently, depending on the organ in
question. Exposure and removal of the spleen is fairly straightforward and well tolerated by the patient,
and thus splenectomy is the favored maneuver for the hemorrhaging spleen. By contrast, hemorrhage
from the liver necessitates packing to control venous bleeding in most instances. Control of the porta
hepatus at the gastrohepatic ligament and application of the Pringle maneuver is often used as an
adjunct to liver packing to control inflow to the organ. Depending on the nature of the wound and the
location of the hepatic bleeding, the liver can be mobilized by dividing the coronary and triangular
ligaments and allowing the left and right lobes to be drawn or compressed together.
Retroperitoneum
Posterior to the peritoneal sac lies the retroperitoneum, which can be divided into four zones. Zone I is
centrally located and contains the aorta and IVC. Hemorrhage often manifests as a hematoma and
should always be explored in this zone. Management of such injuries should adhere to standard
principles of proximal and distal control of the vessel. The aorta can be widely exposed through a left
medial visceral rotation – also referred to as the Mattox maneuver by mobilizing the left colon and
kidney. The IVC can be explored through a right visceral rotation – also referred to as the Cattell–
Braasch maneuver – by mobilizing the large and small bowel fully to the root of the mesentery.
Approaching large-vein injuries in the abdomen is often more challenging than controlling and
repairing arterial hemorrhage. Like bleeding from large arteries, one must be prepared with multiple
suction devices and a good retraction device, and be sure that the anesthesia team is prepared with
warmed rapid transfusion devices. Because large veins often do not tolerate clamps in the setting of
trauma and hematoma, direct pressure should be applied with sponge-sticks or the smaller Kittner
dissector sponges. These devices substitute for manual pressure and allow one to create more visibility
in the operative field.
Zone II is perirenal in location and generally should be managed conservatively in blunt trauma,
provided there is no expansion and the patient is hemodynamically stable. Penetrating trauma requires
a different approach, with an emphasis on exploration and repair of the kidney if possible, or
nephrectomy. If there is concern of injury to or violation of the collecting system, drains should be left
in the perinephric or retroperitoneal space.
Zone III originates from within the pelvis, although these injuries can be extensive, tracking all the
way up to the supracolic compartment. Pelvic hematomas are best managed conservatively in blunt
trauma, and opening them should be avoided. Further management options are outlined below. In
penetrating, vascular control is vital, especially if a direct vessel injury is suspected, and may require
mobilization of the terminal aorta.
Operative management of bleeding from the portal-retrohepatic zone (sometimes referred to as zone
IV) is fraught with difficulty. Control of bleeding from the retrohepatic vena cava is especially
challenging and is associated with high mortality. Contained hematomas should be left undisturbed, and
expanding lesions should be packed in the first instance.
Pelvis
The pelvis is a complex compartment containing several unique anatomic structures typically managed
in the elective setting by specialists from a range of disciplines (e.g., urology, orthopedic surgery,
vascular surgery, and general/colorectal surgery). Operative exposure of the pelvic space can be
achieved through either a transperitoneal approach at the time of laparotomy or with an extraperitoneal
approach, which can be accomplished through a midline or a Pfannenstiel incision. The former is the
quicker approach, enabling access to both the abdomen and the pelvis and permitting access to the aorta
and distal vascular along with the hollow viscera within that region. The extraperitoneal approach
allows access to the external iliac vasculature for suprainguinal arterial control and for packing of the
preperitoneal space. The latter is a useful adjunct to managing venous bleeding in complex pelvic
fractures once bony stabilization has been achieved. Arterial bleeding from the pelvis is most commonly
managed with endovascular techniques such as coil embolization in cases of complex pelvic fracture. In
rare instances of pelvic fracture or open fragmentation or gunshot wounds to the pelvis, ligation of the
internal iliac artery is necessary as a hemorrhage-control maneuver.
A proportion of patients with NCTH present with circulatory collapse, either profoundly hypotensive
or in cardiac arrest. Management of patients presenting in such a fashion has been extensively studied.
713
booksmedicos.org
The current civilian standard of care is to perform a RT, which permits the following maneuvers:
Release of cardiac tamponade
Management of thoracic bleeding
Control of massive air-leaks
Internal cardiac massage
Thoracic aortic occlusion
The latter maneuver is undoubtedly the most practiced, as aortic control theoretically enhances
cerebral and myocardial perfusion. Aortic occlusion can also be achieved by endovascular balloon
occlusion, as demonstrated by the use of percutaneous devices used to control the neck of abdominal
aortic aneurysms during endovascular repair.36 This technique enables the physiologic benefit to be
realized without the additional burden of entering a body cavity. Such a technique has been used in
trauma as early as the Korean War and since.37 With recent improvements in endovascular devices and
resuscitation in general, there is a renewed interest in this approach, which has been termed
resuscitative endovascular balloon occlusion of the aorta (REBOA) (Fig. 27-8).38,39
Figure 27-8. Fluoroscopic image of a compliant balloon inflated in the descending thoracic aorta as part of the maneuver referred
to as resuscitative endovascular balloon occlusion of the aorta or REBOA. This endovascular maneuver was accomplished through
a percutaneous sheath in the right femoral artery and can be accomplished in certain scenarios instead of an open resuscitative
thoracotomy with aortic clamping to restore proximal central aortic pressure and mitigate distal bleeding. (From Scott DJ, Eliason
JL, Villamaria C, et al. A novel fluoroscopy-free, resuscitative endovascular aortic balloon occlusion system in a model of
hemorrhagic shock. J Trauma Acute Care Surg 2013;75:122–128.)
CONCLUSION
Vascular trauma remains a leading cause of mortality and morbidity following civilian and military
injuries. A large volume of military supported epidemiologic and translational research stemming from
the wars in Afghanistan and Iraq has advanced the understanding and treatment of this injury pattern.
Evidence suggests that the commonality of vascular trauma is increasing at a time during which
familiarity with its management (open and endovascular) is on the decline. Supported by an
understanding of modern epidemiologic patterns of injury, including mechanisms and specific scenarios,
and knowledge of the range of options available to examine and image patients, providers will be able
to effectively diagnose or exclude the presence of vascular trauma. This foundational understanding will
also aid providers in their approach to resuscitating severely injured patients and knowing when to
intervene and when not to intervene. The operative management of vascular trauma has changed with
the growth of endovascular approaches to hemorrhage control and resuscitation as well as the specific
treatment of several injury patterns. Still, many of the original principles underpinning the safe and
effective management of vascular injury – from damage control to definitive treatment – find
themselves in knowledge of traditional open operative exposure, with control and repair of the vessels
(Fig. 27-7). Regardless of experience and training level, the foundational principles provided in this
chapter will support one’s attempts to improve his or her effectiveness in managing what is arguably
714
booksmedicos.org
the most challenging injury pattern following significant trauma.
References
1. Eastridge BJ, Mabry RL, Seguin P, et al. Death on the battlefield (2001–2011): implications for the
future of combat casualty care. J Trauma Acute Care Surg 2012;73:S431–S437.
2. White JM, Stannard A, Burkhardt GE, et al. The epidemiology of vascular injury in the wars in Iraq
and Afghanistan. Ann Surg 2011;253:1184–1189.
3. Mattox KL, Feliciano DV, Burch J, et al. Five thousand seven hundred sixty cardiovascular injuries
in 4459 patients: epidemiologic evolution 1958 to 1987. Ann Surg 1989;209:698–705.
4. DeBakey ME, Simeone FA. Battle injuries of the arteries in World War II: an analysis of 2471 cases.
Ann Surg 1946;123:534–579.
5. Hughes CW. The primary repair of wounds of major arteries: an analysis of experience in Korea in
1953. Ann Surg 1955;141:297–303.
6. Rich NM, Baugh JH, Hughes CW. Acute arterial injuries in Vietnam: 1,000 cases. J Trauma
1970;10:359–369.
7. Stannard A, Brown K, Benson C, et al. Outcome after vascular trauma in a deployed military trauma
system. Br J Surg 2011;98:228–234.
8. Clouse WD, Rasmussen TE, Peck MA, et al. In-theater management of vascular injury: 2 years of
the Balad vascular registry. J Am Coll Surg 2007;204:625–632.
9. Fox CJ, Gillespie DL, O’Donnell SD, et al. Contemporary management of wartime vascular trauma.
J Vasc Surg 2005;41:638–644.
10. Norton R, Kobusingye O. Injuries. N Engl J Med 2013;368:1723–1730.
11. Barmparas G, Inaba K, Talving P, et al. Pediatric vs adult vascular trauma: a National Trauma
Databank review. J Pediatr Surg 2010;45:1404–1412.
12. Loh SA, Rockman CB, Chung C, et al. Existing trauma and critical care scoring systems
underestimate mortality among vascular trauma patients. J Vasc Surg 2011;53:359–366.
13. Galindo RM, Workman CR. Vascular trauma at a military level II trauma center. Curr Surg
2000;57:615–618.
14. Sise MJ. Diagnosis of vascular injury. In: Rasmussen TE, Tai NRM, eds. Vascular Trauma. 3rd ed.
Philadelphia, PA: Elsevier, Inc; 2016:35–43.
15. Fox N, Rajani RR, Bokhari F, et al. Eastern Association for the Surgery of Trauma. Evaluation and
management of penetrating lower extremity arterial trauma: an Eastern Association for the Surgery
of Trauma practice management guideline. J Trauma Acute Care Surg 2012;73(5 suppl 4):S315–
S320.
16. Frykberg ER, Dennis JW, Bishop K, et al. The reliability of physical examination in the evaluation
of penetrating extremity trauma for vascular injury: results at one year. J Trauma 1991;31:502–
511.
17. Frykberg ER. Advances in the diagnosis and treatment of extremity vascular trauma. Surg Clin North
Am 1995;75(2):207–223.
18. Dawson DL. Imaging for the evaluation and treatment of vascular trauma. In: Rasmussen TE, Tai
NRM, eds. Vascular Trauma. 3rd ed. Philadelphia, PA: Elsevier, Inc; 2016:44–55.
19. Miller-Thomas MM, West OC, Cohen AM. Diagnosing traumatic arterial injury in the extremities
with CT angiography: pearls and pitfalls. Radiographics 2005;25(suppl 1):S133–S142.
20. Holcomb JB, Fox EE, Scalea TM, et al. Current opinion on catheter-based hemorrhage control in
trauma patients. J Trauma Acute Care Surg 2014; 76:888–893.
21. Dua A, Desai SS, John B, et al., eds. Clinical Review of Vascular Trauma. Springer Berlin
Heidelberg;2014.
22. Dutton RP. Resuscitative strategies to maintain homeostasis during damage control surgery. Br J
Surg 2012;99:21–28.
23. Hess JR, Holcomb JB, Hoyt DB. Damage control resuscitation: the need for specific blood products
to treat the coagulopathy of trauma. Transfusion 2006;46(5):685–686.
24. Shander A, Kaplan LJ, Harris MT, et al. Topical hemostatic therapy in surgery: bridging the
715
booksmedicos.org
knowledge and practice gap. J Am Coll Surg 2014;219(3):570–579.
25. Dua A, Patel B, Desai SS, et al. Comparison of military and civilian popliteal artery trauma
outcomes. J Vasc Surg 2014;59(6):1628–1632.
26. Gill H, Jenkins W, Edu S, et al. Civilian penetrating axillary artery injuries. World J Surg
2011;35(5):962–966.
27. Moore WS. Vascular and Endovascular Surgery: A Comprehensive Review. 7th ed. Philadelphia, PA:
Saunders Elsevier; 2006.
28. Wagner WH, Calkins ER, Weaver FA, et al. Blunt popliteal artery trauma: one hundred consecutive
injuries. J Vasc Surg 1988;7(5):736–743.
29. Núñez DB Jr, Torres-León M, Múnera F. Vascular injuries of the neck and thoracic inlet: helical CT-
angiographic correlation. Radiographics 2004;24(4):1087–1098.
30. du Toit DF, van Schalkwyk GD, Wadee SA, et al. Neurologic outcome after penetrating extracranial
arterial trauma. J Vasc Surg 2003;38(2):257–262.
31. Munera F, Soto JA, Nunez D. Penetrating injuries of the neck and the increasing role of CTA. Emerg
Radiol 2004;10(6):303–309.
32. Cohen JE, Ben-Hur T, Rajz G, et al. Endovascular stent-assisted angioplasty in the management of
traumatic internal carotid artery dissections. Stroke 2005;36(4):e45–e47.
33. Biffl WL, Moore EE, Ryu RK, et al. The unrecognized epidemic of blunt carotid arterial injuries:
early diagnosis improves neurologic outcome. Ann Surg 1998;228(4):462–470.
34. Biffl WL, Ray CE Jr, Moore EE, et al. Treatment-related outcomes from blunt cerebrovascular
injuries: importance of routine follow up arteriography. Ann Surg 2002;235(5):699–706.
35. Kotwal RS, Montgomery HR, Kotwal BM, et al. Eliminating preventable death on the battlefield.
Arch Surg 2011;146(12):1350–1358.
36. Stannard A, Eliason JL, Rasmussen TE. Resuscitative endovascular balloon occlusion of the aorta
(REBOA) as an adjunct for hemorrhagic shock. J Trauma 2011;71(6):1869–1872.
37. Hughes CW. Use of an intra-aortic balloon catheter tamponade for controlling intraabdominal
hemorrhage in man. Surgery 1954;36:65–68.
2013;75(3):506–511.
39. Moore LJ, Brenner M, Kozar RA, et al. Implementation of resuscitative endovascular balloon
occlusion of the aorta as an alternative to resuscitative thoracotomy for noncompressible truncal
hemorrhage. J Trauma Acute Care Surg 2015;79(4):523–530.
716
booksmedicos.org
Chapter 28
The Principles of Orthopedic Surgery for Trauma

Raymond Malcolm Smith
Key Points
1 Establishing bony stability significantly reduces local bleeding.

2 Major pelvic fractures occur in recognizable patterns that predict other injuries.
3 Obtaining bony stability can significantly reduce pelvic bleeding and is an essential part of their
initial care.
4 Early stabilization of major fractures in polytrauma patients facilitates other care and saves lives.
5 Early radical management of open fractures with adequate debridement, bony stabilization, and
specifically early healthy soft tissue cover significantly reduces the risk of infection and decreases
morbidity.
6 Establishing reliable bony stability is the key for local soft tissue healing.
7 The principles of accurate reduction, stable fixation, preservation of a healthy soft tissue envelope,
and early rehabilitation with joint and patient mobility are the keys to general fracture management.
INTRODUCTION – AIMS AND PRIORITIES IN ORTHOPEDIC TRAUMA

CARE
In recent years, the subspecialty of Orthopedic traumatology has become well established dealing with
not only more routine fractures but also the more complex problems presented by very severe localized
high-energy injury and combination multisystem polytrauma. In critical multisystem injury, it is very
important to correctly manage the orthopedic injuries which must not be underestimated. Their
management has a critical role in ensuring survival of the patient and ensuring practical overall clinical
management. In severe local injury, useful limb salvage needs critically appropriate orthopedic
management often combined with plastic surgeons to manage the severe soft tissue injury. Beyond this,
in the vast majority of less severely injured patients the orthopedic surgeon’s care should limit the
medium- and long-term disability caused by fractures and severe peripheral soft tissue injuries. This
general point of view is illustrated in Table 28-1. It is useful to consider the role of the orthopedic
surgeon in this regard.
ORTHOPEDIC TRAUMA SURGERY TO SAVE LIFE

Many orthopedic injuries present as part of severe multisystem trauma cases and as such are a major
part of the trauma burden and the threat to life. This threat comes from hemorrhage (from individual or
multiple injury sites), the general effect of multiple major skeletal injuries, specific early associated
injuries or complications such as vascular injury and compartment syndrome or later complications such
as issues related to infection, immobility, and thromboembolic disease.1
Hemorrhage
1 The most immediate and absolute need for surgery in trauma is the control of bleeding. For the
orthopedic traumatologist this takes two important forms, first a massive general bleeding insult
associated with multiple high-energy fractures and second that associated with a specific major injury,
most typically to the pelvis. Bleeding from multiple fractures is common and often underestimated. In
general good transfusion protocols and early fracture management controls the situation. Bleeding from
fractures will invariably slow and usually stop spontaneously when the fracture is reduced, stabilized,
and the compartment tension restored. However, it is very easy to underestimate the collective blood
717
booksmedicos.org
loss from multiple injuries and get too far behind in resuscitation. Aggressive transfusion protocols with
appropriate attention to replacing volume and clotting factors with early use of blood with plasma and
platelets are essential but emergency orthopedic intervention with provision of skeletal stabilization for
early hemorrhage control is equally important.2 This may involve wound debridement and hemostasis
in the complex open injury or early long-bone stabilization in multiple closed fractures. Occasionally,
temporary external fixation may be required to provide rapid skeletal stabilization when the more
extensive surgery required for definitive stabilization would be inappropriate.
The Bleeding Pelvis

2 Put simply, patients with major pelvic ring injuries bleed to death. Often presenting after a high-
energy injury, the pelvis as the source major hemorrhage may be obvious with massive local swelling
and clear instability. At presentation, a primary plain pelvic x-ray remains the best way to quickly
understand the fracture. It will allow immediate assessment of the fracture pattern, energy involved,
degree of displacement and lead to an estimate of the risk of local bleeding and presence of local or
distal associated injuries.4–8 Today many patients have a binder applied in the field for transport. This is
a very effective way to initially control pelvic volume and tamponade bleeding but may reduce the
deformity and lead to the initial x-ray underestimating the degree of injury.
Pelvic fractures can be classified by two major systems. Young and Burgess4,5 (Fig. 28-1) presented a
classification system based on the implied direction of the initial force. They defined injuries essentially
as anterior–posterior compression (APC), lateral compression (LC), and vertical shear (VS) injuries. This
allows an assessment of the direction of the force applied, the resultant instability and can predict
mortality, transfusion requirements, and associated injuries. It remains very useful in this regard, for
example, a severe LC fracture on the left is likely to be seen after a high-energy motor vehicle crash
(MVC) in which there was a major intrusion into the car on the side of injury. It is therefore likely to be
associated with a major head injury and bleeding mainly from elsewhere; specifically, the associated
ipsilateral chest and abdominal injury. A major AP injury will classically come from a motorcycle crash
and will often produce major bleeding in the pelvis itself. The Tile (after Penall)9,10 (Fig. 28-1) system
considers the injury with regard to the resultant instability and has now been adopted by the AO
Foundation (AO) and Orthopedic Trauma Association (OTA). An “A”-type fracture has a stable pelvic
ring and essentially includes more minor avulsion fractures and undisplaced mechanically stable pelvic
ring injuries (includes APC I & LC I). “B”-type injuries are rotationally unstable but vertically stable
with an intact posterior soft tissue hinge providing some stability (corresponding to APC II or LC II/III
injuries) while “C”-type injuries are both rotationally and vertically unstable, implying that the
posterior hinge is torn (corresponding to APC III and VS injuries). The latter carry the highest risk of
bleeding and death.
Table 28-1 Why We Operate on Fractures: Priorities in Trauma Care
From a surgical management perspective, A-type injuries are unlikely to be a source of major
bleeding while B type and specifically C types are increasingly life-threatening. After initial assessment,
primary radiology, and consideration of the response to initial resuscitation, pelvic fractures can be
considered by the mechanical stability resulting from the injury and the resultant hemodynamic
response (Table 28-2).
Table 28-2 Principles of Management of Major Pelvic Ring Injuries
718
booksmedicos.org
When considered in this way the orthopedic care follows a logical pattern. The essential contribution
of the orthopedic surgeon is to assess the injury with regard to the local and associated problems it will
produce and to provide pelvic mechanical stability when required. Clearly, the hemodynamically stable
patient with a stable pelvic ring injury does not require major active orthopedic management although
it should be noted that even the most apparently simple injury can rarely cause local bleeding and
transfusion may be required.11 The hemodynamically stable patient with a mechanically unstable pelvic
ring injury needs early but nonemergent surgery to restore mechanical stability to the pelvis for pain
relief, normal daily care, and mobilization. Hemodynamically unstable patients need emergent care to
restore their physiologic stability. If the pelvis is mechanically stable, orthopedic intervention has little
to offer, either there is an extrapelvic cause for the bleeding or hemostasis should be obtained by
provision of appropriate clotting factors and platelets or angiographically.
3 The patient in hemorrhagic shock with a major unstable pelvic ring is a very different problem.11,12
Early coordinated multidisciplinary care is essential with appropriate resuscitation within an established
massive transfusion protocol. It is well established that the site of hemorrhage in most bleeding major
pelvic fractures is from the fractured bone surfaces and extensive soft tissue injury, and rarely from
major named arteries. Fortunately, the majority of this will slow significantly or stop when skeletal
stability is achieved. Unfortunately, rapid stabilization of the pelvic ring is a major expert intervention
at best and is commonly not easily achievable in the acute bleeding situation. Initial reduction, stability
and some local tamponade is provided by a pelvic binder. In critical cases it should not be removed
without an available alternative method to provide stability. Internally rotating the hips, slightly flexing
the knees and binding the legs at the thigh should also be used if possible and provides additional
effective control. The provision of early pelvic fixation or a primary angiographic approach depends on
local expertise and protocol. Recently, a move to emergent operative provision of skeletal stability and
packing of bleeding areas has entered practice and is suggested to be a major advance.2,3 This considers
the major bleeding pelvic injury similar to a bleeding liver and where local hemostasis can rarely be
achieved and general hemorrhage control with packing for local pressure and provision of appropriate
clotting factors is essential. For the severe pelvic injury, a systematic protocol with pelvic stabilization
and packing at the end of an appropriate decision-making tree is essential.2,3 Emphasizing the
importance of not getting out of control or reacting too late, “The Denver Protocol”2,3 begins with a
patient with shock, a pelvic ring injury, and a failure to respond to 2 L of crystalloid resuscitation and 2
units of blood transfusion (Algorithm 28-1). The essential principle is early aggressive surgical
management for hemorrhage control with preperitoneal packing and rapid blood and factor replacement
before the patient becomes grossly coagulopathic. From the orthopedic point of view, restoring skeletal
stability is a critical part of this process and close cooperation with the general traumatologist is
essential.
Figure 28-1. A–C: Young and Burgess and Tile (AO-OTA) classifications of pelvic fractures (from Wiss DA. Master Techniques in
Orthopaedic Surgery: Fractures. 3rd ed. Philadelphia, PA: Wolters Kluwer Health; 2012.)
719
booksmedicos.org
Pelvic Packing
The procedure of packing a pelvis for hemorrhage is not complicated and well within the capabilities of
most surgeons but some form of pelvic bony stability has to be achieved first to give a solid base to
pack into. In the emergency situation this commonly means the application of an anterior external
fixation frame although if available and possible, internal fixation has many advantages. Occasionally,
emergency provision of posterior stability with emergent percutaneous sacroiliac fixation or application
of a “C clamp” can be dramatically effective in restoring stability and markedly slowing bleeding.
Preperitoneal packing is done through a small anterior incision just above the pubis. After separating
the rectus muscles (which may be avulsed from the pubis), the cavity created by the trauma is entered,
the hematoma evacuated and rapid mechanical stability obtained (often temporarily, with an immediate
anterior clamp across the pubis). The cavity is then packed with as many packs required. These should
be placed as far back into the true pelvis as possible. The hematoma cavity created by the injury will be
obvious and it is not required or desirable to extend the dissection outside this area but it is essential to
get the packs right to the back of the cavity. Assuming hemostasis is achieved, the packs are left in,
often for 48 hours and under an open but sealed abdomen before they are changed or simply removed
depending on the physiologic response.
Complicated Pelvic Injuries – Open Fractures or Associated Visceral Injury

The initial assessment of any patient with a pelvic fracture must include an inspection of the perineum
with rectal and vaginal examination to check for complex open injuries or associated urologic injuries.
Open pelvic fractures and those complicated by damage to the local viscera need specific treatment
based on the wound or specific visceral damage sustained.13,14 While the mortality and complexity
increases with the risk of contamination and infection the orthopedic principles of open fracture care
remain the same. Any open fracture is considered contaminated and dealt with along the principles
described below of debridement and lavage, establishment of bony stability and early, healthy soft
tissue cover as required. However, in major pelvic injuries there is usually a massive trauma cavity
where contamination and infection would prove fatal. Aggressive decontamination and protection of
this extensive zone of injury from further contamination by diversion of the fecal stream may be
essential.
Algorithm 28-1. The Denver Protocol for management of major pelvic fractures. (Reproduced with permission and copyright © of
the British Editorial Society of Bone and Joint Surgery. Mauffrey C, Cuellar DO 3rd, Pieracci F, et al. Strategies for the management
of hemorrhage following pelvic fractures and associated trauma-induced coagulopathy. Bone Joint J 2014;96(9):1143–1154.)
Complex urologic injuries are commonly seen with specific patterns of pelvic fracture. A significant
APC injury is commonly associated with an extraperitoneal bladder rupture of the anterior bladder wall
directly in line with the plane of injury. LC injuries may be associated with urethral tears as the inferior
ramus cuts the male membranous urethra as it is forced across the midline by the injury. In all cases the
720
booksmedicos.org
presence of hematuria or blood at the meatus is the pathognomonic sign of injury and necessitates
appropriate investigation and joint management with the urologic service. Again from the orthopedic
point of view no soft tissue reconstruction can work without an underlying stable bony skeleton to
support the repair and prevent reinjury. In many situations, the best access the urologist will have is at
the time of the primary bony stabilization and early urologic repair or diversion avoids many problems.
While a staged urologic procedure may be required, very early combined surgery has much to
recommend it.
The Orthopedic Management of Major Polytrauma

4 Major trauma is a surgical problem, and the essence of management is to take control and stay in
control of the trauma and do no further iatrogenic harm. From the orthopedic point of view, this means
that it is essential to gain control by stabilizing the skeleton. This understanding has developed through
quite opposite phases to now consider all elements of the injury and physiologic priorities. The
management protocols have focused on the changing opinions about stabilization of the femur fracture
which has become the index injury in this regard. Essentially, despite the development of long-bone
nailing by Kuntscher15 in the 1940s, through till the late 1980s most Western surgeons believed that
seriously injured patients were “too sick to operate on” and used traction devices as the primary mode
of treatment for major fractures. Concern that this was not the best mode of treatment led to the term
“Horizontal Crucifixion” and several early publications15–17 suggesting a major advantage of early
surgical stabilization of the fractures, specifically with femoral nailing. Johnson18 confirmed this effect
and showed that it appeared to be greater the more severely the patient was injured and in 1989 Bone19
published his landmark paper, a prospective randomized trial of early against late femoral nailing after
severe injury. Essentially he showed that there was a major advantage in early nailing and the
pendulum swung to enthusiastic universal early skeletal stabilization after polytrauma. The patient was
now considered “too sick not to operate on” and a management philosophy now termed “Early Total
Care” developed. This practice was soon questioned, specifically in Germany where the orthopedic
trauma surgeon is closely involved with intensive care and inevitably observed the combined effect of
other injures. Pape et al.20 again considering the femur, looked specifically at the effect of early and
late femoral nailing in severe polytrauma and showed the deleterious effect of an associated chest injury
in association with femur fractures treated by early reamed nailing. While statistically the effect seemed
more related to the chest injury than the nailing, this alerted the profession to the combination effect of
these injuries and stimulated an outpouring of research looking at the general and immunologic effects
of orthopedic procedures and specifically of reaming the femur.21–36 Eventually, a concept of the
general effects of polytrauma and bony injury has become more widely accepted and a concept of the
appropriate surgery (damage control orthopedics – DCO) for the most severely injured patients
developed.
Essential Damage Control Surgery in Orthopedics

Damage control in orthopedics means taking control of the musculoskeletal elements of the injury
without creating an increased trauma load due to increased surgical bleeding or a lengthy surgery
associated with definitive care of complex fractures (Fig. 28-2). After essential hemorrhage and wound
management this involves restoring major skeletal stability usually by the rapid application of external
fixators. The basic physiologic parameters are then normalized in a critical care environment unit and
definitive stabilization is delayed until the peritraumatic immunologic storm has settled.25,26,28,29 The
most critical element is the speed and accuracy of the initial surgery as the critical injured patient
cannot tolerate a long orthopedic procedure. However, it cannot be underemphasized how important
the principle of establishing early skeletal stability remains; this was the major lesson of the early
Johnson/Bone papers18,19 and has never been disputed, the issue is not if, but how this is obtained. In
situations where the patient can tolerate it, there are major advantages in early definitive skeletal
stabilization. The question is, how do we identify which patients are too sick and for what? Long
orthopedic procedures and protracted bleeding must be avoided and nailing the femur seems to be
particularly excessively stimulating. A variety of parameters have been investigated to help with this
decision.25 Measurement of interleukin-6 (IL6)24 has not achieved its initial promise and today a
spectrum of parameters considering the patient’s general condition are commonly used.30 This
essentially means close communication and protocol agreement with the anesthetic/general trauma
team but is primarily a surgical decision as the anesthetic team is less likely to be trauma specialized.
Basic parameters to be considered include the hemoglobin/hematocrit, ventilation parameters, platelet
721
booksmedicos.org
count and coagulation studies, patient temperature and a measure of acidosis, usually the lactate level.
The latter has been widely used as measure of resuscitation and as the primary decision-making
parameter by many orthopedic surgeons. Initially, a level of 2.5 mmol/L was considered the value
above which surgery should not proceed but the more recent work from Vallier et al.30 has suggested a
lactate level of 4 mmol/L is a safe cutoff. However, surgical decision making in critical illness does not
occur in isolation and improvements in early resuscitation and critical care management mean constant
reappraisal and probably another future swing in the pendulum (Table 28-3).
Figure 28-2. Early damage control of extensive limb injuries with external fixation.
Table 28-3 Essential Priorities in Orthopedic Damage Control
Special Polytrauma Situations – Head Injury

The orthopedic priorities change in specific scenarios the most obvious being the associated head injury.
When the brain is at risk the primary aim is to maintain cerebral oxygenation and cerebral perfusion
pressure (CPP); accordingly, orthopedic procedures especially those that would lead to bleeding, swings
in blood pressure and thus episodes of reduced CPP should be avoided. However, there are definite
advantages in having a stable skeleton and being able to sit the patient up which will help oxygenation
and general critical care such that after appropriate discussions bony stabilization at the right time is
strongly indicated.37,38
Special Polytrauma Situations – Chest Injury and Femur Fractures

The effect of the chest injury is discussed above. It was emphasized by Pape and Tscherne and
innumerable papers that followed.20 While multiple studies have shown the advantages of early skeletal
stabilization there is no doubt that the lungs are vulnerable to further insults after injury, and that the
acute lung injury can be worsened by fat embolization especially during femoral canal instrumentation.
While improvements in reamer design reduce canal pressurization and smaller nails have been
722
booksmedicos.org
advocated, delaying definitive nailing for 4 to 5 days after initial external fixation in the most critical
patient is probably the standard of care. The effect seems to be dose dependent such that the patient
with bilateral femur fractures is at a significantly increased risk and some surgeons avoid bilateral
femoral nailing at the same time even in healthy patients.39–42
Specific Orthopedic Scenarios

Major Wounds
5 The ongoing septic effect of major wounds can be critical. In the first instance, debridement of
necrotic tissue from the trauma is essential and commonly inadequately done at the initial surgery.
Wounds will never stabilize until adequately debrided and when associated with fractures will not heal
until bony stability has been established. The management of complex open fractures is described
below; in polytrauma cases the principles remain the same but the ability to obtain early soft tissue
cover is compromised by the patient’s general situation.
Table 28-4 Open Fracture Surgical Principles
ORTHOPEDIC TRAUMA SURGERY TO SAVE LIMBS

Open Fracture Principles
Open fractures can range from simple to destructive injuries but in all the important feature is that the
fracture hematoma communicates with the outside environment and the fracture is thus potentially
contaminated. As such, their specific management revolves around limiting the chance of this
contamination converting to established infection. General measures include the provision of tetanus
cover, early broad spectrum antibiotics, early splintage, wound dressing, and specific surgical
management. The latter is designed to reduce the degree of contamination, to remove necrotic or
threatened tissue likely to become infected and to protect the limb by making it unlikely to develop
further infection due to an unstable open wound (Tables 28-4 and 28-5).
Appropriate and adequate open fracture debridement is one of the most difficult surgical procedures,
it should not be relegated to inexperienced staff and if possible not attempted at night unless the limb is
very seriously threatened. The whole zone of injury must be assessed and all dead and dying tissue
removed, only nerve and vessel must be preserved and poor muscle specifically removed. Any free bone
or fragments attached by flimsy soft tissue should also be removed and the resulting defect dealt with
accordingly, although only rarely is a significant defect produced. Wound extensions need to be placed
with specific consideration for the later closure and must not make the soft tissue reconstruction more
complex. An adequate appropriate debridement must be performed the first time. Repeated
debridements “to make sure” are a result of an inadequate initial operation and massively increase delay
and the infection rate. This should be avoided at all costs.
6 Establishing early bone stability is essential, and ideally the definitive bone stabilization should be
performed at the primary procedure. This reduces the chance of late infection and facilitates the
subsequent soft tissue reconstruction. In truth, the ability to perform an adequate debridement and the
best bony reconstruction depends directly on the orthopedic surgeons’ confidence in the subsequent soft
tissue closure and thus the working relationship with the plastic surgery team. While soft tissue
reconstruction is often delayed for practical reasons there is excellent evidence that the earlier a healthy
closure is obtained the better. This is true to the extent that the best data in the most complex (IIIb)
injuries are with immediate flap cover after an adequate initial debridement and definitive bony
reconstruction as one primary procedure (Fig. 28-3). Few units can achieve this at primary presentation,
such that definitive debridement, fracture stabilization, and appropriate soft tissue assessment at the
primary procedure followed by definitive soft tissue cover at the second visit to the OR (at about 48
hours) after the patient has been appropriately counseled are probably the best achievable standard.
Cooperative care with the plastic surgical service from the start is essential.44–49
723
booksmedicos.org
Table 28-5 Open Fracture Classification (after Gustillo & Anderson43)
Vascular Injuries
An acutely ischemic limb with a fracture or dislocation is major surgical emergency. At presentation, all
fractures must have the distal circulation assessed and documented; if the blood supply is affected the
fracture or dislocation must be rapidly reduced. Fortunately, this commonly results in restoration of
circulation and normal fracture care can continue. If not an emergent, combined vascular–orthopedic
procedure is required. Sometimes a temporary shunt will be used to obtain distal flow while a bony
reconstruction is performed. Bony stability at the correct length must be obtained before definitive
vascular reconstruction, both to allow the vascular repair to be at the correct level and tension, and to
protect it from disruption. Any subsequent reconstruction must be done with provision for awareness
and care of the vascular repair.
Compartment Syndrome
A compartment syndrome is a major surgical emergency as the muscle is acutely ischemic due to an
increased compartment pressure reducing tissue perfusion to below a critical level. Accordingly, the
classical presentation is pain out of proportion to the injury due to the muscle ischemia. The
compartment may be obviously hard with loss of muscle function and distal neurologic symptoms due
to pressure on the nerves passing through the compartment. Loss of arterial flow through the
compartment is exceedingly rare and not useful diagnostically, the presence of a distal pulse does not
contribute to the diagnosis of compartment syndrome. While the diagnosis is often clinical and
straightforward a formal measurement of the perfusion pressure of the compartment (similar to CPP in
head injuries) has been popularized by McQueen.50 Assessing mainly the anterior compartment of the
lower leg after tibial fractures with constant compartment pressure monitoring, they showed that if the
compartment pressure remained at least 30 mm of mercury below the diastolic blood pressure (known
as the D p > 30) the consequences of compartment syndrome (muscle necrosis and contractures) did
not occur. Accordingly, today the definitive test for compartment syndrome is a direct measurement of
the compartment pressure and comparison to the diastolic pressure. This is particularly seen in
situations when the patient is not able to respond appropriately to pain. These include, during
anesthesia, particularly under regional anesthesia, patients sedated on intensive care, patients where
any strong analgesia is being used, or if the patient poorly responsive after a medication overdose. The
diagnosis must not be missed, as immediate fasciotomy is needed to restore muscle perfusion.
Rarely compartment syndromes present late when muscle necrosis is established. There will be a high
creatinine kinase level, myoglobinuria, and even frank renal failure if several compartments are
involved and the presentation is delayed. If compartment syndrome is established at presentation,
perhaps if diagnosed after 12 to 24 hours, fasciotomy is not indicated as it will only expose the necrotic
compartment to infection. Unless deemed that muscle debridement is the only way to reduce the
myoglobin level and reduce the renal damage the tight limb should be simply observed and the
subsequent distal contracture more safely dealt with later by specific muscle or tendon releases.52
724
booksmedicos.org
Figure 28-3. A–E: Management sequence of a major open fracture. This is a III-C injury in a 12 year old treated by immediate “fix
and flap” incorporating the anastomosis for the Lattimus Dorsi free flap into the vascular repair. The subsequent course shows
good soft tissue and bony healing.
Indications for Amputation/Failure of Reconstruction

The indications for amputation can be remembered as the three “D’s” referring to a limb that is “Dead,”
“Dangerous” or a “Damn” nuisance. In the early trauma situation, this may be clearly obvious and early
amputation may be lifesaving while the latter refers to later reconstructive scenarios. While limb
salvage is always an aim the surgery required may be protracted such that salvage should not be
attempted if it puts life at risk. This requires experienced decision making at the acute stage and when
possible agreement between staff surgeons. With an isolated injury situation, the decision essentially
depends on the degree and site of necrotic tissue and reconstructive functional potential of the limb. If
not grossly necrotic, this can be a most difficult decision and should be made by a surgeon experienced
in reconstructive options and their functional outcome. In many situations, an amputee will function as
well if not better than a poor reconstruction especially if several muscle compartments have been lost.
This is clearly a decision for experienced staff and should involve the patient as much as possible. The
application of a temporary external fixator to the severely mangled limb with a view to appropriate
discussion prior to initiating a limb salvage course has much to recommend it.
ORTHOPEDIC TRAUMA SURGERY TO LIMIT DISABILITY –

MANAGEMENT OF FRACTURES
7 The management of fractures has been a core medical discipline for millennia and has developed from
primitive bone setting, through the guild of army barber surgeons to the modern day orthopedic
traumatologist. In general orthopedic practice today, almost half of the work is the care of injury and in
most the modern trauma centers taking a large percentage of blunt trauma 80% to 90% of the surgical
care of the injured falls to the orthopedic service.
Fortunately, fractures have an intrinsic tendency to heal and bone is one of only two tissues to heal
by reforming its own tissue and not with a scar. There are four essential phases in fracture management:
assessment, position, healing, and rehabilitation. The first is self-explanatory but mandates a full limb
assessment with documentation of the relevant clinical signs. This must include assessment and
documentation of the neurovascular state of the distal limb. X-rays need to be taken of the whole bone
involved and centered on the fracture. For example, an x-ray of the humerus which includes the
shoulder is inadequate to assess a specific shoulder injury and separate views of the relevant part must
be obtained. These views must include an AP and appropriate lateral. In many situations, the anatomy is
still not adequately defined by these views and specific additional x-ray views or a computed
tomography (CT) scan will be required to detail the anatomy to fully understand the injury and for
725
booksmedicos.org
surgical planning. Fracture management then centers on obtaining and holding the position of the
fracture through healing. Essentially middiaphyseal fractures need to be held in a position to maintain
overall length, alignment, and rotation but do not need an anatomical reduction of individual
fragments. They are usually treated by long bridging techniques that hold the bone at each end without
an open reduction of the fracture area. In modern practice, this is usually achieved by intramedullary
nailing which also provides the relative stability needed at the fracture site and facilitates healing with
callus (Fig. 28-4). As a contrast, articular fractures usually need a direct open approach to ensure
accurate reduction of the joint surface and the absolute stability of the fixation. The recovery of joint
function is directly related to the quality of the reduction and provision of stable fixation to allow early
motion. In this situation, the bone at the joint would be expected to heal by primary bone union without
callus (Fig. 28-5).
Essentially, the method chosen to hold the position of the fracture will be more or less stable
depending on how firmly it holds the bone. A traditional cast on the tibia will provide only relative
stability but should lead to a high rate of healing with callus. There can be a very good functional
recovery if an adequate position is maintained and cast complications are avoided but it essentially
provides a less reliable hold than an implant directly applied to the bone. Accordingly, the patient
undergoing nonoperative management in cast has to be followed closely, often with weekly x-rays for
up to a month or until the position is deemed stable. The cast then stays until bone healing is considered
adequate to maintain the position faced with functional loads and the cast can be removed. A stable,
painless fracture on clinical examination suggests adequate healing to stay out of cast which should be
confirmed by good bone healing on x-ray.
Nonoperative fracture management is an art that has been practiced for years but is used today only
for stable relatively undisplaced fractures. This includes undisplaced articular fractures, low-energy
nonarticular fractures, and many fractures in children who have a large capacity for remodeling during
and after bone healing and obtain bony healing in about half the time adults with excellent function
results (Table 28-6).
The phase of bone healing from fracture to a stable skeleton progresses from an inflammatory
reaction through fibrous tissue and cartilage formation before immature bone and finally mature
remodeling. A number of biologic stimulatory molecules and specific mechanical features then drive the
normal healing response. Overall there is a progressive stiffening of the fracture environment until bone
can form when the local strain is at or below 2%.53,54 This may be produced by the gradual tissue
stiffening provided by the natural healing process or by an orthopedic implant that creates a local strain
environment in conjunction with the specific fracture anatomy and intrinsic fracture stability. Normal
healing with splintage or with devices that produce relative stability (some fracture motion under
physiologic loads) lead to the progressive stiffening effect described briefly above and healing by callus
when the strain reduces to a level where bone can form. If an implant confers absolute stability, usually
through direct compression of the fracture surfaces, the strain is less than 2% from the start and the
bone heals by a modified remodeling process termed “primary bone healing,” callus does not form. In
planning a bony reconstruction the surgeon specifically decides what degree of stability is required to
treat a specific fracture and the appropriate implant to do this. This follows basic AO55,56 principles
which are the key to fracture surgery. Essentially, diaphyseal fractures need treatment with relative
stability and indirect reduction techniques to maximize the local healing process. In contrast, articular
fractures require usually a direct reduction for perfect anatomy and subsequent fixation with absolute
stability (no deformation occurs under physiologic load) to facilitate joint recovery.
The rehabilitation process should be considered from the immediate decision-making process and
begins as soon as the soft tissues are stable enough to allow dependency and joint motion. This confers
the major advantages of mobility to the limb and whole patient. With articular fractures the cartilage is
only nourished by diffusion from joint fluid which is effectively pumped into the hyaline cartilage as a
secondary effect of motion. Accordingly, fracture fixation must be stable enough to allow early range-
of-motion (ROM) exercises as tolerated but weight bearing is usually limited to protect the
reconstruction from early displacement.
726
booksmedicos.org
Figure 28-4. Assessment and surgical management of a diaphyseal fracture of the femur. A,B: Anterioposterior x-rays of a
diaphyseal femur fracture C,D: Reamed fully locked intramedullary nailing of a diaphyseal femur fracture showing progressive
healing.
Complex Articular Fractures

Major joint injuries are significant joint-threatening injuries and can be very complex.57–59 The aim of
care involves articular reconstruction with perfect joint anatomy and stable fixation with absolute
stability. Surgical reconstruction often requires detailed preoperative assessment with a CT scan and
application of specific implants often designed for the specific joint and side involved. The basic
principles used for surgical reconstruction of these injuries were developed over 50 years ago by the AO
and have only seen minimal modifications since. However, modern implants and particularly the
development of locking plates have improved the capability of our implants to hold fractures securely
and specifically a cantilever hold of local fragments that allows fractures to be held well in position
with less extensile exposures. The modern implant offers major mechanical advantages and the more
limited approach reduces the chance of additional surgical damage to the injured bone and thus
maximizes its healing potential. Occasionally the primary injury (even if closed) is associated with
significant degloving of the local soft tissues, manifest by early fracture blisters and precludes an early
open surgical approach.60 Surgical management then takes the form of temporary bridging external
fixation, applied outside the zone of injury which confers some stability and allows the soft tissues to
settle prior to conversion to an internal fixation often after 1 to 2 weeks. However, in most fractures
excellent results can be obtained by much earlier surgery which is much easier than a delayed
reconstruction.61
Special Fracture Groups – Proximal Femur

Like many injuries, fractures of the proximal femur have a bimodal distribution with rarer high-energy
injuries in the young and extremely common bone fragility fractures in the elderly. As a public health
727
booksmedicos.org
issue, osteoporosis and its related fractures are at epidemic proportions with many fracture units
admitting one or two patients every day.62 The general medical care of the elderly dominates the
clinical picture where across the board the mortality is of the order of 15% to 20% in the 3 months after
fracture. Major efforts to optimize the care of this group of patients are essential both on an individual
and community basis. Massive numbers of injured frail elderly patients produce a major load on hospital
and rehabilitation services. In addition, specific attention to long-term bone health is essential. The
orthopedic issues of proximal femoral fracture take two forms and produce specifically different
problems and solutions. The fractures essentially occur inside (intracapsular) or outside the hip capsule
(extracapsular). Intracapsular fractures carry a risk of avascular necrosis (AVN) of the femoral head
depending on the displacement of the fracture, while intratrochanteric fractures are mechanically
unstable due to the anatomy and offset of the proximal femur creating marked mechanical instability
with a tendency to collapse into varus.
Figure 28-5. Assessment and surgical management of a complex articular fracture of the distal tibia (pilon). Despite virtually
anatomic reduction it progresses to degenerative arthritis in the medium term. A,B: AP and lateral x-rays of an intra-articular
fracture of the distal articular surface of the tibia. C,D: CAT scans show the marked damage and displacement at the joint surface,
underappreciated by initial x-rays. E: Open reduction and internal fixation to restore the joint surface for function and joint
longevity. F: After healing and removal of the majority of the hardwear there is significant degenerative arthritis of the joint that
may need joint arthrodesis.
Table 28-6 Bone Healing Timeframes
728
booksmedicos.org
Intracapsular fractures (femoral neck) are classically classified by Garden.63 Garden grade 1&2
injuries are essentially undisplaced and carry a low risk of AVN, they are usually treated by fixation
unless the patient’s bone quality is considered too poor for fixation. In that situation and in displaced
fractures (Garden grade 3&4) a replacement of the femoral head with hemiarthroplasty or total hip
replacement in a biologically younger patient is required.64,65
Extracapsular fractures (trochanteric) are mechanically unstable. They will collapse into varus
without fixation and have a tendency to settle and shorten with healing due to the intrinsic bone
weakness and pull of local muscles. Accordingly, fixation devices need the ability to mechanically
control the angle of the femoral neck and accommodate some shortening without protrusion of the
device into the hip. The instability is associated with the degree and position of any comminution which
also indicates which device is appropriate to use. Essentially a sliding hip screw device can be used for
any trochanteric fracture unless the lateral wall is incompetent (reverse obliquity injuries or their
equivalent) or where there is subtrochanteric extension. In these cases an intramedullary nail with a
retrograde locking device is specifically indicated although many surgeons use these nails for most
fractures. When using a sliding hip screw for a trochanteric fracture it is essential to get the tip of the
screw within a 1 cm of the articular surface to avoid failure.66,67
Complications
Infection Nonunion and Malunion
Specific healing problems may require later specialist care.68 Infection is unfortunately common after
complex fracture care, especially if the initial injury was open. Failure of healing (nonunion) is not
usually diagnosed before 6 months and commonly suggested by persistence of pain on loading and
failure of progression of bone healing on x-Ray. Malunion is assessed with regard to the specific
problem produced and may require specific corrective surgery for limb alignment, joint function, or
longevity. While these complications are minimized by good primary fracture care, they still occur and
many specialist services attract referrals of these problems. Commonly they are combined with infection
and failure of bone healing often occurring together. In principle, infection after fracture creates a
similar situation to osteomyelitis with acute and chronic clinical pictures. In general, the management of
infection involves the same principles as the management of open fractures with debridement and
lavage, skeletal stability and healthy soft tissue cover; with the addition of long-term antibiotics guided
by perioperative cultures and under the supervision of an infectious disease specialist. Again adequate
debridement of the poor often dead infected bone, the provision of bony stability and healthy soft tissue
cover is the key to management.
Surgical management of the acute infection before fracture healing involves urgent washout of the
wound, biopsy, cultures, appropriate antibiotics, and healthy wound management, often necessitating
delayed primary closure after a secondary washout. While unstable fixation should be removed and
stability regained stable fracture fixation should be maintained even if superficially contaminated until
adequate fracture union. An implant can then be safely removed and usually any residual infection
eradicated. Chronic infection with a united fracture needs similar treatment but in this scenario the
fracture is stable. The key here is removal of a contaminated implant and debridement of dead bone to
remove the source of infection. Subsequent, local profuse washout and healthy soft tissue closure then
proceeds as above. However, in the chronic situation affected tissues are stiff and nonpliable such that
bone and soft tissue debridement may produce a dead space, soft tissue defect, or skeletal instability
with a bony defect. Filling a soft tissue defect will require appropriate soft tissue to be imported and
commonly the help of a plastic surgeon. If a bony defect is created there are multiple potential options
for treatment ranging from bone grafting through use of a cement spacer and the Masqulet technique69
to bone transport with an Ilizarov device.70 or complex free bone/soft tissue transfer. Unfortunately,
often limb salvage may end up being protracted and not be the best option for the patient.
Malunions cause considerable disability and can be very rewarding to correct (Fig. 28-6). Each needs
to be fully assessed for the specifics of the deformity and consideration to a variety of methods of
correction given. There are champions of a variety of acute correction methods with an osteomy and
fixation or gradual correction usually with a ring fixation device.
729
booksmedicos.org
Figure 28-6. Assessment and surgical management of a proximal femoral malunion after implant failure. A: Proximal femoral
malunion (collapsed in to varus) with a broken implant in place. B: Correction of the malunion with a Valgus osteotomy held
with a blade plate.
Orthopedic Injury/Disaster Triage

Given the predominance of orthopedic injuries in the injured patient and the frequency of multiple
patient events surgeons are often faced with prioritizing the care of a number of injuries in one complex
patient or of a number of patients at the same time. In common day practice a major motor vehicle
crash with several victims can stress a system and require appropriate prioritization. In major
international disasters these situations can be extreme. In these situations simple reliable rules are
needed to guide staff through the process especially when there are multiple problems to consider and
the situation is critical. ATLS dealt with this superbly with the A, B, C, alphabetic system for the
primary survey. While this remains an excellent system for initial patient evaluation and can guide some
immediate surgical decisions it does not help the surgeon who will have to make critical priority
decisions beyond this. From the orthopedic traumatology point of view the variety of injuries often
cover the whole spectrum of clinical need and produce complex decision-making situations. The easiest
way for the supervising surgeon to plan the care of an individual is to stand back and work along simple
priority guidelines, asking “what is needed here to save the life,” “what is needed to save a limb,” and
“what is disability limiting.” Considering each injury in turn then allows a logical plan to be made to
prioritize the care required. In multiple patient scenarios the process is the same but modified by the
number of patients involved and the medical resources available. With adequate resources each patient’s
problems are dealt with individually as needed and no consideration to major disaster triage is required.
If resources are reasonable although stressed, patients with life-threatening problems are dealt with first
prioritized by their individual acuity while others with important but initially stable issues can be
managed safely later. In the massive disaster situation priorities change, resources are overwhelmed,
and first priority is given to the group of patients who will gain the most while not tying up or
exhausting scarce resources. The critical patient who would often be dealt with first when if more
resources were available are not prioritized as their care would swamp the resources available and not
allow simpler care to many others.52 Going in to situations (such as the immediate medical relief after
the 2010 Haiti earthquake) without preplanning or the experience to deal with difficult decisions like
this is not advisable.
References
1. Bucholz RW, Heckman JD, Court-Brown CM, eds. Rockwood & Green’s Fractures in Adults 6th ed.
Lippincott Williams & Wilkins. Philadelphia, PA: 2006.
2. Mauffrey C, Cuellar DO 3rd, Pieracci F, et al. Strategies for the management of haemorrhage
following pelvic fractures and associated trauma-induced coagulopathy. Bone Joint J
2014;96B:1143–1154.
3. Biffl WL, Smith WR, Moore EE, et al. Evolution of a multidisciplinary clinical pathway for the
730
booksmedicos.org
management of unstable patients with pelvic fractures. Ann Surg 2001;233(6):843–850.
4. Burgess AR, Eastridge BJ, Young JW, et al. Pelvic ring disruptions: effective classification systems
and treatment protocols. J Trauma 1990;30:848–856.
5. Dalal SA, Burgess AR, Siegel JH, et al. Pelvic fracture in multiple trauma: classification by
mechanism is key to pattern of organ injury, resuscitative requirements and outcome. J Trauma
1989;29(7):981–1000.
6. Poole GV, Ward EF, Muakkassa FF, et al. Pelvic fracture from major blunt trauma: outcome is
determined by associated injuries. Ann Surg 1991;213(6):532–538.
7. Demetriades D, Karaiskakis M, Toutouzas K, et al. Pelvic fractures: epidemiology and predictors of
associated abdominal injuries and outcomes. J Am Coll Surg 2002;195(1):1–10.
8. Starr AJ, Griffin DR, Reinert CM, et al. Pelvic ring disruptions: prediction of associated injuries,
transfusion requirement, pelvic arteriography, complications and mortality. J Orthop Trauma
2002;16(8):553–561.
9. Tile M, Pennal GF. Pelvic disruption: Principles of Management. Clin Orthop Relat Res 1980;151:56–
64.
10. Tile M. Classification of fractures of the pelvis and acetabulum. In: Tile M, ed. Fractures of the Pelvis
and Acetabulum. 2nd ed. London: Williams and Wilkins; 1995:66–101.
11. Bramos A, Velmahos GC, Butt UM, et al. Predictors of bleeding from stable pelvic fractures. Arch
Surg 2011;146(4):407–411.
12. Gruen GS, Leit ME, Gruen RJ, et al. The acute management of hemodynamically unstable multiple
trauma patients with pelvic ring fractures. J Trauma 1994;36(5):706–711.
13. Rothenberger DA, Fischer RP, Strate RG, et al. The mortality associated with pelvic fractures.
Surgery 1978;84(3):356–361.
14. Rothenberger D, Velasco R, Strate R, et al. Open pelvic fracture: a lethal injury. J Trauma
1978;18(3):184–187.
15. Kuntscner G. The intramedullary nailing of fractures. Clin Orthop Relat Res 1968;60:5–12.
16. Riska EB, von Bonsdorff H, Hakkinen S, et al. Primary operative fixation of long bone fractures in
patients with multiple injuries. J Trauma 1977;17(2):111–121.
17. Goris RJ, Gimbrere JS, van Niekerk JL, et al. Early osteosynthesis and prophylactic mechanical
ventilation in the multitrauma patient. J Trauma 1982;22:895–903.
18. Johnson KD, Cadambi A, Seibert GB. Incidence of adult respiratory distress syndrome in patients
with multiple musculoskeletal injuries: effect of early operative stabilization of fractures. J Trauma
1985;25:375–384.
19. Bone LB, Johnson KD, Weigelt J, et al. Early versus delayed stabilization of femoral fractures. A
prospective randomized study. J Bone Joint Surg Am 1989;71(3):336–340.
20. Pape HC, Auf’m’Kolk M, Paffrath T, et al. Primary intramedullary femur fixation in multiple
trauma patients with associated lung contusion–a cause of posttraumatic ARDS?J Trauma
1993;34(4):540–547.
21. Bosse MJ, MacKenzie EJ, Riemer BL, et al. Adult respiratory distress syndrome, pneumonia, and
mortality following thoracic injury and a femoral fracture treated either with intramedullary
nailing with reaming or with a plate. A comparative study. J Bone Joint Surg Am 1997;79(6):799–
809.
22. Pape HC, Hildebrand F, Pertschy S, et al. Changes in the management of femoral shaft fractures in
polytrauma patients: from early total care to damage control orthopedic surgery. J Trauma
2002;53(3):452–461.
23. Giannoudis PV, Smith RM, Banks RE, et al. Stimulation of inflammatory markers after blunt
trauma. Br J Surg 1998;85:986–990.
24. Giannoudis PV, Smith RM, Bellamy MC, et al. Stimulation of the inflammatory system by reamed
and unreamed nailing of femoral fractures; an analysis of the second hit. J Bone Joint Surg Br
1999;81(2):356–361.
25. Pape HC, Grimme K, Van Griensven M, et al. Impact of intramedullary instrumentation versus
damage control for femoral fractures on immunoinflammatory parameters: prospective randomized
analysis by the EPOFF Study Group. J Trauma 2003;55(1):7–13.
26. Harwood PJ, Giannoudis PV, van Griensven M, et al. Alterations in the systemic inflammatory
731
booksmedicos.org
response after early total care and damage control procedures for femoral shaft fracture in severely
injured patients. J Trauma 2005;58(3):446–452.
27. Giannoudis PV, Pape HC, Cohen AP, et al. Review: systemic effects of femoral nailing: From
Kuntscher to the immune reactivity era. Clin Orthop Relat Res 2002;(404):378–386.
28. Pape HC, Rixen D, Morley J, et al; EPOFF Study Group. Impact of the method of initial
stabilization for femoral shaft fractures in patients with multiple injuries at risk for complications
(borderline patients). Ann Surg 2007;246(3):491–499.
29. Nahm NJ, Vallier HA. Timing of definitive treatment of femoral shaft fractures in patients with
multiple injuries: a systematic review of randomized and nonrandomized trials. J Trauma Acute
Care Surg 2012;73(5):1046–1063.
30. Vallier HA, Wang X, Moore TA, et al. Timing of orthopaedic surgery in multiple trauma patients:
development of a protocol for early appropriate care. J Orthop Trauma 2013;27(10):543–551.
31. Vallier HA, Cureton BA, Ekstein C, et al. Early definitive stabilization of unstable pelvis and
acetabulum fractures reduces morbidity. J Trauma 2010;69(3):677–684.
32. Nahm NJ, Como JJ, Wilber JH, et al. Early appropriate care: definitive stabilization of femoral
fractures within 24 hours of injury is safe in most patients with multiple injuries. J Trauma
2011;71(1):175–185.
33. Vallier HA, Super DM, Moore TA, et al. Do patients with multiple system injury benefit from early
fixation of unstable axial fractures? The effects of timing of surgery on initial hospital course. J
Orthop Trauma 2013;27(7):405–412.
34. O’Toole RV, O’Brien M, Scalea TM, et al. Resuscitation before stabilization of femoral fractures
limits acute respiratory distress syndrome in patients with multiple traumatic injuries despite low
use of damage control orthopedics. J Trauma 2009;67(5):1013–1021.
35. Canadian Orthopaedic Trauma Society. Reamed versus unreamed intramedullary nailing of the
femur: comparison of the rate of ARDS in multiple injured patients. J Orthop Trauma
2006;20(6):384–387.
36. Weninger P, Figl M, Spitaler R, et al. Early unreamed intramedullary nailing of femoral fractures is
safe in patients with severe thoracic trauma. J Trauma 2007;62(3):692–696.
37. Brundage SI, McGhan R, Jurkovich GJ, et al. Timing of femur fracture fixation: effect on outcome
in patients with thoracic and head injuries. J Trauma 2002;52(2):299–307.
38. Giannoudis PV, Veysi VT, Pape HC, et al. When should we operate on major fractures in patients
with severe head injuries? Am J Surg 2002;183(3):261–267.
39. Giannoudis PV, Abbott C, Stone M, et al. Fatal systemic inflammatory response syndrome following
early bilateral femoral nailing. Intensive Care Med 1998;24:641–642.
40. Copeland CE, Mitchell KA, Brumback RJ, et al. Mortality in patients with bilateral femoral
fractures. J Orthop Trauma 1998;12(5):315–319.
41. Nork SE, Agel J, Russell GV, et al. Mortality after reamed intramedullary nailing of bilateral femur
fractures. Clin Orthop Relat Res 2003;(415):272–278.
42. Kobbe P, Micansky F, Lichte P, et al. Increased morbidity and mortality after bilateral femoral shaft
fractures: myth or reality in the era of damage control?Injury 2013;44(2):221–225.
43. Gustilo RB, Anderson JT. Prevention of infection in the treatment of one thousand and twenty-five
open fractures of long bones: retrospective and prospective analyses. J Bone Joint Surg Am
1976;58(4):453–458.
44. Blachut PA, Meek RN, O’Brien PJ. External fixation and delayed intramedullary nailing of open
fractures of the tibial shaft. A sequential protocol. J Bone Joint Surg Am 1990;72(5):729–734.
45. Gopal S, Majumder S, Batchelor AG, et al. Fix and Flap: The radical orthopaedic and plastic
treatment of severe open fractures of the tibia. J Bone Joint Surg Br 2000;82:959–966.
46. Gopal S, Giannoudis PV, Murray A, et al. The functional outcome of severe, open tibial fractures
managed with early fixation and flap coverage. J Bone Joint Surg Br 2004;86(6):861–867.
47. Wood T, Sameem M, Avram R, et al. A systematic review of early versus delayed wound closure in
patients with open fractures requiring flap coverage. J Trauma Acute Care Surg 2012;72(4):1078–
1085.
48. Hull PD, Johnson SC, Stephen DJ, et al. Delayed debridement of severe open fractures is associated
with a higher rate of deep infection. Bone Joint J 2014;96:379–384.
732
booksmedicos.org
49. Lack WD, Karunaker MA, Angerame MR, et al. Type III open tibia fractures: immediate antibiotic
prophylaxis minimizes infection. J Orthop Trauma 2015;29(1):1–6.
50. McQueen MM, Court-Brown CM. Compartment monitoring in tibial fractures: the pressure
threshold for decompression. J Bone Joint Surg Br 1996;78:99–104.
51. Harrington P, Bunola J, Jennings AJ, et al. Acute compartment syndrome masked by intravenous
morphine from a patient-controlled analgesia pump. Injury 2000;31:387–389.
52. Smith RM, Dyer GS, Antonangeli K, et al. Disaster triage after the Haitian earthquake. Injury
2012;43(11):1811–1815.
53. Perren SM. Physical and biological aspects of fracture healing with special reference to internal
fixation. Clin Orthop Relat Res1979;138:175–196.
54. Perren SM. Evolution of the internal fixation of long bone fractures. The scientific basis of
biological internal fixation: choosing a new balance between stability and biology. J Bone Joint Surg
Br 2002;84(8):1093–1110.
55. Mueller ME, Allgower M, Schneider R, et al. Manual of Osteosynthesis. Berlin/Heidelberg/New York:
Springer Verlag; 1970.
56. Helfet DL, Haas NP, Schatzker J, et al. AO philosophy and principles of fracture management-its
evolution and evaluation. J Bone Joint Surg Am 2003;85(6):1156–1160.
57. Schatzker J, McBroom R, Bruce D. The tibial plateau fracture. The Toronto experience 1968–1975.
Clin Orthop Relat Res 1979;(138):94–104.
58. Matta JM. Fractures of the acetabulum: accuracy of reduction and clinical results in patients
managed operatively within three weeks after the injury. J Bone Joint Surg Am 1996;78:1632–1645.
59. Moed BR, Yu PH, Gruson KI. Functional outcomes of acetabular fractures. J Bone Joint Surg Am
2003;85(10):1879–1883.
60. Sirkin M, Sanders R, DiPasquale T, et al. A staged protocol for soft tissue management in the
treatment of complex pilon fractures. J Orthop Trauma 1999;13(2):78–84.
61. White TO, Guy P, Cooke CJ, et al. The results of early primary open reduction and internal fixation
for treatment of OTA 43.C-type tibial pilon fractures: a cohort study. J Orthop Trauma
2010;24(12):757–763.
62. Donaldson LJ, Cook A, Thomson RG. Incidence of fractures in a geographically defined population.
J Epidemiol Community Health 1990;44(3):241–245.
63. Garden RS. Low-angle fixation in fractures of the femoral neck. J Bone Joint Surg Br. 1961;43 :647–
663.
64. Parker MJ, Gurusamy K. Arthroplasties (with and without bone cement) for proximal femoral
fractures in adults. Cochrane Database Syst Rev 2006;(3):CD001706.
65. Bhandari M, Devereaux PJ, Swiontowski MF. Internal fixation compared with arthroplasty for
displaced fractures of the femoral neck: a meta-analysis. J Bone Joint Surg Am 2003;85:1673–1681.
66. Queally JM, Harris E, Handoll HH, et al. Intramedullary nails for extracapsular hip fractures in
adults. Cochrane Database Syst Rev 2014;9:CD004961.
67. Baumgaertner MR, Curtin SL, Linskog DM, et al. The value of the tip apex distance in prediciting
failure of fixation of peritrochanteric fractures of the hip. J Bone Joint Surg Am 1995;77(7):1058–
1064.
68. Schatzker J. Intra-articular malunions and nonunions.Orthop Clin North Am 1990;21(4):743–757.
69. Masquelet AC, Begue T. The concept of induced membrane for reconstruction of long bone defects.
Orthop Clin North Am 2010;41(1):27–37.
70. García-Cimbrelo E, Martí-González JC. Circular external fixation in tibial nonunions. Clin Orthop
Relat Res 2004;(419):65–70.
733
booksmedicos.org
Chapter 29
Pediatric Trauma
Elizabeth S. Soukup and Peter T. Masiakos
Key Points
1 Epidemiology: Pediatric trauma significantly impacts the lives of children and families in the United
States and around the world. Traumatic injuries remain the no. 1 killer of children and adolescents in
the United States. Injury, both intentional and unintentional, accounts for more than 50% of deaths
in children younger than 18 years. Therefore, pediatric trauma is a significant public health problem,
with management strategies that should include not only emergency medical care but also injury
prevention and systems of trauma care to meet the needs for pediatric patients.
2 ABCs: As in adults, the primary survey should focus on the identification of acute life-threatening
injuries. Attention to the airway, breathing, and circulation (ABCs) supersedes all other interventions
in the initial resuscitation phase. All centers that care for children should have sequestered
resuscitation equipment designed for children, that is, endotracheal tubes, laryngoscopes, catheters,
and passive warming lamps. Room temperature should be kept warm to limit insensible heat losses
in small children. The Broselow Pediatric Emergency Tape aides in estimating the weight of the child
by measuring his or her length and is used to facilitate pediatric resuscitation.
3 C-spine clearance: Much of the imaging that is done to clear the c-spine in a child is unnecessary.
The clinical evaluation of pediatric trauma patients with suspected c-spine injury is quite effective in
predicting which subset of patients will benefit from cross-sectional imaging. Simple clinical criteria,
like Glasgow Coma Scale, used in concert with the physical examination, can safely predict cervical
spine injury in children, safely reducing the dependence on clinical imaging for the vast majority of
patients (even the very young).
4 Nonaccidental trauma: Nonaccidental trauma is a leading cause of trauma in children, with
650,000 confirmed cases of physical abuse annually in the United States, accounting for 1,500 deaths
per year, mostly in children younger than 4 years.105 Nonaccidental trauma and abuse may be
difficult to recognize, and a high index of suspicion is needed when evaluating children with injuries.
The American Academy of Pediatrics guidelines published in 2015 provide a resource to help identify
these children, because unrecognized cases of abuse can represent with serious or even fatal injuries.
5 Injury prevention: As policy makers struggle to allocate limited resources in order to improve
population health, injury prevention programs will play a particularly important role. The rationale
is straightforward: regulatory efforts specifically aimed at injury primary and secondary prevention,
if well designed, can be very successful at health care cost reduction, thereby freeing resources for
other concerns.
INTRODUCTION AND EPIDEMIOLOGY

1 Pediatric trauma significantly impacts the lives of children and families in the United States and
around the world. Traumatic injuries remain the no. 1 killer of children and adolescents in the United
States. Injury, both intentional and unintentional, accounts for more than 50% of deaths in children
younger than 18 years.1 The pediatric mortality rate from trauma in the United States is double that of
other developed countries, and for every pediatric death there were more than 2,000 emergency
department visits.2 In the United States alone, more than 50,000 children are permanently disabled after
trauma, most commonly the result of traumatic brain injury (TBI).2 Injuries account for almost a third
of the total burden of disease in children by disability-adjusted life years.2 According to data that are
now longer than 20 years, these disabilities account for $14 billion in lifetime medical spending and $66
billion in future wages lost.3 Therefore, pediatric trauma is a significant public health problem, with
management strategies that should include not only emergency medical care but also injury prevention
and systems of trauma care to meet the needs for pediatric patients.3
734
booksmedicos.org
Although there is a rise in the incidence of penetrating trauma, which now accounts for up to 10% to
20% of trauma activations, the vast majority of pediatric injuries result from blunt trauma with
associated closed head injuries that require nonoperative management.
TRAUMA SYSTEMS
The concept of a trauma system was shaped by the publication of a US government report in 1966
“Accidental Death and Disability: the Neglected Disease of Modern Society”4 and has led to
improvements in infrastructure, processes of emergency response, communication, and outcome
measurements and quality indicators of responding hospital centers. The Committee on Trauma first
categorized Trauma Center designations in 1976.2 The first Pediatric trauma centers were organized in
the 1970–1980s; however, even today in the United States, there are too few designated pediatric
trauma centers to care for all pediatric trauma patients. There are 35 level I and 32 level II pediatric
trauma centers verified by the American College of Surgeons and a handful of other pediatric trauma
centers that are verified by their own states. Because the vast majority of pediatric patients are cared
for at adult trauma centers,5,6 the exchange of ideas between adult and pediatric trauma centers and the
development of integrated regional trauma systems remain critically important for our care of injured
children.2,7
Inclusive trauma systems include all facilities within a region according to a tiered-triage system.
Each participating facility receives a level designation, and this is used to appropriately triage and refer
patients as necessary. Along with these regionalization efforts, advances in pediatric transport have also
improved how we care for injured children. Inclusive systems have been shown to improve outcomes
because more timely and appropriate transfers can occur. It has become increasingly important to
develop and study various “performance indicators” of the quality of care that is delivered to injured
pediatric patients. For example, rate of successful splenic salvage is a commonly cited quality indicator
in pediatric trauma, and there are reports that children cared for at an adult trauma center have a
fivefold higher risk of splenectomy than those at pediatric trauma center.6,8,9 In addition, beyond simply
benchmarking mortality rates, other measurable quality indicators include availability of a pediatric
intensive care unit with in-house intensivists; radiation exposure from imaging; early neurosurgical
intervention for severe head injury; early fixation of femur fractures; operative rates for solid organ
injuries; and participation in registry databases to monitor performance over time, such as the Trauma
Quality Improvement Program set up by the American College of Surgeons-Committee on Trauma.10,11
It is unclear whether superior care is offered to injured children in a dedicated pediatric hospital,
compared to an adult hospital; however, it has been demonstrated that pediatric trauma certification
and expertise in care of trauma patients are both important factors in optimal care.12–17
Pediatric trauma centers should provide a broad range of pediatric-specific expertise, including
pediatric emergency medicine, pediatric surgery and surgical specialties, pediatric anesthesiologists, and
pediatric medical subspecialists, most importantly pediatric intensivists with a dedicated pediatric
intensive care unit for intensive monitoring and care of critically ill pediatric patients. Furthermore,
pediatric imaging protocols, sedation and pain management protocols, and overall principles of family
centered care add a layer of safety to the care of the child. Child-life specialists and personnel to help
transfer to posthospital all work to improve the care of the pediatric patient. The youngest and sickest
children should preferentially be transferred to these higher-level designated pediatric trauma centers.3
INITIAL ASSESSMENT, RESUSCITATION, AND STABILIZATION

The evaluation and treatment of traumatic injuries of infants and children requires specific knowledge
of pediatric physiology and the physiologic response to injury. Generally, the trauma resuscitation of
children follows similar rules that have been described for adults by advanced trauma life support
standards. However, there are several special considerations in the initial assessment and subsequent
care for children and specific paradigms regarding ancillary studies that are different from those in
adults. These special considerations will be discussed here.
735
booksmedicos.org
Figure 29-1. Broselow pediatric emergency resuscitation tape.
2 As in adults, the primary survey should focus on the identification of acute life-threatening injuries.
Attention to the airway, breathing, and circulation (ABCs) supersedes all other interventions in the
initial resuscitation phase. All centers that care for children should have sequestered resuscitation
equipment designed for children, that is, endotracheal tubes (ETTs), laryngoscopes, catheters, and
passive warming lamps. Room temperature should be kept warm to limit insensible heat losses in small
children. The Broselow Pediatric Emergency Tape aides in estimating the weight of the child by
measuring his or her length. A color-coded bar on the tape measures the length of the child and
indicates the appropriate equipment sizes and medication doses to perform emergency resuscitation on
the child. Designated resuscitation equipment is contained in corresponding, color coded equipment
pouches or drawers (Fig. 29-1).
Pediatric vital signs vary by age (Table 29-1). Children are able to maintain normal blood pressures
until late hemorrhagic shock (>30% blood loss), and, therefore, subtle changes in heart rate and
respiratory rate must be noted. As a general rule, the lower limit of acceptable systolic blood pressure
= Age × 2) + 70 mm Hg. For newborns, acceptable systolic blood pressure is 60 mm Hg or greater.
Airway control (“A”) is the first priority. Cardiac arrest in a child is most often of respiratory
etiology, and an injured child who is obtunded, unresponsive, or combative may need to be intubated.
An uncooperative child who needs radiologic imaging may also need to be intubated. Intubation must
be performed with the jaw thrust technique and in-line cervical stabilization. Keep in mind these key
anatomic differences for intubation in children: larger tongue, more narrow and anterior glottis, and
shorter trachea. You may find that a straight Miller blade is easier than the curved Mac blade because
the epiglottis is floppy (less cartilaginous). The appropriate size of ETT can be estimated by the size of
pinkie finger (or the formula = [age + 16]/4). The Broselow Pediatric Emergency Resuscitation Tape
is also a useful tool to estimate ETT (and other device) size and medication doses, given a child’s height
or weight. Use an uncuffed ETT in a young child (<8 years of age or approximately 60 lb), because the
subglottic trachea is narrow and provides a sufficient seal. However, cuffed ETT may be used (except in
newborns), if appropriate cuff pressures are used. Rapid sequence intubation is similar to adults,
including preoxygenation with 100% FiO2, medication administration, cricoid pressure, cervical spine
stabilization, laryngoscopy, and advancement of tube to an appropriate distance beyond the cords.
Confirm exhaled CO2 and secure the tube. In the rare event of acute airway obstruction, needle
cricothyroidotomy with a 14 g catheter is preferential to open cricothyroidotomy because of the
increased incidence of subglottic stenosis.
Table 29-1 Pediatric Vital Signs
736
booksmedicos.org
Figure 29-2. A: Intraosseous line placement. B: EZ-IO drive.
After securing the airway, assess the child’s breathing (“B”). If there is difficulty with respiration,
assist the ventilation and assess for potential life-threatening thoracic injuries: pneumothorax (open
chest wound or tension pneumothorax), hemothorax, flail chest/pulmonary contusions, and rib fractures
with splinted breathing. The mediastinum of a child is very compliant and can lead to rapid decline
from a tension pneumothorax. These life-threatening injuries must be rapidly identified and treated.
Children are diaphragmatic breathers and, therefore, gastric distension can be an unrecognized
contributor to respiratory distress, especially in the young child who is distended from swallowing air
while crying. If there are concerns for abdominal distension, a nasogastric tube should be placed to
decompress the stomach. Use an orogastric tube in babies, who are obligate nose breathers.
Hemorrhage is the most common etiology of Circulatory compromise (“C”) in trauma, but do not
overlook obstructive etiologies (cardiac tamponade and tension pneumothorax) and distributive
etiologies (neurogenic shock). Assessment of volume status and shock is difficult in the child. Children
have impressive physiologic reserve and can maintain systolic blood pressure until late-stage
hypovolemic shock (>30% blood loss). Tachycardia, tachypnea, altered level of consciousness, and
poor peripheral perfusion (mottled cool extremities, weak thready pulses, narrowed pulse pressure,
delayed capillary refill) are early but subtle signs of blood loss. Establishing vascular access in an
injured child is a priority and can be challenging. Peripheral intravenous lines are ideal, but when they
cannot be obtained, intraosseous lines are quick, reliable, and allow high-volume infusion of any fluid
(crystalloid, blood products, and even medications, including pressors). An intraosseous line is placed in
the anteromedial tibia, 2- to 3-cm distal to the tibial tuberosity after a quick skin preparation for
sterility (Fig. 29-2). Avoid wounds, fractures, or infected areas. They should ideally be placed with a
single attempt because multiple holes can lead to leakage of infusion fluids and resultant compartment
syndrome. If contraindicated, definitive intravenous (IV) access can be obtained with a central line in
the femoral vein or a peripheral vein cut down (i.e., saphenous vein).
Initial fluid resuscitation is indicated when there are signs of hypovolemic shock. Initial bolus consists
of 20 mL/kg of warmed normal saline or lactated Ringer’s solution. This may be repeated if there is no
response or only a transient response. All subsequent volume resuscitation should be performed with
blood products (10 mL/kg = “1 unit”) (Table 29-2). If there is no time for cross-matched, type-specific
blood, “O-negative” blood is indicated. Massive transfusion protocols may be initiated at this time if
indicated and should include hemostatic resuscitation with packed red blood cells, fresh frozen plasma,
and platelets, targeting high plasma-to-red blood cell and platelet-to-red blood cell ratios.18 In the most
recent advanced trauma life support protocols, this has become known as “damage control
resuscitation,”19 espousing permissive hypotension, minimizing crystalloid resuscitation, and promoting
early blood product administration for the treatment of the lethal triad (acidosis, coagulopathy, and
hypothermia) of severe uncontrolled hemorrhage. There is, however, no evidence-based support for
permissive hypotension strategies in pediatric trauma patients. As in adults, ongoing hemodynamic
instability from blood loss in a child must be controlled expeditiously. Sources of bleeding can be
thought of in terms of body compartments: including the chest, peritoneal cavity,
retroperitoneum/pelvis, femur fracture/thigh compartment, and external injury (especially the scalp).
In an infant, prior to suture closure of the skull, intracranial hemorrhage may produce hemodynamic
instability. Once resuscitated, maintenance fluid requirements (Table 29-2) can be estimated using the
“4-2-1” rule and should be administered as D5 1/2NS (or D10 1/2NS for neonates).
Table 29-2 Fluid Management in Children

737
booksmedicos.org
A brief neurologic assessment is part of the primary survey (“D” for disability). Head injury accounts
for the highest degree of morbidity and mortality in children and is the principle determinant of
outcome after trauma. However, children have the potential for more frequent and fuller recovery from
even serious head injury, when compared to similar injuries in adults.20 Therefore, careful attention to
preventing secondary injury and maximizing tissue perfusion to the brain can greatly improve outcome.
These secondary insults include ischemia, hypoxia, hypotension, hyperthermia, hypercapnia, acidosis,
and increased intracranial pressure (ICP). The Glasgow Coma Scale (GCS) is modified in young children
who are preverbal to measure neurologic function and prognosis. The motor response scale tends to
provide the most reliable assessment of function in a preverbal or intubated child (Table 29-3).
In preparation for the secondary survey, the child must be Exposed (“E”) completely for a complete
head-to-toe physical examination. Keep in mind that they also have a larger body surface area ratio and,
therefore, lose heat and water quickly and can become hypothermic. Use warm fluids, bare huggers,
warming lights, and warm ambient room temperature to prevent heat loss in a child and the secondary
coagulopathy that is associated with hypothermia.
Only after the primary assessment is complete, and ABCs are secured, do we move on to the full
secondary survey. In reality, with a team approach to management of the pediatric trauma patient,
much of the supportive care happens concurrently with the primary and secondary surveys, including
placement of intravenous lines, drawing laboratories, applying monitors and oxygen, and obtaining
ancillary diagnostic tests. Adjunct diagnostic modalities and imaging may be used to provide additional
information in the evaluation of a pediatric trauma patient. Although diagnostic peritoneal aspiration
has been traditionally used to evaluate intra-abdominal injuries in the unstable patient, it has no role in
the pediatric population where solid organ injuries are unlikely to require surgery. Focused assessment
with sonography in trauma (FAST) examination has significant advantages over more invasive
diagnostic maneuvers: the FAST examination can be performed quickly and exposes the patient to no
potential harm from delay or ionizing radiation. However, children with intra-abdominal injuries are
more frequently managed nonoperatively, and thus the need for rapid decision making regarding
operative management is less common. Children also have a relatively higher incidence of solid organ
injury without free fluid, and consequently, a negative FAST examination may not obviate the need for
an abdominal computed tomography (CT) when there is a clinical suspicion of significant injury. The
FAST examination should not be relied on as a stand-alone screening tool in the pediatric
population.21,22 Findings from chest radiography, anteroposterior pelvis radiography, and the FAST
examination, along with the primary and secondary surveys, guide decisions regarding further
radiographic examination, including CT or plain radiography.
In addition to a full physical examination, a brief history is essential and is often provided by
emergency medical services (EMS) personnel or the parents. An “AMPLE” history helps the provider
focus on essential information such as Allergies, Medications, Past medical history, Last meal, and
Events surrounding the traumatic incident. Blunt trauma is the most common mechanism after which
children present for evaluation. Children are more prone to multisystem trauma due to their small body
size and more compliant body (less protective bones, muscle, and torso fat). Blunt trauma can result in
injury patterns that resemble penetrating injuries, without significant external signs of trauma. Careful
attention to a bruise on the abdominal wall resulting from a bicycle handlebar should lead to a more
thorough investigation of the abdomen. A lap belt mark across the abdomen may raise concerns of
lumbar spine fracture (Chance fracture), with an associated risk of small bowel injury. A history of
significant hemorrhage at the scene may instigate a more thorough investigation of the vessels in the
proximity of injury in an otherwise hemodynamically stable patient who has no hard signs of vascular
injury. Therefore, a thorough history, mechanism of injury, and focused examination of the entire child
is mandated so that signs of forceful impact can be elucidated.
738
booksmedicos.org
Table 29-3 Modified Glasgow Coma Scale in Children
MANAGEMENT OF SPECIFIC INJURIES

Traumatic Brain Injury
Traumatic brain injury is the leading cause of death and disability in children,20,23,24 and is an important
determinant of outcome. Physical abuse such as shaken baby syndrome is the most common cause of
head injury in children younger than 2 years, and blunt head trauma from motor vehicle accidents, falls,
or bicycle/pedestrian accidents are responsible for most injuries in children older than 2 years. Injury
prevention strategies are necessary for improving outcomes of the primary TBI. However, reduction of
secondary injury patterns is critical in children, who have impressive physiologic reserve and potential
for rehabilitation after brain injury. Focus must be on preserving cerebral oxygenation and perfusion
and mitigate toxic exposures to minimize secondary brain injury. This includes treating or preventing
hypotension, hypoxia, hyper or hypocarbia, hyperoxia with generation of ischemia reperfusion free-
radicals, hyperthermia, seizures, and intracranial hypertension.
Mild Traumatic Brain Injury
Children with minor head trauma can present the greatest challenge to emergency department
personnel. Eastern Association for the Surgery of Trauma (EAST) guidelines define mild traumatic brain
injury (MTBI) to be interchangeable with the term “Concussion,” involving a blunt force mechanism
with alteration in brain function (i.e., GCS score of 13 to 15) but by definition must have a normal head
CT if performed.25 Significant brain injuries need to be identified early and treatment instituted rapidly.
CT scans provide the most accurate and expeditious means of diagnosis but expose many pediatric
patients to unnecessary radiation. Evidence-based clinical decision tools have helped identify the
population of children who benefit most from radiologic evaluation. The TBI study group for PECARN
(Pediatric Emergency Care Applied Research Network) has developed tools for assessment of children
after blunt head injury.25–30 The “PECARN Rules,”26 (Algorithm 29-1) identify children at very low risk
(<0.05%) of having clinically important TBI requiring intervention. These patients can avoid CT and be
discharged safely with appropriate instructions. Children with abnormal GCS score (GCS score of ≤14)
or evidence of skull fracture are at the highest risk for clinically important injury and should be
evaluated emergently by CT scan. If there is a history of loss of consciousness, severe injury mechanism,
abnormal behavior to the parent or nonfrontal scalp location (<2 years), or vomiting and severe
headache (≥2 years), then further observation or CT should be offered as reasonable management
options. Subsequent analyses also identified children with only isolated loss of consciousness (and no
other PECARN predictors) to be at very low risk for clinically important TBI.27 Children with MTBI
(GCS score of 14 to 15) who underwent CT can be safely discharged home without further neurologic
monitoring, if their head CT scan is normal.25,28 Even those with an isolated skull fracture can be
739
booksmedicos.org
discharged home from the emergency department with strict discharge instructions and return
precautions.29,30,31,32 At this point, routine structural or functional imaging modalities such as magnetic
resonance imaging, functional magnetic resonance imaging, or positron emission tomography for
diagnosis or prognosis of MTBI are not supported.25
Algorithm 29-1. PECARN rules to identify children at very low risk of clinically important TBI. CT algorithm for children younger
than 2 years (A) and for those aged 2 years and older (B) with GCS scores of 14–15 after head trauma. ciTBI, clinically important
traumatic brain injury; GCS, Glasgow Coma Scale; LOC, loss of consciousness. (From Kuppermann N, Holmes JF, Dayan PS, et al.
Identification of children at very low risk of clinically-important brain injuries after head trauma: A prospective cohort study.
Lancet 2009;374(9696):1160–1170.)
Prognosis and outcome in MTBI, especially as it relates to “return to learn or return to play” after
concussion, is still hotly debated. Most studies agree that patients with MTBI return to baseline within 3
months (majority within 10 to 14 days), but certainly symptom resolution can take longer. Lingering
symptoms of headache, dizziness, fatigue, sleep disturbance, impairment in memory and concentration,
irritability, anxiety, or depression are referred to as the “postconcussive syndrome,” which is not a well-
understood entity.25 Standardized tools exist, such as the Immediate Postconcussion Assessment and
Cognitive Testing Battery (ImPACT), to aid clinicians in functional assessment of patients with MTBI.33
The well-known NCAA Concussion Study from 2003 found that high-level athletes were more likely to
sustain repeat concussions, which were associated with a longer recovery time,34 and it has been
increasingly recognized that repeat concussions can have permanent and sometimes devastating effects.
In 2010, the American Academy of Pediatrics officially endorsed the International Conference on
Concussion in Sport recommendations for a graduated “Return to Play” protocol (available online:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004129/table/T1/, last accessed April 5, 2016).35,36
The CDC HEADS UP guidelines also incorporate these recommendations37 and provide resources for
schools, coaches, and primary care providers on returning to school and sports after a concussion. Data
are lacking in the efficacy of these guidelines and their role in preventing recurrent concussions.38
740
booksmedicos.org
Moderate to Severe TBI
More serious head injury needs to be evaluated and treated expeditiously. The GCS (and modified GCS
for infants) is a universal tool that can be used for rapid assessment of neurologic function and is based
on verbal response, motor function, and eye opening. Moderate TBI is considered GCS score of 9 to 12
or 13 and severe TBI includes GCS score of ≤8, the definition of a coma. The goal of initial assessment
and resuscitation in a severely brain injured patient is to minimize or prevent secondary brain injury.
Attention to ABCs is critical, with maintenance of normotension and normoxia. Management of severe
TBI in the pediatric intensive care unit is largely focused on management of elevated ICP and
maintenance of cerebral perfusion pressure.39 In 2003 and again in 2012, guidelines for the acute
medical management of severe TBI in infants, children, and adolescents were published, which
represented the first recommendations made specifically for pediatric patients (Tables 29-4 and 29-
5).40–43 These guidelines, composed mostly of class II or III evidence, included recommendations on
management of intracranial hypertension, hypoxia/airway management, indications for ICP monitoring,
thresholds for treatment and management of cerebral perfusion pressure, and hypotension. It also
addressed therapies such as cerebrospinal fluid drainage, hyperosmolar therapies, hyperventilation,
barbiturates, decompressive surgery, temperature control, corticosteroids, and supportive care such as
sedatives/neuromuscular antagonists and nutrition, although the guidelines are mostly based on expert
panel opinion rather than large clinical trials. Prehospital management focused on the benefit of
pediatric trauma centers rather than adult trauma centers for children with severe TBI. Supplemental
oxygen should be administered. There was no superiority of endotracheal intubation versus bag-mask
ventilation in the prehospital setting, but if endotracheal intubation is to be undertaken, specialized
training and the use of end-tidal CO2 monitoring is encouraged. Hyperventilation with hypocarbia
(pCO2 <30 to 35) is to be avoided. There was class II support for ICP monitoring for children with GCS
score of 8 or less; using an ICP threshold of 20 mm Hg and a cerebral perfusion pressure of 40 to 65
mm Hg; efficacy of hypertonic saline solutions in lowering ICP; and the role for decompressive surgery
in the treatment of elevated ICP. From these guidelines, an algorithm for the management of acute
intracranial hypertension was developed on the basis of the expert opinions of the committee
(Algorithm 29-2), which has served as a template for clinical protocols for patient care and research.
The 2012 guidelines changed a few of the recommendations (Table 29-5). Only hyperosmolar therapy
was supported by two small studies (class II data); the remaining therapeutics could not be supported by
the literature, including use of corticosteroids, immune-modulating diets, and induction of moderate
hypothermia (“Cool Kids” trial).44,45 Other topics with class III evidence were added including advanced
neuromonitoring (using a brain–tissue oxygen partial pressure of 10 mm Hg), neuroimaging (avoiding
routine repeat head CT unless neurologic deterioration), cerebrospinal fluid drainage, and the use of
antiseizure prophylaxis (phenytoin prophylaxis) to reduce posttraumatic seizures. For a variety of other
topics, including glycemic control, cerebrospinal fluid drainage, and
analgesics/sedatives/neuromuscular blockade, definitive recommendations could not be made on the
basis of the available literature. Overall, there is still a paucity of high-quality evidence to make specific
treatment plans for children with severe TBI, but this allows for a wide variety of clinical approaches
that are considered within the guidelines of pediatric care.
Spine Trauma
3 Cervical spine injuries (CSI) in blunt trauma pediatric patients occur in less than 2% of seriously
injured children. Despite this low incidence, it is clear that many clinicians obtain radiographs in order
to exclude CSI. The added benefit of routine imaging in the pediatric trauma evaluation is debatable. In
recent years, concerns have been raised about the liberal use of plain films, CT scans, and magnetic
resonance images in children with reference to imaging-related short- and long-term morbidity, resource
consumption, and cost. The increased risk of fatal and nonfatal cancers associated with CT-related
radiation has gained attention both by physicians and also by consumers. Both the U.S. Food and Drug
Administration Center for Devices and Radiological Health (FDA) and the National Cancer Institute have
published guidelines designed to limit unnecessary imaging in children. Although proponents of liberal
imaging argue that a single missed CSI may cost more than multiple diagnostic tests, the use of non–
evidence-based tests may inspire suboptimal practice with an undefined risk-benefit ratio.
Two seminal studies (NEXUS and Canadian Cervical Spine Rules [CCR])46,47 have examined whether
clinical criteria (neurologic deficit, cervical spine tenderness, intoxication, decreased mental status, and
distracting injuries) can rule out CSI in adults without the need of imaging. These criteria have been
applied to pediatric patients in a manuscript by Viccellio and colleagues,48 who evaluated 3,065 blunt
741
booksmedicos.org
trauma patients younger than 18 years and found that nearly 20% of patients fell into the “low-risk”
category where imaging could have been avoided. In another retrospective review of 206 pediatric
patients (from birth to 16 years of age), Jaffe and colleagues49 suggested that the absence of eight
clinical criteria (neck pain; neck tenderness; abnormality of reflexes, strength, or sensation; direct
trauma to the neck; limitation of neck mobility; abnormal mental status) enabled a clinician to detect
CSI in children with a sensitivity of 98% and a specificity of 54%. The PECARN group has also reported
on its series of 540 cervical spine injuries in children, presenting a model with eight predictors to
identify children who should be evaluated for CSIs after blunt trauma.50 These include altered mental
status, focal neurologic deficits, complaint of neck pain, torticollis, substantial torso injury, predisposing
condition, diving, and high-risk motor vehicle crash, with a sensitivity of 98%.
Table 29-4 Summary of Standards, Guidelines, and Options Generated from the
2003 Pediatric TBI Guidelines
742
booksmedicos.org
Table 29-5 Summary of Evidence Generated from the 2012 Pediatric TBI
Guidelines
Location of Injury
Conventional wisdom has taught that the position of a CSI in children was related to age with the
predominance of upper c-spine injuries seen in infants and toddlers and lower c-spine injuries seen in
adolescents. This was thought to be a result of the mechanism of injury (flexion/extension and axial
load, respectively). However, in a recent evaluation of the pediatric national trauma database, Polk et
al.51 identified a greater percentage of injuries to the lower c-spine than previously reported. A large
database study evaluated the tendency for injuries to occur at certain levels of the cervical spine over a
5 year period and found that younger children (≤10 years of age) sustained upper (C1–C4) CSI more
frequently than lower (C4–C7) CSI (87% vs. 57%).49 Data from a 24-year retrospective study of patients
admitted with CSI to a level 1 trauma center similarly concluded that for younger patients (≤8 years of
age), significantly more injuries occurred in the upper cervical spine.46 However, the National Trauma
Data Bank (NTDB) data for this study revealed that the number of fractures to the upper c-spine and
lower c-spine was nearly equal (53% and 47%), and that more than half of cervical spinal cord injuries
were located in the lower c-spine (53%).51
743
booksmedicos.org
744
booksmedicos.org
Algorithm 29-2a. Algorithm generated by the Brain Trauma Foundation Committee for the first edition of the Guidelines for the
Medical Management of Severe Traumatic Brain Injury in Infants, Children, and Adolescents for first-tier therapies (A) and second-tier
therapies (B). AFDO2, arteriovenous difference in oxygen; CBF, cerebral blood flow; CPP, cerebral perfusion pressure; CSF,
cerebrospinal fluid; CT, computed tomography; EEG, electroencephalogram; GCS, Glasgow Coma Scale; HOB, head of bed; ICP,
intracranial pressure; PaCO2, partial pressure of carbon dioxide; PRN, as needed; SjO2, jugular bulb venous oxygen saturation.
(From Bell MJ, Kochanek PM. Pediatric traumatic brain injury in 2012: The year with new guidelines and common data elements.
Crit Care Clin 2013;29(2):223–238, with permission.)
Mechanism of Injury
Motor Vehicle Crash (MVC) remains the most common mechanism of CSI for the youngest age
group.46–49,52 A study of children younger than 14 years observed that while MVC was the most
common mechanism for this large age group, when ages were further stratified, MVC ranked the
highest for infants.53 This same study also found that falls were the most common mechanism for the 2
to 9 years age group. While the focus on children younger than 3 years in this study was unique,
conclusions about mechanism of injury remained consistent with previous literature. The frequency of
MVC as mechanism for blunt trauma CSI is significantly greater than all other mechanisms, with falls
ranking second (66% and 15%, respectively). Given that this patient population is just learning to walk,
falls are a concern. However, the high energy of an MVC has greater potential for major neurologic
impairment and mortality.
The observations generated from analysis of the NTDB data suggest that the lower C-spine needs to
be adequately evaluated on the basis of the near equal distribution of injuries. In addition, the
association of CSI with high-energy mechanisms (i.e., MVAs) warrants a higher index of suspicion of
this subset of young pediatric patients. In addition, those patients requiring at scene intubation and/or
admission to the intensive care unit (ICU) should also be evaluated thoughtfully. Despite the low
incidence of CSI, until the cervical spine is cleared, it should be immobilized, ideally with an age/size
appropriate hard collar. Such collars should be stocked in all trauma centers that care for pediatric
patients.
The authors of the reviewed paper53 implemented a similar clinical guidelines strategy emphasizing
the use of physical examination and NEXUS criteria in order to clear the cervical spine in children
presenting after trauma. The primary outcome measure was to determine the use of CT scans in children
younger than 15 years and to compare the extent of use of CT scans for cervical spine clearance 12
months before and after implementation of these guidelines. A total of 233 children were evaluated
745
booksmedicos.org
during the 2-year period (128 before guidelines were in place and 105 afterward). For children
clearable by NEXUS criteria, the implementation guidelines had an immediate effect, decreasing CT use
by 23%. Furthermore, there were no missed injuries. These results offer even more evidence that much
of the imaging that is done to clear the c-spine in a child is unnecessary. The clinical evaluation of
pediatric trauma patients with suspected c-spine injury is quite effective in predicting which subset of
patients will benefit from cross-sectional imaging. Simple clinical criteria, like GCS, used in concert with
the physical examination, can safely predict CSI in children, safely reducing the dependence on clinical
imaging for the vast majority of patients (even the very young).
Spinal Cord Injury without Radiographic Abnormality

Spinal cord injury without radiographic abnormality was first defined in a series of children with signs
of acute traumatic spinal cord injury in the absence of bony findings on cervical spine radiographs,
flexion–extension films, or CT scans.54 The authors noted that these patients had neurologic deficits or a
history of transient paresthesias, numbness, or paralysis, and a delay of symptoms occurred in
approximately half of the patients.
In recent years, as attention to limit ionizing radiation exposure in children has increased, magnetic
resonance imaging has become a mainstay in the workup of children with presumed CSI or neurologic
deficits on physical examination. As a result, more children have been found to have demonstrable
injury to the spinal cord, soft tissue components of the spinal column vertebral body growth plates.55,56
As a result of this advent of new neuroimaging paradigms, the diagnosis of spinal cord injury without
radiographic abnormality has become questionable. Although the trend in the workup has been to limit
radiography in children (with good reason), it is important to remember that young patients with blunt
trauma who have a history of any transient neurologic symptom may have a significant injury to the
spinal cord and/or spinal column, and these children warrant thorough radiographic evaluation.
Cerebrovascular Injury
Blunt trauma force to the neck or cervical spine fractures can result in vascular injuries to the carotid or
vertebral arteries. Stroke and permanent neurologic deficit is the most feared outcome from this rare
injury, and in children, because of ill-defined screening criteria, neurologic deficit is the most common
presenting symptom for diagnosis. 2010 EAST guidelines are aimed at adult patients and provide little
evidence toward screening criteria or management in either adults or children.57 Risk factors for
cerebrovascular injury include injury mechanism with severe hyperextension or hyperflexion with
rotation, maxillary or mandibular injuries, TBI with diffuse axonal injury, near hanging, “seat belt sign”
or other soft tissue contusion to the neck, and fractures involving the carotid canal or cervical vertebral
body, particularly the vertebral foramen. A recent meta-analysis of pediatric blunt cerebrovascular
injury recommended screening high-risk pediatric patients with CT angiography of the neck and
treatment with anticoagulation in patients with confirmed injuries.58
Thoracic Trauma
Blunt trauma, most commonly from motor vehicle crashes, is the most common mechanism for thoracic
trauma in pediatric patients. Children have a more flexible, cartilaginous rib cage, and, therefore,
serious intrathoracic injuries can occur in the absence of obvious external trauma or rib fractures.
Children also have a more mobile mediastinum, predisposing them to tension pneumothorax with
subsequent cardiopulmonary collapse from impaired venous return. The primary survey is designed to
identify these acute life-threatening thoracic injuries such as airway injury, tension pneumothorax, open
pneumothorax, hemothorax, flail chest with pulmonary contusion, or cardiac tamponade, which require
immediate intervention (Table 29-6).59 Once bilateral breath sounds and adequate ventilation and
oxygenation are confirmed, CXR is an urgent part of any pediatric trauma evaluation and can identify
most other acute thoracic injuries. FAST examination can evaluate for pericardial fluid and in
experienced hands can identify pneumothorax or pleural effusion. Many injuries can be observed or
managed with tube thoracostomy.
Pulmonary contusions are one of the most common thoracic injuries after blunt trauma. The diagnosis
is made on CXR in which infiltrates are identified that do not follow anatomic boundaries. Parenchymal
edema peaks at 24 to 36 hours postinjury, as the contusion “blossoms” on CXR, and requires admission
for monitoring, oxygen therapy, or intubation and respiratory support if needed. Any evidence of
hemothorax or pneumothorax seen on CXR should be managed initially with tube thoracostomy. Stable
patients with an occult pneumothorax (seen only on CT scan but not on CXR) may be safely observed
without thoracostomy drainage, even if requiring positive pressure ventilation. Traditional indications
746
booksmedicos.org
for thoracotomy in adults include an initial chest tube output of 1,500 mL and a persistent output of 150
to 200 mL/hr for 4 hours. In children, this equates to a chest tube output of approximately 20% of the
patient’s estimated blood volume, or ongoing output of 2 to 3 mL/kg/hr. However, patient physiology
should be the primary indication for surgical treatment rather than the absolute blood output. The
thoracoscopic approach has become increasingly acceptable in stable patients for the management of
retained hemothorax, persistent air leak, or select diaphragmatic injuries after penetrating
thoracoabdominal trauma. The EAST practice management guidelines for thoracic trauma provide a
good overview of the evidence for management of thoracic trauma in adults, but no specific guidelines
exist for pediatric patients.60
Emergency bedside thoracotomy is indicated for patients who present pulseless to the emergency
department with signs of life and penetrating thoracic trauma. The evidence is more controversial for
patients who do not have signs of life or who sustained penetrating extrathoracic injuries or blunt
trauma and should be based on clinical judgment. There is no role for emergency thoracotomy for
patients without signs of life after blunt trauma.61 Advanced trauma life support guidelines recommend
application of these guidelines to children on the basis of existing literature,62,63 but these data are
sparse.
Table 29-6 Acute Life-Threatening Thoracic Injuries
Other serious thoracic injuries are very rare in children but include blunt aortic injury and blunt
cardiac injury. Aortic injury can be effectively diagnosed with CT scan with IV contrast (CT angiogram).
Widened mediastinum on CXR from a physiologic thymic shadow is quite commonly seen in young
children. However, with the appropriate mechanism, including blunt thoracic trauma with a significant
deceleration mechanism, and abnormal contour of mediastinum, CT chest angiography with contrast
may be required to rule out this injury.64,65 Treatment, as in adults, relies on strict antihypertensive
therapy and operative repair, including the endovascular approach in those children who are big enough
to accommodate a stent (although this has not been standardized in pediatric patients). Blunt cardiac
injury (most commonly myocardial contusion) can also be challenging to diagnose but occurs most
commonly after motor vehicle collision or pedestrian trauma. Abnormalities on EKG are the main
findings in myocardial contusion. Traditional risk factors such as sternal fracture or upper rib fractures
do not appear to correlate with blunt cardiac injury. The new EAST guidelines, although designed for
adult patients, recommend an EKG and troponin I if blunt cardiac injury is suspected. If both studies are
normal, this effectively rules it out. If either is abnormal, the child should be admitted to a monitored
bed. Echocardiogram is recommended only for patients with hypotension or arrhythmias.66
Traumatic asphyxia occurs in children because of their flexible thoracic wall in the setting of direct
blunt compression, most often after a motor vehicle collision or crush injury. At the time of injury, if
the glottis is closed and the thoracoabdominal muscles are tensed, the increased intrathoracic pressure is
transmitted through the central venous system (inferior and superior vena cava) to the brain and solid
organs. Typical signs of traumatic asphyxia include subconjunctival hemorrhage and petechiae of the
chest, shoulders, and head, with subsequent bronze discoloration of the skin. Supportive care in a
monitored setting is the standard of care for these children, watching for signs of airway edema.
Abdominal Trauma
Blunt mechanism of injury is the most common cause of abdominal trauma in children. Assessment of
abdominal trauma in pediatric patients can be challenging. Vomiting, abdominal tenderness, and seat
belt signs are signs and symptoms that increase the likelihood of abdominal injuries. FAST examination
747
booksmedicos.org
is a standard assessment in adult trauma patients, but its role in pediatric patients is still controversial.
In an unstable patient, FAST examination can help identify the presence hemoperitoneum and triage a
patient to the operating room or interventional radiology suite. CT scan with IV contrast is the best
assessment for abdominal trauma in a stable pediatric patient. Despite concerns for radiation exposure,
this is an important study if indicated. PECARN has similarly developed rules and algorithms to identify
a low-risk patient who can safely avoid abdominal CT.67–69 If an examinable child (GCS score of >13)
had no evidence of abdominal or chest wall trauma (including seat belt sign), no abdominal pain,
tenderness or vomiting, and normal bilateral breath sounds, the rule had a 99.9% negative predictive
value for intra-abdominal injuries requiring intervention67,69 and was more sensitive than clinical
suspicion.68 After a normal abdominal CT scan, most patients can safely be discharged if otherwise
stable (sensitivity 97.8%). However, most missed injuries were hollow viscous injuries, which are
difficult to identify on CT and should be suspected in patients with seat belt sign, free fluid on CT, or
leukocytosis.70
Penetrating abdominal trauma is much less common in children than in adults but should be managed
similarly. There is increasing evidence toward a nonoperative, conservative approach to abdominal stab
wounds that penetrate the fascia, relying on serial examinations and imaging to guide operative
approach. Laparotomy is still largely recommended for gunshot wounds to the abdomen on the basis of
the most recent 2010 EAST guidelines, although this area remains controversial.71
Damage control laparotomy is an established operative approach for hemodynamically unstable
trauma patient in hemorrhagic shock and is utilized in approximately 5% of all laparotomies for trauma
in both adults and children. The goal of this approach is to avoid the onset of the lethal triad:
hypothermia, coagulopathy, and acidosis. The procedure is abbreviated and focused on maintaining the
priorities of hemorrhage control, followed by control of contamination and temporary abdominal
closure, with plans to return for definitive repairs after resuscitation and warming in the ICU, usually 24
to 48 hours later. The decision for damage control should be made early in the operative course in order
to minimize exposure time in the operating room and avoid irreversible shock and its sequelae.
Although well described and widely adopted within the adult trauma population, data are less available
in the pediatric population but theoretically of even greater importance as children have small
circulating blood volumes and are more prone to hypothermia.72 As discussed in a previous section,
damage control resuscitation is managed in parallel, with a focus on initiating the massive transfusion
protocol, minimizing crystalloid fluids, and resuscitating with blood products using a high ratio of
plasma and platelets for each unit of red blood cells transfused.72
Solid Organ Injuries

Most solid organ injuries (spleen, liver, and kidney) are managed nonoperatively after blunt trauma.73
Most of these injuries are identified or evaluated by CT and can be graded according to American
Association for the Surgery of Trauma (AAST) grading system for prognostic value.74 In a large series of
pediatric patient with solid organ injury, 11% received a blood transfusion, 1.4% underwent
angiographic embolization, and 4% required laparotomy.75 Laparotomy rates ranged from 5.4% at adult
trauma centers to 2.8% at freestanding children’s hospitals, raising concerns for optimal and consistent
management of pediatric patients who are cared for in adult centers.75–77 Across all institutions, there is
wide variability of care of pediatric patients with solid organ injuries. In those managed successfully
with nonoperative management, there is no standard of care for level of monitored care (whether
children are admitted to ICU vs. floor vs. home), frequency of blood draws, duration of bed rest or
bowel rest, and timing of discharge home and resumption of activities.75 In the 1990s, the American
Pediatric Surgical Association proposed an algorithm for posttrauma management of solid organ
injuries, which has commonly been adopted by institutions but has never been rigorously verified
(Table 29-778). These recommendations include ICU admission only for grade IV solid organ injury,
observation on the pediatric floor for a duration of injury grade +1 days, liberation of diet and
ambulation once the hematocrit has stabilized (and hematuria resolved in renal injuries), and exertional
activity restriction for a duration of injury grade +2 weeks. No routine reimaging of injuries is
recommended.78 Indications for laparotomy include hemodynamic instability, ongoing blood loss
(hematocrit drop) with blood transfusion requirement of greater than 20 mL/kg, or evidence of hollow
viscous injury. More recently, the American College of Surgeons’ pediatric trauma consortium
(ATOMAC) developed a practice management guideline for solid organ injury, which is now used at
many additional pediatric trauma centers throughout the United States.79 The guidelines support
management on the basis of hemodynamic status rather than injury grade. Transfusion triggers have
748
booksmedicos.org
been debated and although there are no class I data to support a number at which blood should be
given, it is generally agreed that transfusion should be considered at a threshold of 7.0 g/dL. It supports
abbreviated bed rest and earlier discharge than the older APSA guidelines (Algorithm 29-3). The
approach to angiographic embolization for splenic salvage is still controversial in pediatric patients and
has a wide variability among institutions.79–82
Table 29-7 Original American Pediatric Surgical Association Guidelines for

Posttrauma Management of Pediatric Solid Organ Injury
The role of FAST examination for diagnosis of solid organ injury in children is still unclear. Whereas
its use has long been the standard of care in adults, recent PECARN data of pediatric trauma centers
suggest that only 13% of pediatric trauma patients with a suspicion for intra-abdominal injuries undergo
FAST examination.83,84 Sensitivity in pediatric patients ranges from 50% to 92%, with a rigorous meta-
analysis suggesting the sensitivity to be around 66%.21,22,85–87 Specificity is also very low, and in a
hemodynamically stable patient, a positive FAST examination should be followed up with an urgent CT.
Bedside FAST may have utility in hemodynamically unstable patients to rapidly identify or rule out
intraperitoneal hemorrhage when patients cannot undergo CT, but decision making should include other
features such as patient physiology, mechanism, clinical suspicion, and responsiveness to initial
resuscitation measures.22,88 As its use in children increases, it is likely that FAST will become more
reliable, with greater sensitivity and specificity. Until a prospective study is done, it should remain a
screening tool and that physical examination findings should dictate next steps.
749
booksmedicos.org
Algorithm 29-3. New ATOMAC guidelines for management of pediatric solid organ injury. Hb, hemoglobin; ICU, intensive care
unit; LR, lactated ringers; NOM, nonoperative management; NPO, non per os; NS, normal saline; PICU, pediatric intensive care
unit; PRBC, packed red blood cell; q6h, every 6 hours. (From Notrica DM, Eubanks JW III, Tuggle DW, et al. Nonoperative
management of blunt liver and spleen injury in children: Evaluation of the ATOMAC guideline using GRADE. J Trauma Acute Care
Surg 2015;79(4):683–693, with permission.)
Hollow Viscous Injury

Hollow viscous injuries occur after blunt trauma, in particular bicycle handlebar injuries, lap belt
injuries (often with seat belt sign and associated with Chance vertebral fracture), and direct blows to
the abdomen. Diagnosis is challenging with current radiographic techniques. Subtle findings on CT must
be elicited, including free fluid in the absence of solid organ injuries, free intraperitoneal air, or
extravasation of oral contrast. In the setting of abdominal wall ecchymosis (seat belt sign), leukocytosis,
or abdominal tenderness, patients should be closely monitored with serial abdominal examinations and
blood count. Evidence for evolving peritonitis, fever, leukocytosis, or systemic inflammatory response
syndrome physiology should prompt surgical exploration, either laparoscopic or by laparotomy.
Intramural duodenal hematomas are managed conservatively without surgical intervention but may
take several weeks to completely resolve, requiring nasogastric tube (NG) drainage and Total Parenteral
Nutrition (TPN) in the interim. Delayed stricture after partial thickness luminal injury or mesenteric
injury can present days to weeks after an injury, with symptoms of partial or complete small bowel
obstruction.
Pancreatic and Biliary Injury

Pancreatic injury classification by AAST injury grade divides patients into those without ductal injury
(grades 1 to 2) and those with duct disruption (grades 3 to 5). Currently there is no universal standard
750
booksmedicos.org
for management of pancreatic trauma in pediatric patients, but evidence is beginning to emerge.89–97
Amylase and lipase are useful to screen for pancreatic injury but may be normal immediately after
trauma; by 3 hours after trauma, they are universally elevated (100% sensitivity), although with low
specificity.91 CT scan of the abdomen can help determine the integrity of the duct, but endoscopic
retrograde cholangiopancreotography (ERCP) may be a useful adjunct in some patients. In general,
higher-grade pancreatic injuries with duct disruption result more frequently in operative intervention.
Although early literature promoted nonoperative management for pediatric pancreatic injuries,91–95
recent reports and multi-institutional studies have suggested improved outcomes, reduced need for
drainage procedures, and decreased length of stay (LOS) for operative intervention, most commonly
distal pancreatectomy.89,96,97
Biliary injury is rare in children, representing <0.1% of all trauma patients, and includes intrahepatic
and extrahepatic ductal injuries, biloma, and gallbladder injury. Literature is sparse but many injuries
can be managed nonoperatively with ERCP with biliary stent placement and percutaneous peritoneal
drainage. These patients are at risk for delayed stricture and require close follow-up.
Hepaticojejunostomy remains the definitive repair for extrahepatic biliary tract transections.98
Anorectal Injuries
Anorectal injuries are uncommon in children and usually occur after penetrating mechanism. Isolated
anal trauma can be repaired primarily, including sphincter repair. Extraperitoneal rectal injuries should
be repaired primarily if possible and often require fecal diversion and/or presacral drainage.
Intraperitoneal rectal injuries can be managed similarly to colon injuries, with or without fecal
diversion. Associated genitourinary injuries should be sought with examination under anesthesia.99,100
Pelvic Fracture and Extremity Trauma

Fractures represent one of the most common injuries in pediatric trauma patients. Children have more
malleable bones, more absorptive cartilage, and a higher potential for bone remodeling and healing
than adults. Anatomic differences in radiology of pediatric bones can make recognition of injuries
challenging. Injury to the growth plates can result in premature fusion and asymmetric limb growth.
Greenstick fractures occur when the bone bends before it breaks. Options for stabilization include
casting, splinting, traction, internal fixation, or external fixation. A thorough neurovascular examination
is essential. Although vascular injury requiring repair is rare, children are more prone to vascular
spasm, resulting in asymmetric pulse examination and transient ischemic symptoms.101
Pelvic fractures are a source of morbidity and mortality in pediatric patients and occur most
commonly after high-mechanism blunt trauma such as MVC or pedestrians struck. Pelvic fractures are
usually present in the setting of multiple injuries including TBI, abdominal injuries, and genitourinary
trauma. The Young-Burgess Classification system for pelvic fractures is most commonly used in adults
and categorizes injuries into lateral compression, anterior–posterior compression, and vertical shear
injuries to the pelvic ring. Pediatric classifications exist but are not standard. The pediatric pelvis is
more elastic, allowing for significant displacement before fracture. Pelvic hematoma and ongoing
hemorrhage requiring angiographic intervention or preperitoneal packing occurs less commonly in
children than in adults but should be a major consideration in the hemodynamically unstable child. The
2011 EAST guidelines for the treatment of hemorrhage in pelvic fracture are limited to adult data, but
many principles can be extrapolated to the pediatric population.102 These guidelines recommend the use
of early external stabilization, particularly with a size-appropriate pelvic orthotic device, to stabilize
fractures, reduce pelvic volume, and theoretically limit blood loss. The hemodynamically unstable
pediatric patient with a pelvic fracture represents a diagnostic challenge – does one proceed to the
operating room for abdominal exploration or to the angiography suite for embolization? FAST
examination does not have the sensitivity to rule out abdominal hemorrhage. If stable enough, a CT
scan of the abdomen and pelvis is preferable to help identify the injuries and determine treatment
course. Despite classification systems, fracture patterns on anteroposterior pelvic plain film do not
predict bleeding or need for angiographic embolization. Angiographic embolization should be
considered in hemodynamically unstable patients after other sources of hemorrhage have been ruled
out. In the adult literature, arterial contrast extravasation on CT scan warrants empiric embolization,
even in a stable patient, but these data are unclear in the pediatric population. Similarly, preperitoneal
packing is a newer technique for the control of pelvic hemorrhage, and its use can be considered
alongside pelvic embolization.102 Treatment of pelvic fractures in children is usually nonoperative with
non–weight bearing, Spica casts, or traction. In some cases, external fixation or open reduction, internal
751
booksmedicos.org
fixation (ORIF) is necessary. Fractures involving the acetabulum are complex, especially when the
triradiate cartilage complex is involved, as premature fusion can result in long-term problems with leg-
length discrepancy and acetabular failure.
Venous Thromboembolism
The incidence of venous thromboembolism in pediatric trauma patients is very low, ranging from 0.02%
to 0.3%.103 Although evidence in adult trauma populations supports chemical prophylaxis, such as low–
molecular-weight heparin, no standard evidence-based guidelines exist for pediatric patients.
Recommendations are based on small series and retrospective data. A recent meta-analysis and review
of the literature suggests that older and more severely injured patients are at higher venous
thromboembolism risk.103 In particular, those with spine or spinal cord injury, or major vascular injuries
are at the highest risk. Other risk factors include admission to an ICU, presence of a central venous
catheter, lower extremity or pelvic fracture, or TBI, and when one or more of these are present,
pediatric patients should be considered for prophylaxis. Clinical prediction tools based on large
databases, such as the National Trauma Data Bank, have been proposed but require validation.104
Nonaccidental Trauma (Child Abuse)

4 Nonaccidental trauma is a leading cause of trauma in children, with 650,000 confirmed cases of
physical abuse annually in the United States, accounting for 1,500 deaths per year, mostly in children
younger than 4 years.105 Nonaccidental trauma and abuse may be difficult to recognize and a high index
of suspicion is needed when evaluating children with injuries. The American Academy of Pediatrics
guidelines published in 2015 provide a resource to help identify these children, because unrecognized
cases of abuse can re-present with serious or even fatal injuries. Features of the history that should
increase suspicion include unexplained significant injury, denial of trauma, changes in the story or
differences in the story by different witnesses, explanation that is inconsistent with the pattern, age or
severity of injury or with the child’s developmental capabilities, and delay in seeking medical care.
Findings on examination that may suggest abuse include any injury in a preambulatory infant, multiple
organ system injuries or multiple injuries at different stages of healing, patterned injuries, injuries to
unusual locations (mnemonic “TEN-4” = injury to torso, ears, or neck in a child younger than 4 years),
or other evidence of neglect (failure to thrive, dental caries, poor hygiene). Burns with sharply
demarcated edges, bite marks, cigarette burns, and other markers of being hit with an object are high-
risk injuries. Certain fracture patterns should raise concern for nonaccidental trauma including fractures
in nonambulatory infants, multiple fractures, rib fractures, infants and toddlers with midshaft femur or
humerus fractures, and other unusual fractures such as scapular and metaphyseal fractures. Skeletal
survey is recommended in children younger than 2 years who have suspicion for abuse (see Indications
for Obtaining a Skeletal Survey available online from the study by Christian105; see Skeletal Survey
Guidelines available from the study by Wood et al.106). If there is a reasonable suspicion that a child has
been abused, a report to child protective services for further investigation is mandated by law. See
Christian, CW105 for outlines recommending workup in a child suspected of nonaccidental trauma,
including blood work, imaging, and consultation of specialists such as ophthalmology, in order to
identify injury and obtain forensic evidence.
INJURY PREVENTION
5 In 1911, the Triangle Shirtwaist Company in New York City’s Greenwich Village became the site of
the deadliest industrial disaster in US history. In a fire that engulfed the 10-story building, 146
sweatshop workers (mostly young women) died when elevators and fire escapes failed. Following this
incident, the labor movement was born and policy makers began to take a hard look at working
conditions and addressed safety in the work place by passing meaningful legislation. Although the
concept of injury prevention legislation can be dated back to the early 20th century, it was not until
1964 when the four major US auto manufacturers installed two front-seat lap belts as standard
equipment did injury prevention develop into a true science. In 1968, the National Traffic and Motor
Vehicle Safety Act established the National Highway Traffic Safety Administration, which has influenced
the improvement of road infrastructure, automobile, and driver and passenger safety, resulting in
precipitous drops in roadway fatalities.
There are many examples where comprehensive state and federal laws have resulted in statistical
752
booksmedicos.org
drops in injuries and deaths.107–109 In the following section, we provide several examples where federal
mandates and state laws have been implicated in the reduction of pediatric injuries. In many cases,
surgeon advocates where integral in the legislative process.
Smoke Detectors and Carbon Monoxide Detectors

Smoke detectors have been legislated into building codes in all 50 states. As a result, the early warnings
of a fire are thought to have prevented thousands of deaths. More than 10,000 Americans are poisoned
by carbon monoxide and more than 500 people in the United States die annually from carbon monoxide
poisoning. As of August 2015, 30 states have enacted statutes regarding carbon monoxide detectors, and
another 11 have promulgated regulations on CO detectors. Several states now require CO detectors in
hotels and schools.
Drunken Driving Laws

Alcohol is known to play a role in many MVCs. Drivers younger than 21 years are more likely than
older drivers to be involved in fatal crashes, and alcohol use adds to the risk of fatal crashes. This group
has been the target of several interventions to reduce alcohol-impaired driving, including “zero
tolerance” blood alcohol concentration standards for drivers under the legal drinking age with
mandatory license revocation after a first offense.110
Junior Driver Laws/Safe Driving Laws

The increased risk of car crashes associated with texting and cell phone use has been well documented –
among adults and teens alike. But for teens, who are immersed in a world of smart phones and texting,
these types of laws send a powerful message that driving demands their undivided attention. Although
not exclusive to children or adolescents, “safe driving laws” ban text messaging for all drivers, prohibit
junior drivers from using cell phones, and institute new license renewal procedures for mature drivers,
among other provisions. Graduated driver licensing programs that require new drivers to progress
through stages allowing them increased driving privileges as they gain experience have, in some form,
been enacted in all 50 states. Many states have also incorporated parental education and curfews to
these laws and have seen up to a 40% decrease in the number of injuries and fatalities as novice drivers
have become engaged in this process.111,112
Child Passenger Restraints

Seat belt use around the country has steadily increased. There is mounting evidence that seat belt use
and airbag implementation have been the greatest cause for decreased road fatalities per miles driven,
which is at an all-time low according to National Highway Traffic Safety Administration statistics.
Furthermore, there is evidence that educating pediatricians improves the use of car seats for children.
Although the rate of use of car seats for newborns and infants is approximately 75%, their use in
toddlers is estimated at only 29%, and more than half of car seats for children are not used correctly. In
the child older than 4 years or 40 lb, there is ample evidence that booster seats should be used rather
than adult-type restraints. Many states now have legislation aimed at this population.
All-Terrain Vehicle Laws

In the United States, all-terrain vehicle crashes account for a rising number of injuries and deaths in all
age. Approximately 30% of the injured/dead are children. In 1988, in response to this trend, the
Consumer Product Safety Commission and the all-terrain vehicle industry agreed upon a set of standards
designed to limit injury. This agreement included regulations that restricted operators younger than 16
years halted the sale of three-wheeled vehicles and included a mandatory educational safety training
module and improved safety warnings. However, in 1998, 10 years after they were established, these
consent decrees expired and since that time, the rate of injuries has risen steeply. Several states have
recently enacted restrictions on ridership and in Massachusetts, where these restrictions have included
an age cutoff, the number of injuries have fallen dramatically (unpublished data).
Finally, as policy makers struggle to allocate limited resources in order to improve population health,
injury prevention programs will play a particularly important role. The rationale is straightforward:
regulatory efforts specifically aimed at injury primary and secondary prevention, if well designed, can
be very successful at health care cost reduction, thereby freeing resources for other concerns.
753
booksmedicos.org
References
1. Osterman MJ, Kochanek KD, MacDorman MF, et al. Annual summary of vital statistics: 2012–2013.
Pediatrics 2015;135(6):1115–1125.
2. Wesson DE. Pediatric trauma centers: Coming of age. Tex Heart Inst J 2012; 39(6):871–873.
3. American Academy of Pediatrics Section on Orthopaedics; American Academy of Pediatrics
Committee on Pediatric Emergency Medicine; American Academy of Pediatrics Section on Critical
Care; American Academy of Pediatrics Section on Surgery; American Academy of Pediatrics Section
on Transport Medicine; American Academy of Pediatrics Committee on Pediatric Emergency
Medicine; Pediatric Orthopaedic Society of North America, Krug SE, Tuggle DW. Management of
pediatric trauma. Pediatrics 2008;121(4):849–854.
4. Committee on Trauma and Committee on Shock, Division of Medical Sciences, National Academy of
Sciences, Nation Research Council. Accidental Death and Disability: The Neglected Disease of Modern
Society. Washington, DC: The National Academies Press; 1966.
5. Segui-Gomez M, Chang DC, Paidas CN, et al. Pediatric trauma care: an overview of pediatric
trauma systems and their practices in 18 US states. J Pediatr Surg 2003;38:1162–1169.
6. Simpson AJ, Rivara FP, Pham TN. Quality care in pediatric trauma. Int J Crit Illn Inj Sci
2012;2(3):149–155.
7. Kelly ML, Banerjee A, Nowak M, et al. Decreased mortality in traumatic brain injury following
regionalization across hospital systems. J Trauma Acute Care Surg 2015;78(4):715–720.
8. Bowman SM, Zimmerman FJ, Christakis DA, et al. Hospital characteristics associated with the
management of pediatric splenic injuries. JAMA 2005;294:2611–2617.
9. Hamlat CA, Arbabi S, Koepsell TD, et al. National variation in outcomes and costs for splenic injury
and the impact of trauma systems: a population-based cohort study. Ann Surg 2012;255:165–170.
10. http://www.emscnrc.org/emsc-resources/toolboxes/emergency-department-pediatric-performance-
measures-toolbox. Accessed June 27, 2016.
11.
http://www.emscnrc.org/~/media/emsc/files/pdf/emsc_resources/hospitalbased_performance_measures/traum
la=en. Accessed June 27, 2016.
12. Lorch SA, Myers S, Carr B. The regionalization of pediatric health care. Pediatrics 2010;126:1182–
1190.
13. MacKenzie EJ, Rivara FP, Jurkovich GJ, et al. A national evaluation of the effect of trauma-center
care on mortality. N Engl J Med 2006;354:366–378.
14. Densmore JC, Lim HJ, Oldham KT, et al. Outcomes and delivery of care in pediatric injury. J
Pediatr Surg 2006;41:92–98; discussion 92–98.
15. Amini R, Lavoie A, Moore L, et al. Pediatric trauma mortality by type of designated hospital in a
mature inclusive trauma system. J Emerg Trauma Shock 2011;4:12–19.
16. Hulka F, Mullins RJ, Mann NC, et al. Influence of a statewide trauma system on pediatric
hospitalization and outcome. J Trauma 1997;42:514–519.
17. Pracht EE, Langland-Orban B, Tepas JJ III et al. Analysis of trends in the Florida Trauma System
(1991–2003): changes in mortality after establishment of new centers. Surgery 2006;140:34–43.
18. Camazine MN, Hemmila MR, Leonard JC, et al. Massive transfusion policies at trauma centers
participating in the American College of Surgeons Trauma Quality Improvement Program. J Trauma
Acute Care Surg 2015; 78(6 suppl 1):S48–S53.
19. Hughes NT, Burd RS, Teach SJ. Damage control resuscitation: Permissive hypotension and massive
transfusion protocols. Pediatr Emerg Care 2014;30(9):651–666; quiz 657–658.
20. Daley BJ, Lee S, Raju R, et al. Emedicine. Considerations in pediatric trauma. Available from:
http://emedicine.medscape.com/article/435031-overview#a1. Accessed September 9, 2015.
21. Murphy R, Ghosh A. Towards evidence based emergency medicine: best BETs from the Manchester
Royal Infirmary. The accuracy of abdominal ultrasound in paediatric trauma. Emerg Med J
2001;18(3):208–209.
22. Scaife ER, Rollins MD, Barnhart DC, et al. The role of focused abdominal sonography for trauma
(FAST) in pediatric trauma evaluation. J Pediatr Surg 2013;48(6):1377–1383.
23. National Center for Injury Prevention and Control. Traumatic Brain Injury in the United States:
754
booksmedicos.org
Assessing Outcomes in Children. Atlanta, GA: Centers for Disease Control and Prevention; 2006.
24. http://www.cdc.gov/TraumaticBrainInjury/. Accessed November 2, 2015.
25. Barbosa RR, Jawa R, Watters JM, et al. Eastern Association for the Surgery of Trauma. Evaluation
and management of mild traumatic brain injury: An Eastern Association for the Surgery of Trauma
practice management guideline. J Trauma Acute Care Surg 2012;73(5 suppl 4):S307–S314.
26. Kuppermann N, Holmes JF, Dayan PS, et al. Pediatric Emergency Care Applied Research Network
(PECARN). Identification of children at very low risk of clinically-important brain injuries after
head trauma: a prospective cohort study. Lancet 2009;374(9696):1160–1170.
27. Lee LK, Monroe D, Bachman MC, et al. Traumatic Brain Injury (TBI) Working Group of Pediatric
Emergency Care Applied Research Network (PECARN). Isolated loss of consciousness in children
with minor blunt head trauma. JAMA Pediatr 2014;168(9):837–843.
28. Holmes JF, Borgialli DA, Nadel FM, et al. TBI Study Group for the Pediatric Emergency Care
Applied Research Network. Do children with blunt head trauma and normal cranial computed
tomography scan results require hospitalization for neurologic observation? Ann Emerg Med
2011;58(4):315–322.
29. Powell EC, Atabaki SM, Wootton-Gorges S, et al. Isolated linear skull fractures in children with
blunt head trauma. Pediatrics 2015;135(4):e851–e857.
30. Dayan PS, Holmes JF, Hoyle J Jr, et al. Pediatric Emergency Care Applied Research Network
(PECARN). Headache in traumatic brain injuries from blunt head trauma. Pediatrics
2015;135(3):504–512.
31. Metzger RR, Smith J, Wells M, et al. Impact of newly adopted guidelines for management of
children with isolated skull fracture. J Pediatr Surg 2014;49(12):1856–1860.
32. Blackwood BP, Bean JF, Sadecki-Lund C, et al. Observation for isolated traumatic skull fractures in
the pediatric population: unnecessary and costly. J Pediatr Surg 2016;51(4):654–658.
33. Schatz P, Pardini JE, Lovell MR, et al. Sensitivity and specificity of the ImPACT Test Battery for
concussion in athletes. Arch Clin Neuropsychol 2006;21(1):91–99.
34. McCrea M, Guskiewicz KM, Marshall SW, et al. Acute effects and recovery time following
concussion in collegiate football players: The NCAA Concussion Study. JAMA 2003;290(19):2556–
2563.
35. Halstead ME, Walter KD; Council on Sports Medicine and Fitness. American Academy of Pediatrics.
Clinical report–sports-related concussion in children and adolescents. Pediatrics 2010;126(3):597–
615.
36. May KH, Marshall DL, Burns TG, et al. Pediatric sports specific return to play guidelines following
concussion. Int J Sports Phys Ther 2014; 9(2):242–255.
37. http://www.cdc.gov/headsup/index.html. Accessed November 2, 2015.
38. Cancelliere C, Hincapié CA, Keightley M, et al. Systematic review of prognosis and return to play
after sport concussion: results of the International Collaboration on Mild Traumatic Brain Injury
Prognosis. Arch Phys Med Rehabil 2014;95(3 suppl):S210–S229.
39. Dawes AJ, Sacks GD, Cryer HG, et al. Los Angeles County Trauma Consortium. Intracranial
pressure monitoring and inpatient mortality in severe traumatic brain injury: a propensity score-
matched analysis. J Trauma Acute Care Surg 2015;78(3):492–501; discussion 501–502.
40. Adelson PD, Bratton SL, Carney NA, et al. Guidelines for the acute medical management of severe
traumatic brain injury in infants, children, and adolescents. Chapter 5. Indications for intracranial
pressure monitoring in pediatric patients with severe traumatic brain injury. Pediatr Crit Care Med
2003;4(suppl 3):S19–S24.
41. Kochanek PM, Carney N, Adelson PD, et al. Chapter 4. Threshold for treatment of intracranial
hypertension. Pediatr Crit Care Med 2012;13: S18–S23.
42. Bell MJ, Kochanek PM. Pediatric traumatic brain injury in 2012: the year with new guidelines and
common data elements. Crit Care Clin 2013;29(2):223–238.
43. Kochanek PM, Carney N, Adelson PD, et al. Guidelines for the acute medical management of severe
traumatic brain injury in infants, children and adolescents: Second edition. Pediatr Crit Care Med
2012;13(suppl 1):S1–S82.
44. Hutchison JS, Ward RE, Lacroix J, et al. Hypothermia therapy after traumatic brain injury in
children. N Engl J Med 2008;358(23):2447–2456.
755
booksmedicos.org
45. Adelson PD, Wisniewski SR, Beca J, et al. Paediatric Traumatic Brain Injury Consortium.
Comparison of hypothermia and normothermia after severe traumatic brain injury in children (Cool
Kids): a phase 3, randomised controlled trial. Lancet Neurol 2013;12(6):546–553.
46. Hoffman JR, Wolfson AB, Todd K, et al. Selective cervical spine radiography in blunt trauma:
Methodology of the National Emergency X-Radiography Study (NEXUS). Ann Emerg Med
1998;32(4):461–469.
47. Steill IG, Wells GA, Vandemheen KL, et al. The Canadian C-Spine rule for radiography in alert and
stable trauma patients. JAMA 2001;286(15):1841–1848.
48. Viccellio P, Simon H, Pressman BD, et al. A prospective multicenter study of cervical spine injury in
children. Pediatrics 2001;108(2):E20.
49. Jaffe DM, Binns H, Radkowski MA, et al. Developing a clinical algorithm for early management of
cervical spine injury in child trauma victims. Ann Emerg Med 1987;16(3):270–276.
50. Leonard JC, Kuppermann N, Olsen C, et al. Pediatric Emergency Care Applied Research Network.
Factors associated with cervical spine injury in children after blunt trauma. Ann Emerg Med
2011;58(2):145–155.
51. Polk-Williams A, Carr BG, Blinman TA, et al. Cervical spine injury in young children: A National
Trauma Data Bank review. J Pediatr Surg 2008;43(9):1718–1721.
52. Leonard JR, Jaffe DM, Kuppermann N, et al. Pediatric Emergency Care Applied Research Network
(PECARN) Cervical Spine Study Group. Cervical spine injury patterns in children. Pediatrics
2014;133(5):e1179–e1188.
53. Pieretti-Vanmarcke R, Velmahos GC, Nance ML, et al. Clinical clearance of the cervical spine in
blunt trauma patients younger than 3 years: a multi-center study of the American association for
the surgery of trauma. J Trauma 2009;67(3):543–549; discussion 549–550.
54. Pang D, Wilberger JE Jr. Spinal cord injury without radiographic abnormalities in children. J
Neurosurg 1982;57:114–129.
55. Pang D. Spinal cord injury without radiographic abnormality in children, 2 decades later.
Neurosurgery 2004;55:1325–1342; discussion 1342–1343.
56. Yucesoy K, Yuksel KZ. SCIWORA in MRI era. Clin Neurol Neurosurg 2008;110:429–433.
57. Bromberg WJ, Collier BC, Diebel LN, et al. Blunt cerebrovascular injury practice management
guidelines: The Eastern Association for the Surgery of Trauma. J Trauma 2010;68(2):471–477.
58. Malhotra A, Wu X, Kalra VB, et al. Screening for pediatric blunt cerebrovascular injury: Review of
literature and a cost-effectiveness analysis. J Pediatr Surg 2015;50(10):1751–1757.
59. Sharma MS, Kupferschmid J. Pediatric thoracic trauma.
http://emedicine.medscape.com/article/905863-overview#a1. Updated September 15, 2013.
Accessed November 6, 2015.
60. Mowery NT, Gunter OL, Collier BR, et al. Practice Management guidelines for management of
hemothorax and occult pneumothorax. J Trauma 2011;70(2):510–518.
61. Seamon MJ, Haut ER, Van Arendonk K, et al. An evidence-based approach to patient selection for
emergency department thoracotomy: a practice management guideline from the Eastern Association
for the Surgery of Trauma. J Trauma Acute Care Surg 2015;79(1):159–173.
62. Easter JS, Vinton DT, Haukoos JS. Emergent pediatric thoracotomy following traumatic arrest.
Resuscitation 2012;83(12):1521–1524.
63. Working Group, Ad Hoc Subcommittee on Outcomes, American College of Surgeons, Committee on
Trauma. Practice management guidelines for emergency department thoracotomy. Working Group,
Ad Hoc Subcommittee on Outcomes, American College of Surgeons-Committee on Trauma. J Am
Coll Surg 2001;193:303–309.
64. Fox N, Schwartz D, Salazar JH, et al. Evaluation and management of blunt traumatic aortic injury: a
practice management guideline from the Eastern Association for the Surgery of Trauma. J Trauma
Acute Care Surg 2015;78(1)136–146.
65. Anderson SA, Day M, Chen MK, et al. Traumatic aortic injuries in the pediatric population. J Pediatr
Surg 2008;43(6):1077–1081.
66. Clancy K, Velopulos C, Bilaniuk JW, et al. Screening for blunt cardiac injury: An Eastern
Association for the Surgery of Trauma practice management guideline. J Trauma Acute Care Surg
2012;73(5 suppl 4):S301–S306.
756
booksmedicos.org
67. Holmes JF, Lillis K, Monroe D, et al. Pediatric Emergency Care Applied Research Network
(PECARN). Identifying children at very low risk of clinically important blunt abdominal injuries.
Ann Emerg Med 2013; 62(2):107–116.e2.
68. Mahajan P, Kuppermann N, Tunik M, et al. Intra-abdominal Injury Study Group of the Pediatric
Emergency Care Applied Research Network (PECARN). Comparison of clinician suspicion versus a
clinical prediction rule in identifying children at risk for intra-abdominal injuries after blunt torso
trauma. Acad Emerg Med 2015;22(9):1034–1041.
69. Adelgais KM, Kuppermann N, Kooistra J, et al. Intra-Abdominal Injury Study Group of the Pediatric
Emergency Care Applied Research Network (PECARN). Accuracy of the abdominal examination for
identifying children with blunt intra-abdominal injuries. J Pediatr 2014;165(6):1230–1235.e5.
70. Kerrey BT, Rogers AJ, Lee LK, et al. Pediatric Emergency Care Applied Research Network. A
multicenter study of the risk of intra-abdominal injury in children after normal abdominal
computed tomography scan results in the emergency department. Ann Emerg Med 2013;62(4):319–
326.
71. Como JJ, Bokhari F, Chiu WC, et al. Practice management guidelines for selective nonoperative
management of penetrating abdominal trauma. J Trauma 2010;68(3):721–733.
72. Lamb CM, MacGoey P, Navarro AP, et al. Damage control surgery in the era of damage control
resuscitation. Br J Anaesth 2014;113(2):242–249.
73. Stassen NA, Bhullar I, Cheng JD, et al. Selective nonoperative management of blunt splenic injury:
an Eastern Association for the Surgery of Trauma practice management guideline. J Trauma Acute
Care Surg 2012; 73(5):S294–S300.
74. Injury Scoring Scales: A Resource for Trauma Care Professionals.
http://www.aast.org/library/traumatools/injuryscoringscales.aspx. Accessed November 8, 2015.
75. Wisner DH, Kuppermann N, Cooper A, et al. Management of children with solid organ injuries after
blunt torso trauma. J Trauma Acute Care Surg 2015;79(2):206–214; quiz 332.
76. Bowman SM, Bulger E, Sharar SR, et al. Variability in pediatric splenic injury care: Results of a
national survey of general surgeons. Arch Surg 2010;145(11):1048–1053.
77. Safavi A, Skarsgard ED, Rhee P, et al. Trauma center variation in the management of pediatric
patients with blunt abdominal solid organ injury: A national trauma data bank analysis. J Pediatr
Surg 2016;51(3):499–502.
78. Stylianos S. Evidence-based guidelines for resource utilization in children with isolated spleen or
liver injury. The APSA Trauma Committee. J Pediatr Surg 2000;35(2):164–169.
79. Notrica DM, Eubanks JW III, Tuggle DW, et al. Nonoperative management of blunt liver and spleen
injury in children: Evaluation of the ATOMAC guideline using GRADE. J Trauma Acute Care Surg
2015;79(4):683–693.
80. Gross JL, Woll NL, Hanson CA, et al. Embolization for pediatric blunt splenic injury is an
alternative to splenectomy when observation fails. J Trauma Acute Care Surg 2013;75(3):421–425.
81. Cloutier DR, Baird TB, Gormley P, et al. Pediatric splenic injuries with a contrast blush: Successful
nonoperative management without angiography and embolization. J Pediatr Surg 2004;39(6):969–
971.
82. Kiankhooy A, Sartorelli KH, Vane DW, et al. Angiographic embolization is safe and effective
therapy for blunt abdominal solid organ injury in children. J Trauma 2010;68(3):526–531.
83. Menaker J, Blumberg S, Wisner DH, et al. Intra-abdominal Injury Study Group of the Pediatric
Emergency Care Applied Research Network (PECARN). Use of the focused assessment with
sonography for trauma (FAST) examination and its impact on abdominal computed tomography use
in hemodynamically stable children with blunt torso trauma. J Trauma Acute Care Surg
2014;77(3):427–432.
84. Scaife ER, Fenton SJ, Hansen KW, et al. Use of focused abdominal sonography for trauma at
pediatric and adult trauma centers: A survey. J Pediatr Surg 2009;44(9):1746–1749.
85. Soudack M, Epelman M, Maor R, et al. Experience with focused abdominal sonography for trauma
(FAST) in 313 pediatric patients. J Clin Ultrasound 2004;32(2):53–61.
86. Ben-Ishay O, Daoud M, Peled Z, et al. Focused abdominal sonography for trauma in the clinical
evaluation of children with blunt abdominal trauma. World J Emerg Surg 2015;10:27.
87. Holmes JF, Gladman A, Chang CH. Performance of abdominal ultrasonography in pediatric blunt
757
booksmedicos.org
trauma patients: a meta-analysis. J Pediatr Surg 2007;42(9):1588–1594.
88. Holmes JF, Brant WE, Bond WF, et al. Emergency department ultrasonography in the evaluation of
hypotensive and normotensive children with blunt abdominal trauma. J Pediatr Surg
2001;36(7):968–973.
89. Mattix KD, Tataria M, Holmes J, et al. Pediatric pancreatic trauma: Predictors of nonoperative
management failure and associated outcomes. J Pediatr Surg 2007;42(2):340–344.
90. East Guidelines for the Diagnosis and Management of Pancreatic Trauma. Eastern association for
the surgery of trauma practice management guidelines. https://www.east.org/education/practice-
management-guidelines/pancreatic-trauma-diagnosis-and-management-of. Accessed November 8,
2015.
91. Adamson WT, Hebra A, Thomas PB, et al. Serum amylase and lipase alone are not cost-effective
screening methods for pediatric pancreatic trauma. J Pediatr Surg 2003;38(3):354–357; discussion
354–357.
92. Bass J, Di Lorenzo M, Desjardins JG, et al. Blunt pancreatic injuries in children: The role of
percutaneous external drainage in the treatment of pancreatic pseudocysts. J Pediatr Surg
1988;23(8):721–724.
93. Shilyansky J, Sena LM, Kreller M, et al. Nonoperative management of pancreatic injuries in
children. J Pediatr Surg 1998;33(2):343–349.
94. Nadler EP, Gardner M, Schall LC, et al. Management of blunt pancreatic injury in children. J
Trauma 1999;47(6):1098–1103.
95. Wales PW, Shuckett B, Kim PC. Long-term outcome after nonoperative management of complete
traumatic pancreatic transection in children. J Pediatr Surg 2001;36(5):823–827.
96. Iqbal CW, St. Peter SD, Tsao K, et al. Pancreatic Trauma in Children (PATCH) Study Group.
Operative vs nonoperative management for blunt pancreatic transection in children: Multi-
institutional outcomes. J Am Coll Surg 2014;218(2):157–162.
97. Wood JH, Partrick DA, Bruny JL, et al. Operative vs nonoperative management of blunt pancreatic
trauma in children. J Pediatr Surg 2010;45(2):401–406.
98. Soukup ES, Russell KW, Metzger R, et al. Treatment and outcome of traumatic biliary injuries in
99. Russell KW, Soukup ES, Metzger RR, et al. Fecal continence following complex anorectal trauma in
100. Samuk I, Steiner Z, Feigin E, et al. Anorectal injuries in children: A 20-year experience in two
centers. Pediatr Surg Int 2015;31(9):815–819.
101. Mommsen P, Zeckey C, Hildebrand F, et al. Traumatic extremity arterial injury in children:
Epidemiology, diagnostics, treatment and prognostic value of Mangled Extremity Severity Score. J
Orthop Surg Res 2010;5:25, 1–8.
102. Cullinane DC, Schiller HJ, Zielinski MD, et al. Eastern Association for the Surgery of Trauma
practice guidelines for hemorrhage in pelvic fracture—update and systematic review. J Trauma
2011;71(6):1850–1868.
103. Thompson AJ, McSwain SD, Webb SA, et al. Venous thromboembolism prophylaxis in the pediatric
trauma population. J Pediatr Surg 2013;48(6):1413–1421.
104. Connelly CR, Laird A, Barton JS, et al. A clinical tool for the prediction of venous
thromboembolism in pediatric trauma patients. JAMA Surg 2016;151(1):50–57.
105. Christian CW; Committee on Child Abuse and Neglect, American Academy of Pediatrics. The
evaluation of suspected child physical abuse. Pediatrics 2015;135(5):e1337–e1354.
106. Wood JN, Fakeye O, Feudtner C, et al. Development of guidelines for skeletal survey in young
children with fractures. Pediatrics 2014;134(1):45–53.
107. Mendelson KG, Fallat ME. Pediatric injuries: Prevention to resolution. Surg Clin North Am
2007;87:207–228, viii.
108. Brussoni M, Towner E, Hayes M. Evidence into practice: combining the art and science of injury
prevention. Inj Prev 2006;12:373–377.
109. Tepas JJ III. The national pediatric trauma registry: a legacy of commitment to control of
childhood injury. Semin Pediatr Surg 2004;13:126–132.
110. Brehaut JC, Miller A, Raina P, et al. Childhood behavior disorders and injuries among children and
758
booksmedicos.org
youth: a population based study. Pediatrics 2003;111(2):262–269.
111. Kaafarani H, Lee J, Cropano C, et al. The impact and sustainability of the graduated driver
licensing program in preventing motor vehicle crashes in Massachusetts. J Trauma Acute Care Surg
2015;78(2):265–270; discussion 270–271.
112. Rajaratnam SM, Landrigan CP, Wang W, et al. Teen crashes declined after Massachusetts raised
penalties for graduated licensing law restricting night driving. Health Aff (Millwood)
2015;34(6):963–970.
759
booksmedicos.org
Chapter 30
Geriatric Trauma
Carlos V.R. Brown, Zara Cooper, and Ali Salim
Key Points
1 The physiology of aging affects nearly every organ system including cardiovascular, pulmonary,
renal, and gastrointestinal. Altered physiology may also be associated with comorbid conditions in
the elderly patient including hypertension, cardiac disease, chronic obstructive pulmonary disease
(COPD), chronic renal insufficiency, and altered drug metabolism.
2 The American Geriatrics Society has published the Beers Criteria for potentially inappropriate
medication use in older adults that can be used to refine inpatient medication management for
elderly trauma patients.
3 Falls are far and away the most common mechanism of injury in elderly trauma patients, causing
almost 75% of injuries in elderly patients; 90% of elderly falls are ground level falls.
4 An underreported but important mechanism of injury in elderly trauma patients is elderly abuse.
5 Imaging with head CT in elderly trauma patients should be used liberally.
6 Severely injured older patients may not display standard signs of hemodynamic instability.
7 Due to the broad range of age-related factors that can contribute to injury and adversely affect
recovery in geriatric patients, injured individuals should receive a comprehensive geriatric
assessment during their hospital stay.
8 Frailty is a syndrome of decreased physiologic reserve distinct from the normal aging process and
other comorbidities. Frailty is associated with higher mortality and complications, and worse
functional outcomes after trauma, and is more predictive than age or injury severity of hospital
complications, in-hospital mortality, or discharge to an institution.
9 Palliative care is appropriate in the management of a broad range of injured patients who die or
suffer with acute and chronic pain, functional disability, or life-limiting conditions such as severe
frailty and underlying organ failure.
10 Four-fifths of in-hospital deaths among geriatric trauma patients involve decisions to withdraw or
withhold of life-sustaining therapies.
INTRODUCTION
The elderly population in the United States is steadily growing and Americans >65 years old are
expected to number more than 80 million by the year 2050, more than double the population in 2012.1
Trauma and acute care surgeons will be increasingly responsible for caring for this complex population
of patients. Even prior to injury, the elderly patient brings unique challenges including altered
physiology, numerous comorbid conditions, and preinjury medications. The epidemiology and triage
complexities of elderly trauma patients make it challenging to ensure these patients are transported to
the appropriate receiving facility. Elderly patients are most often injured by a blunt mechanism and are
particularly at risk for falls from standing. In addition, they sustain unique injuries that may escape
diagnosis during the initial evaluation. Trauma centers may need to alter activation criteria for elderly
trauma patients in order to avoid the pitfall of undertriage that is associated with poor outcomes in this
population. Though the initial trauma evaluation for elderly patients is similar to younger adults, the
trauma surgeon must understand the nuances associated with caring for the injured elderly patient. The
elderly trauma patient more frequently has issues that relate end-of-life care in the postinjury period.
PHYSIOLOGY, COMORBIDITY, AND PREINJURY MEDICATIONS
760
booksmedicos.org
1 Elderly individuals present with a vast array of body systems affected by the deranged physiology
associated with aging. The physiology of aging affects nearly every organ system including
cardiovascular, pulmonary, renal, and gastrointestinal. Altered physiology may also be associated with
comorbid conditions in the elderly patient including hypertension, cardiac disease, chronic obstructive
pulmonary disease (COPD), chronic renal insufficiency, and altered drug metabolism.
Cardiovascular
The cardiovascular system is most commonly affected by the physiology of aging and has a significant
impact on care of the injured elderly patient. Alterations to physiology of the vascular system in the
aging adult are primarily the result of changes in the large arteries including elongation, dilatation, and
arterial wall thickening as a result of changes in the intima and media.2 Changes in large arteries lead to
decreased compliance, stiffness, and hypertension or other cardiovascular diseases in elderly adults. The
aging process will affect cardiac physiology including reduced systolic and diastolic functions of the
right ventricle as well as left ventricular hypertrophy with associated impaired contractility and
relaxation. Resting cardiac output and ejection fraction are preserved.3 While there are significant
changes in cardiac and vascular physiology in elderly patients at baseline, the lack of cardiovascular
response to stress may be the most important component of altered cardiovascular physiology in elderly
patients, especially in the setting of hemorrhagic shock. The blunted response to alpha-adrenergic
stimulation limits vasoconstriction2,4 while lack of response to beta-adrenergic stimulation limits the
ability to mount a tachycardic response.3,5 Elderly individuals are also at increased risk to develop atrial
fibrillation, ischemic heart disease, and congestive heart failure.
Table 30-1 Changes in Cardiovascular and Pulmonary Physiology and Commonly

Encountered Comorbidities in the Elderly
Pulmonary
The aging process also brings significant baseline anatomic and physiologic changes to the pulmonary
system.6 The chest wall of the elderly individual changes over time with increasing kyphosis as well as
decreasing height of intervertebral spaces. There is a decrease in strength of the intercostal muscles and
diaphragm. After trauma, these anatomic changes place elderly patients at risk for earlier or more rapid
respiratory failure as well as difficulty in liberation from the ventilator.6–8 In addition to alterations in
the chest wall, there are several changes in the pulmonary parenchyma of elderly individuals. These
changes lead to increased compliance due to loss of elasticity and elastic recoil, emphysematous
changes, and dysfunction of the mucociliary system. While anatomic changes are important, the altered
pulmonary physiology of aging may lead to significant clinical implications when caring for the injured
elderly patient. The elderly individual will have changes to pulmonary physiology including alterations
in lung volumes, gas exchange, and respiratory drive.6 Lung volumes in elderly patients will have
increased residual volume and functional residual capacity but decreased vital capacity and FEV1.9,10
Alterations of pulmonary gas exchange in elderly patients include increased ventilation–perfusion
mismatch as well as decreased diffusion across the alveolar–arterial membrane, both associated with a
decrease in baseline PaO2.11,12 Due to deranged respiratory drive seen with aging, elderly patients will
761
booksmedicos.org
have a diminished physiologic response to both hypoxemia and hypercapnia.13 Some of the most
common pulmonary comorbidities in the elderly trauma patients include COPD, asthma, and obstructive
sleep apnea. Table 30-1 displays changes in cardiovascular and pulmonary physiology as well as
common comorbidities encountered in the elderly trauma patient.
Renal and Gastrointestinal

Aging causes deterioration in renal function over time due to alterations in renal vasculature,
microanatomy, as well as changes in renal physiology.14 Elderly patients commonly have low-grade
and/or undiagnosed chronic renal insufficiency putting them at risk for development of acute kidney
injury after trauma. Avoiding nephrotoxic agents, intravenous contrast, hyperglycemia, and
hypovolemia can help prevent acute kidney injury in elderly trauma patients. Gastrointestinal
derangements in the elderly patient may include dysphagia, gastroesophageal reflux, gastroparesis, and
diarrhea or constipation.15 In addition, many elderly trauma patients will present in a state of
malnutrition established long before the time of injury. It is important to screen elderly trauma patients
for nutritional status and begin enteral nutrition early in the postinjury course.
Elderly trauma patients present with a wide array of altered physiology and comorbid conditions.
These pre-existing medical conditions are usually treated in the outpatient setting by primary care
providers, and the mainstay of treatment is often a long list of medications. These preinjury medications
can have a profound effect on the management and outcomes of elderly trauma patients. In addition,
elderly individuals have an altered ability to metabolize the medications they encounter prior to injury
as well as during their hospitalization.
Medications
Elderly trauma patients may be taking a variety of medications that may affect initial presentation,
evaluation and treatment, and eventually outcomes. As hypertension is the most common comorbidity,
elderly trauma patients will often be taking preinjury antihypertensive medications. Diuretics will cause
patients to present in a hypovolemic state prior to injury or hemorrhage. Preinjury beta-blockers will
blunt the tachycardic response and may confound the initial presentation.16 The most significant
preinjury medications in elderly trauma patients are anticoagulants and antiplatelet agents. Elderly
patients may be on anticoagulants or antiplatelet agents for a variety of conditions including atrial
fibrillation, ischemic cardiac disease, valvular heart disease, cerebrovascular accidents, or
thromboembolic disease. The most common outpatient anticoagulant is coumadin (vitamin K
antagonist), but there have been several newer anticoagulants brought to market recently. These
include the direct thrombin inhibitor dabigatran as well as the Xa inhibitors, rivaroxaban and apixaban.
The most common antiplatelet agents include aspirin (cyclo-oxygenase inhibitor) and clopidogrel (ADP
inhibitor). Newer antiplatelet agents include newer ADP inhibitors, prasugrel and ticagrelor.
Table 30-2 Common Preinjury Anticoagulants in the Elderly
Reversal of anticoagulants and antiplatelet agents in elderly trauma patients can be a challenging and
complex clinical scenario. The clinician must balance reversal to eliminate hemorrhage and
thromboembolic complications associated with reversing anticoagulation or antiplatelet agents.
Coumadin may be reversed with either fresh frozen plasma (FFP) or prothrombin complex concentrate
762
booksmedicos.org
(PCC).17,18 There is limited evidence regarding reversal of direct thrombin inhibitors or Xa
inhibitors.19–22 Dabigatran may be reversed with Idarucizumab (Praxnind). Intragastric activated
charcoal may be administered if drug has been taken within 2 hours of presentation or hemodialysis
may be considered. PCC may be considered for reversal of dabigatran but FFP is unlikely to have any
therapeutic effect. Reversal agents for Xa inhibitors (Adnexanet alfa) are currently under investigation.
Activated charcoal may be used or PCC may also be considered. Antiplatelet agents may be reversed
with either DDAVP or platelet transfusion, but the indications for either therapy have not been
elucidated.21,23,24 Table 30-2 displays common preinjury anticoagulants and antiplatelet agents in the
elderly trauma patient.
2 Once hospitalized, particular attention must be paid to medications ordered for the elderly trauma
patient. Elderly patients have changes in pharmacokinetics and pharmacodynamics including alterations
in absorption, bioavailability, distribution, metabolism, and elimination.25 The American Geriatrics
Society has published the Beers Criteria for potentially inappropriate medication use in older adults that
can be used to refine inpatient medication management for elderly trauma patients.26 Of particular
importance to the management of the elderly trauma patients is the plan for pain control. Pain
medications may have significant side effects in elderly patients including delirium, nausea, vomiting,
constipation, renal dysfunction, and gastrointestinal bleeding. A multimodal approach with the lowest
effective dose for pain control should be used for elderly trauma patients.25
MECHANISM AND INJURIES

3 Mechanisms of injury for elderly trauma patients are most often a result of blunt trauma with falls,
motor vehicle crashes, and pedestrian struck by auto being the most frequent. Falls are far and away the
most common mechanism in elderly trauma patients, causing almost 75% of injuries.16 Fully, 90% of
elderly falls are ground level falls. After hospitalization, older patients are at further risk for inpatient
falls.27 There are a variety of reasons that elderly individuals are at risk for falls including weakness,
deconditioning from chronic illness, vision loss, gate and balance disturbances, slowed reaction time,
and cognitive impairments.16 The American Geriatrics Society has developed clinical practice guidelines
(Table 30-3) for the prevention of falls in older adults.28
Elderly Abuse
4 An underreported but extremely important mechanism of injury in elderly trauma patients is abuse.
Elderly abuse is committed by an individual who has a relationship with and is responsible for the well
being of an elderly individual. Perpetrators of elderly abuse may include family members or care givers
either in the home or at an assisted living facility. Abuse of the elderly is associated with depression,
cognitive impairment, loss of functional capacity, and increased morbidity and mortality.29 Several risk
factors and warning signs for elderly abuse have been identified and are listed in Table 30-4.30 If elderly
trauma patients appear to be at risk for or display warning signs of possible abuse they may be assessed
using a variety of available screening tools30 including the American Medical Association (AMA)
screening tool, the Conflict Tactics Scale (CTS), the Brief Abuse Screen for the Elderly (BASE), the Elder
Assessment Instrument (EAI), or the Comprehensive Geriatric Assessment (CGA).
Traumatic Brain Injury

5 Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in elderly trauma
patients.31,32 TBI in elderly patients leads to almost 100,000 emergency department visits each year
with the large majority requiring hospitalization. The most common mechanism causing TBI in elderly
patients is falls (51%) followed by motor vehicle–related injuries (9%). All other causes combined make
up 18% of TBI and about 20% are from an unknown cause. Imaging with head CT in elderly trauma
patients should be used liberally for several reasons: (1) elderly patients have progressive brain atrophy
leading to stretching of bridging veins and increased risk of subdural hemorrhage after trauma,33 (2)
clinical tools such as the New Orleans Criteria and Canadian CT Head Rule exclude elderly patients,34,35
and (3) neurologic examination may be unreliable in elderly trauma patients.36,37 The catastrophic
combination of TBI and preinjury anticoagulation should prompt to rapid reversal of
anticoagulation.38,39
Fractures
763
booksmedicos.org
Elderly patients have decreased cortical bone mass increasing their risk for fractures at lower levels of
kinetic energy. As a consequence, older patients have increased risk of rib, spinal, pelvic, and extremity
fractures after falls and other low impact mechanisms than younger patients.
Rib fractures are a significant cause of morbidity and mortality among older patients.40 Retrospective
studies show that in-hospital mortality for patients >65 years is double that of younger patients.41,42
The risk of mortality and pneumonia increases with increasing number of ribs fractured, and patients
with more than three fractures have worse outcomes.41,43 Up to a third of older patients with rib
fractures develop pneumonia and rib fractures are associated with mechanical ventilation and ICU
length of stay.41
Osteoporosis, prior fracture, and functional impairment are all risk factors for pelvic fracture.44 Over
80% of pelvic fractures are caused by falls, and morbidity and mortality after pelvic fractures is
significant. In-hospital mortality approaches 8% and is up to five times higher than for younger
patients.45 Many patients after pelvic fracture require a cane or a walker, up to one-third are
institutionalized, and 27% will die within a year of injury.44
Table 30-3 AGS/BGS Clinical Practice Guideline: Prevention of Falls in Older

Persons
764
booksmedicos.org
Table 30-4 Risk Factors and Warning Signs for Elderly Abuse
Spinal trauma is increasingly common in elderly patients.46 The risk of cervical fracture after falls
increases with age due to higher rates of cervical stenosis and degenerative disk disease.47 An estimated
5% to 10% will sustain spinal injury and permanent neurologic deficit after cervical fracture, and 1-year
mortality is estimated to be 20% to 30%.48
Fourteen percent of elderly patients who sustain hip fracture after falls die within 6 months and
765
booksmedicos.org
almost one-fourth dies within a year.49,50 Most do not regain prior functional abilities, and patients after
hip fracture are five times more likely to live in an institution a year after injury. Hip fracture in older
patients often leads to depression,51 social isolation, and worse overall health. Up to half of patients
with hip fracture experience pain for many months after injury.52 Shorter time to surgery is associated
with decreased mortality and fewer complications.53
TRIAGE CRITERIA FOR OLDER PATIENTS

6 Trauma center care reduces in-hospital mortality for older trauma patients,54,55 and the benefit of
treatment at trauma centers for older patients increases with age.56 However, triage of older patients
can be quite challenging. Even severely injured older patients may not display standard signs of
hemodynamic instability. Furthermore, because older patients cannot tolerate large blood loss and
shock, some have advocated that systolic blood pressure ≤120 mm Hg should trigger trauma activation
to prompt earlier intervention.57 The Centers for Disease control suggest that injured patients >55
years should be transferred to a trauma center, regardless of injury severity.58 The Eastern Association
for Trauma (EAST) guidelines recommend that trauma centers should lower threshold for trauma team
activation for elderly patients. Further, the guidelines suggest that older patients should be transferred
to a level I center if they have a base deficit of –6 or greater, or one body system AIS is >3.59 In a
retrospective study using the National Trauma Data Bank, Pandit et al.60 showed that shock index
(HR/SBP) >1 was associated with higher rates of blood transfusions, exploratory laparotomy, in-
hospital complications, and in-hospital mortality. Based on these findings, the authors recommend that
patients with a shock index >1 should be transferred to level I trauma centers.
Despite evidence supporting higher triage, multiple studies show that older patients are routinely
undertriaged. Data from the Washington State database showed that the likelihood of being transferred
to a trauma center decreased above age 45.61 Compared to younger patients in the cohort, patients 81
years and older were only 11% as likely to be transported to a level I trauma center from the scene, and
only 24% as likely to be transferred from a lower level center to a level I center. The relationship
between trauma center admission and longer-term outcome is controversial. One study of severely
injured older patients (ISS >15) in three counties in California showed that older patients were less
likely to receive care at trauma centers, yet mortality at 60 days after injury was no different.62
EVALUATION AND MANAGEMENT

Comprehensive Geriatric Assessment
Older patients are much more likely to have medical comorbidities, extensive lists of medications and
social needs that require special attention. A retrospective study of older trauma patients showed that
69% of patients age 75 to 79 years and 90% of those >80 years have comorbidities.63 The most
common are cardiopulmonary (coronary disease, hypertension, congestive heart failure, and COPD).
Geriatric syndromes such as dementia and frailty also play important roles and are frequently the
primary contributors in falls and motor vehicle crashes. Malnutrition, hearing loss, vision loss,
incontinence, polypharmacy, and osteoporosis all increase the risk of falls; weakness from sarcopenia
and sensory deficits also place elders at high risk for being either struck by motor vehicles, or driving in
motor vehicle crashes. Alcohol and substance abuse are under-recognized contributors to injury in
geriatric trauma patients.64
7 Due to the broad range of age-related factors that can contribute to injury and adversely affect
recovery in geriatric patients, patients should receive a comprehensive geriatric assessment (CGA)
during their hospital stay. This is a multidimensional and multidisciplinary evaluation including
functional ability, physical health, cognition and mental health, and medication review. A recent meta-
analysis of 22 randomized trials showed that hospitalized elders who receive a CGA are less likely to die
in hospital, have higher rates of discharge home, and improved long-term functional outcomes.65
Functional status is evaluated with a review of activities of daily living (ADL) (eating, dressing, bathing,
transfers, toileting, continence) and instrumental ADL (housework, bills, meal preparation, medication
management, using the telephone).66 Physical and occupational therapists can assess gait, balance, home
safety, and ability to carry out ADL.
Medications commonly used in older patients can exacerbate injury. Postural hypotension is a
766
booksmedicos.org
common condition in older adults, leading to falls, and can be caused by medication side effects
(diuretics, antiarrhythmics, benzodiazepines, antidepressants, and psychotropic agents).67,68
Antidepressants and psychotropic agents can cause gait impairment. Most patients should receive a
nutritional assessment because malnutrition in elderly patients is highly prevalent; 38% of community-
dwelling elders are either malnourished or at risk of malnourishment.69 Social workers can assess social
supports, caregiver needs, financial assets and identify resources for the patient and family after
hospital discharge. Poverty rates are highest for those 85 and older, and rates are increasing.70 Social
isolation is also a major contributor to poor health in this age group.71 Those without social support
have more frequent hospitalizations and higher healthcare costs near the end-of-life.72 They are also
more likely to be discharged to institutions. In cases where it is impractical to thoroughly evaluate each
condition during hospitalization, patients should be referred for outpatient follow-up at discharge.
Assessing Frailty
8 Frailty is a syndrome of decreased physiologic reserve distinct from the normal aging process and
other comorbidities. Frailty is associated with higher mortality and complications, and worse functional
outcomes after trauma, and is more predictive than age or injury severity as a predictor of hospital
complications, in-hospital mortality, or discharge to an institution.73 The prevalence of frailty increases
with age: 7% of 65 year olds are frail whereas 30% of patients 80 and older are frail.74 Components of
the frailty syndrome include shrinkage, weakness, exhaustion, low physical activity, and slowness.
Presence of three or more of these indicates frailty.75 Multimorbidity and side effects from certain
medications may exacerbate frailty.
Screening for frailty identifies patients at risk for adverse outcomes, but frailty remains difficult to
quantify. Frailty can be assessed using a number of different measures.76 Investigators at the University
of Arizona recently developed a frailty index using 50 preadmission variables that included data about
demographics, comorbidities, medications, social history, ADLs, and mood. A frailty index was
calculated based on the proportion of the 50 variables that were present; high score was indicative of
frailty. These investigators demonstrated that after adjusting for age injury severity score and Glasgow
coma score, higher frailty index predicted increased odds of unfavorable discharge (death or skilled
nursing facility).73,77 Other investigators have considered sarcopenia, a loss of muscle leading to
decreased strength and impaired mobility, as a surrogate measure of frailty in trauma patients.
Sarcopenia is associated with more days on the ventilator, and higher postacute care needs.78 Sarcopenia
can be measured using the cross-sectional area of the psoas muscle on abdominal CT, a measure which is
inversely related to functional dependence.79 The Vulnerable Elders-13 Survey, an assessment of
functional status, has been validated as a screening tool to predict discharge to nursing facility, and
surgical complication or death in trauma patients 65 years or older. In a prospective study of 63
geriatric trauma patients, each VES-13 point increased the odds of complication by 1.53.80
Patient Management
Data are emerging that unique expertise, and specialized pathways and processes of care improve
outcomes in injured geriatric patients. A retrospective study of the Pennsylvania State database found
that trauma centers with the highest volume of geriatric patients, rather than the highest overall trauma
volume, had lower mortality, fewer complications, and lower rates of failure-to-rescue, suggesting that
experience with older patients at the center level improves outcome.81 A recent meta-analysis in hip
fracture patients showed that routine geriatric consultation, comanagement, or geriatric admission with
orthopedic consultation reduced in-hospital mortality by 40% and longer-term mortality by 17%.82
Among trauma patients, triggered or proactive, geriatric consultation is associated with lower rates of
delirium, fewer consults to medicine and psychiatry, and fewer discharges to facilities among patients
who were admitted from home.83 In another pre–post study of routine geriatric consult in trauma
patients over 65 years, Tillou et al.84 showed that patients who received a geriatric consultation had
better functional recovery at 6 and 12 months after injury than patients without the consultation.
Some centers have reported success in developing clinical pathways for geriatric trauma patients.
Bradburn et al.85 implemented a high-risk geriatric protocol at their level II trauma center. As part of
the protocol, patients received arterial blood gas determination at the time of trauma activation, were
admitted to the ICU, and received a geriatric consultation. If the initial base deficit was >6, it was
rechecked every 4 hours until normalized. Patients treated under the protocol had 40% lower mortality
than those who did not receive the protocol. Bar-Or et al.86 also showed improved mortality among
trauma patients >65 years who routinely received serial venous lactate measurement and early surgical
767
booksmedicos.org
consultation. Mangram et al.87 created the dedicated G-60 unit at their level II trauma center for trauma
patients over 60 years who were admitted within 48 hours of injury. Patients were evaluated by a
surgeon and a hospitalist at the time of trauma activation, and admitted to the surgical service. Other
services including physical medicine and rehabilitation, palliative care, physical and occupational
therapy, respiratory therapy, the G-60 nurse supervisor, social work, nutrition, pharmacy were also
notified at the time of activation and evaluated patients within 24 hours of admission. Surgeon-led
multidisciplinary rounds occurred twice weekly. As compared to historical controls, patients on the G-60
service had significantly shorter ED length of stay, time to OR, hospital length of stay, and ICU length
of stay. Although mortality was unchanged, there were also significantly lower rates of medical
complications.
OUTCOMES
Mortality Outcomes
The relationship between age and adverse outcomes among older trauma patients is well recognized.88
As compared to younger patients, in-hospital mortality for older patients are 4.4% versus 1.6% for low
severity injuries and 5.9% versus 1.4% for moderate severity injuries. Moreover, mortality among older
trauma patients increases with the number of comorbidities; patients with minor injuries and
comorbidities are at increased risk of death compared to age-matched counterparts without
comorbidities.89 It is important for clinicians to recognize that significant numbers of geriatric trauma
patients die shortly after hospital discharge, and patients have higher mortality than age-matched
counterparts for years after injury. Clark et al.90 showed that mortality at 30 days was nearly double
the in-hospital mortality. Fleischman et al.91 found that 89% of postinjury mortality occurs by 60 days
and that mortality rates level off at 6 months. Davidson et al.92 found that while all trauma patients had
higher mortality up to 3 years after injury than age-matched controls, older patients and those
discharged to skilled nursing facilities fared particularly poorly.
Functional Outcomes
Most older trauma patients will return to their prior level of function, and thus an initial aggressive
approach to treatment in a trauma center is warranted.59 A significant portion experiences long-term
functional decline after injury. A follow-up study of blunt trauma patients showed that 87% were
functionally independent 1 to 3 years after injury, and another with mean follow-up 2.8 years after
injury showed that 63% remained independent but with reduced function.93 Studies with 12 months or
less follow-up show higher rates of decreased functional abilities. In a prospective study of 37 patients
>65 years, Kelley-Quon et al.94 showed that most patients had lost 1 ADL at 12 months. More recent
data from this group show that a geriatric consultation during the index hospitalization is associated
with less long-term functional decline.84 Quality of life in older patients is significantly impaired.
Among patients 1 year after hip fracture 90% have reduced mobility, 69% have pain, and 33% who
were independent live in a nursing home. As compared to patients without TBI, a cohort of patients
>50 years old had poorer cognitive and psychosocial function a year post injury.
PALLIATIVE AND END-OF-LIFE CARE IN THE GERIATRIC TRAUMA

PATENT
9 Palliative care is an approach to medical care aimed at relieving suffering and improving quality of
life for patients with serious illness and for their families. Palliative care is appropriate in the
management in a broad range of injured patients who die or suffer with acute and chronic pain,
functional disability, or life-limiting conditions such as severe frailty and underlying organ failure.95
Clinical domains of palliative care encompass symptom management. Spiritual, religious, psychosocial,
and bereavement support can be delivered alongside aggressive life prolonging care and should not be
limited to only those patients near the end-of-life.96 Thus palliative care can be provided to patients who
are “cured” of their illnesses or recover from injury. Palliative care should not be confused with hospice
care which is an administrative benefit provided to patients with terminal illness and typically provided
to patients expected to survive less than 6 months.
768
booksmedicos.org
End-of-Life Care
10 Four-fifths of in-hospital deaths among geriatric trauma patients involve decisions to withdraw or
withhold of life-sustaining therapies.97 Advanced directives, including living wills and proxy forms are
intended to guide medical decisions in the event a patient loses capacity to make decisions.
Unfortunately, many patients, even those with terminal illness, do not have advanced directives or the
advanced directives are too specific or too broad to be useful.98 Therefore, it is critically important that
clinicians make every effort to engage patients and their families in conversations about the overall
goals of care and expectations for recovery. Patients may forego heroic measures and prolonged life-
sustaining treatments if all possible outcomes are not acceptable to them.99 It is advisable for clinicians
to identify healthcare proxies and address code status early in the hospital stay and ideally with the
patient.
Physicians play an important role in providing a comfortable death experience for patients and
families. In death, patients want to minimize discomfort, to avoid a prolonged dying process, to achieve
a sense of control, and time to strengthen relationships with loved ones.100 Survivors and surrogates
suffer high rates of depression, posttraumatic stress disorder, and complicated grief after a loved one
dies in the ICU.101 Better outcomes for survivors are achieved when they feel that they have been well
informed and had appropriate responsibility in decision-making.102 It is important for physicians to
provide emotional support for surrogates who are often conflicted and distressed.
In cases where the primary goal is comfort, liberal use of opioids can reduce pain and dyspnea. Some
clinicians may be reluctant to use opioids for fear of causing respiratory depression and death. Opioid
use is ethically justifiable in these scenarios as long as the intent is symptom relief and not euthanasia.
Patients should receive doses adequate to achieve comfort; target respiratory rate is 15 to 20 breaths
per minute. When patients die, physicians should be available to answer questions and address
bereavement needs. The way death is communicated is important. In a study of survivors of patients
who died in the ICU, failure to find the physician comforting was most strongly associated with
developing a psychiatric diagnosis in the year after death.101 In another study of 70 survivors of cancer
patients, feeling unprepared was a predictor of major depressive disorder up to 9 months.103
Hospice
Hospice is an interdisciplinary approach to care that provides comprehensive, medical, nursing,
counseling, and bereavement to terminally ill patients and their families. Referral for hospice care is
appropriate when patients have a limited prognosis and the primary goal is comfort and symptom
management. In the care of geriatric trauma patients, hospice may be relevant to patients with severe
TBI or patients who sustain injury in the setting of other advanced serious underlying illnesses with life
expectancy 6 months or less. Hospice care is associated with better quality of life, better bereavement
outcomes, lower healthcare costs, and either equivalent or improved survival in patients with a terminal
diagnosis.104–107 The impact of transition to hospice on trauma center mortality reporting is unclear.
Kozar et al. found wide variation among 167 trauma centers enrolled in the Trauma Quality
Improvement Project as to whether they reported patients discharged to hospice as in-hospital deaths or
survivors. The authors advised that hospice discharge should be considered death across centers to
prevent distortion of actual performances.108
References
1. Ortman JM, Velkoff VA. An aging nation: the older population in the United States. U.S.
Department of Commerce, Economics and Statistics Administration; May, 2014.
2. Villella E, Cho SJ. Effect of aging on the vascular system plus monitoring and support. Surg Clin N
Am 2015;95:37–51.
3. Martin RS, Farrah JP, Chang MC. Effect of aging on cardiac function plus monitoring and support.
Surg Clin North Am 2015;95:23–35.
4. Elliott HL, Sumner DJ, McLean K, et al. Effect of age on the responsiveness of vascular alpha-
adrenoceptors in man. J Cardiovasc Pharmacol 1982;4(3):388–392.
5. Christou DD, Seals DR. Decreased maximal heart rate with aging is related to reduced {beta}-
adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate. J Appl
Physiol (1985) 2008;105(1):24–29.
769
booksmedicos.org
6. Ramly E, Kaafarani HM, Velmahos G. The effect of aging on pulmonary function: implications for
monitoring and support of the surgical and trauma patient. Surg Clin North Am 2015;95:53–69.
7. Sevransky JE, Haponik EF. Respiratory failure in elderly patients. Clin Geriatr Med 2003;19(1):205–
224.
8. Sprung J, Gajic O, Warner DO. Review article: age related alterations in respiratory function—
anesthetic considerations. Can J Anaesth 2006;53(12):1244–1257.
9. Zaugg M, Lucchinetti E. Respiratory function in the elderly. Anesthesiol Clin North America
2000;18(1):47–58, vi.
10. Knudson RJ, Slatin RC, Lebowitz MD, et al. The maximal expiratory flow-volume curve. Normal
standards, variability, and effects of age. Am Rev Respir Dis 1976;113(5):587–600.
11. Cardus J, Burgos F, Diaz O, et al. Increase in pulmonary ventilation-perfusion inequality with age
in healthy individuals. Am J Respir Crit Care Med 1997;156(2 Pt 1):648–653.
12. Guenard H, Marthan R. Pulmonary gas exchange in elderly subjects. Eur Respir J 1996;9(12):2573–
2577.
13. Kronenberg RS, Drage CW. Attenuation of the ventilatory and heart rate responses to hypoxia and
hypercapnia with aging in normal men. J Clin Invest 1973;52(8):1812–1819.
14. Baldea AJ. Effect of aging on renal function plus monitoring and support. Surg Clin North Am
2015;95:71–83.
15. Nohra E, Bochicchio GV. Management of the gastrointestinal tract and nutrition in the geriatric
surgical patient. Surg Clin North Am 2015;95:85–101.
16. Bonne S, Schuerer DJ. Trauma in the older adult. Epidemiology and evolving geriatric trauma
principles. Clin Geriatr Med 2013;29:137–150.
17. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy.
Chest 2012;141(2):e152S–e184S.
18. Sarode R, Milling TJ, Refaai MA, et al. Efficacy and safety of a 4-factor prothrombin complex
concentrate in patients on vitamin K antagonists presenting with major bleeding. Circulation
2013;128:1234–1243.
19. Kaatz S, Kouides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and
factor Xa inhibitors. Am J Hematol 2012;87:S141–S145.
20. Heidbuchel H, Verhamme P, Alings M, et al. European Society of Cardiology practical guide on the
use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Eur Heart J
2013;15:625–651.
21. Spahn DR, Bouillon B, Cerny V, et al. Management of bleeding and coagulopathy following major
trauma: an updated European Guidelines. Crit Care 2013;17(2):R76.
22. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by
prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy
subjects. Circulation 2011; 124(14):1573–1579.
23. Levi M, Eerenberg E, Kamphuisen PW, et al. Bleeding risk and reversal strategies for old and new
anticoagulants and antiplatelet agents. J Thromb Haemost 2011;9(9):1705–1712.
24. Makris M, Van Veen JJ, Tait CR, et al. Guideline on the management of bleeding in patients on
antithrombotic agents. Br J Haematol 2012;160:35–46.
25. Then J, Tisherman SA. Pharmacology for the geriatric surgical patient. Surg Clin North Am
2015;95:139–147.
26. American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society
updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc
2012;60(4):616–631.
27. Brown CV, Ali S, Fairley R, et al. Risk factor for falls among hospitalized trauma patients. Am Surg
2013;79(5):465–469.
28. Panel on Prevention of Falls in Older Persons, American Geriatrics Society and British Geriatrics
Society. Summary of the Updated American Geriatrics Society/British Geriatrics Society clinical
practice guideline for prevention of falls in older persons. J Am Geriatr Soc 2011;59(1):148–157.
29. Lachs MS, Pillemer K. Elder abuse. Lancet 2004;364(9441):1263.
30. Halphen JM, Dyer CB. Elder mistreatment: abuse, neglect, and financial exploitation. In: Schmader
770
booksmedicos.org
KE, Sokol HN, eds. UpToDate. Waltham, MA: Wolters Kluwer; Accessed on December 31, 2014.
31. Thompson HJ, McCormick WC, Kagan SH. Traumatic brain injury in older adults: epidemiology,
outcomes, and future implications. J Am Geriatr Soc 2006;54(10):1590–1595.
32. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury in the United States: Emergency
Department Visits, Hospitalizations, and Deaths. Atlanta, GA: National Center for Injury Prevention
and Control; 2004.
33. Adhiyaman V, Asghar M, Ganeshram KN, et al. Chronic subdural haematoma in the elderly. Postgrad
Med J 2002;78(916):71–75.
34. Haydel MJ, Preston CA, Mills TJ, et al. Indications for computed tomography in patients with
minor head injury. N Engl J Med 2000;343(2):100–105.
35. Stiell IG, Wells GA, Vandemheen K, et al. The Canadian CT Head Rule for patients with minor head
injury. Lancet 2001;357:1391–1396.
36. Rathlev NK, Medzon R, Lowery D, et al. Intracranial pathology in elders with blunt head trauma.
Acad Emerg Med 2006;13(3):302–307.
37. Mack LR, Chan SB, Silva JC, et al. The use of head computed tomography in elderly patients
sustaining minor head trauma. J Emerg Med 2003;24(2):157–162.
38. Goldstein JN, Thomas SH, Frontiero V, et al. Timing of fresh frozen plasma administration and
rapid correction of coagulopathy in warfarin-related intracerebral hemorrhage. Stroke 2006;37:151–
155.
39. Ivascu FA, Janczyk RJ, Junn FS, et al. Treatment of trauma patients with intracranial hemorrhage
on preinjury warfarin. J Trauma 2006;61(2):318–321.
40. Sharma OP, Oswanski MF, Jolly S, et al. Perils of rib fractures. Am Surg 2008;74(4):310–314.
41. Bulger EM, Arneson MA, Mock CN, et al. Rib fractures in the elderly. J Trauma 2000;48(6):1040–
1046; discussion 1046–1047.
42. Bergeron E, Lavoie A, Clas D, et al. Elderly trauma patients with rib fractures are at greater risk of
death and pneumonia. J Trauma 2003;54(3):478–485.
43. Holcomb JB, McMullin NR, Kozar RA, et al. Morbidity from rib fractures increases after age 45. J
Am Coll Surg 2003;196(4):549–555.
44. Rapp K, Cameron ID, Kurrle S, et al. Excess mortality after pelvic fractures in institutionalized older
people. Osteoporos Int 2010;21(11):1835–1839.
45. O’Brien DP, Luchette FA, Pereira SJ, et al. Pelvic fracture in the elderly is associated with increased
mortality. Surgery 2002;132(4):710–714; discussion 714–715.
46. Kannus P, Niemi S, Palvanen M, et al. Continuously increasing number and incidence of fall-
induced, fracture-associated, spinal cord injuries in elderly persons. Arch Intern Med
2000;160(14):2145–2149.
47. Bonne S, Schuerer DJ. Trauma in the older adult. Epidemiology and evolving geriatric trauma
principles. Clin Geriatr Med 2013;29:137–150.
48. Harris MB, Reichmann WM, Bono CM. Mortality in elderly patients after cervical spine fractures. J
Bone Joint Surg Am 2010;92(3):567–574.
49. Hannan EL, Magaziner J, Wang JJ, et al. Mortality and locomotion 6 months after hospitalization
for hip fracture: risk factors and risk-adjusted hospital outcomes. JAMA 2001;285(21):2736–2742.
50. Lu-Yao GL, Baron JA, Barrett JA, et al. Treatment and survival among elderly Americans with hip
fractures: a population-based study. Am J Public Health 1994;84(8):1287–1291.
51. Lenze EJ, Munin MC, Skidmore ER, et al. Onset of depression in elderly persons after hip fracture:
implications for prevention and early intervention of late-life depression. J Am Geriatr Soc
2007;55(1):81–86.
52. Herrick C, Steger-May K, Sinacore DR, et al. Persistent pain in frail older adults after hip fracture
repair. J Am Geriatr Soc 2004;52(12):2062–2068.
53. Zuckerman JD, Skovron ML, Koval KJ, et al. Postoperative complications and mortality associated
with operative delay in older patients who have a fracture of the hip. JBone Joint Surg Am
1995;77(10):1551–1556.
54. Meldon SW, Reilly M, Drew BL, et al. Trauma in the very elderly: a community-based study of
outcomes at trauma and nontrauma centers. J Trauma 2002;52(1):79–84.
771
booksmedicos.org
55. Mann NC, Mullins RJ, MacKenzie EJ, et al. Systematic review of published evidence regarding
trauma system effectiveness. J Trauma 1999;47(3 suppl):S25–S33.
56. Goodmanson NW, Rosengart MR, Barnato AE, et al. Defining geriatric trauma: when does age make
a difference? Surgery 2012;152(4):668–674; discussion 674–665.
57. Oyetunji TA, Chang DC, Crompton JG, et al. Redefining hypotension in the elderly: normotension
is not reassuring. Arch Surg 2011;146(7):865–869.
58. Centers for Disease Control and Prevention. 2011 guidelines for field triage of injured patients.
2011. http://www.cdc.gov/fieldtriage/pdf/decisionscheme_poster_a.pdf. Accessed December 29,
2014.
59. Jacobs DG, Plaisier BR, Barie PS, et al. Practice management guidelines for geriatric trauma: the
EAST Practice Management Guidelines Work Group. J Trauma Acute Care Surg 2003;54(2):391–416.
60. Pandit V, Rhee P, Hashmi A, et al. Shock index predicts mortality in geriatric trauma patients: an
analysis of the National Trauma Data Bank. J Trauma Acute Care Surg 2014;76(4):1111–1115.
61. Gage AM, Traven N, Rivara FP, et al. Compliance with Centers for Disease Control and Prevention
field triage guidelines in an established trauma system. J Am Coll Surg 2012;215(1):148–154;
62. Staudenmayer KL, Hsia RY, Mann NC, et al. Triage of elderly trauma patients: a population-based
perspective. J Am Coll Surg 2013;217(4):569–576.
63. Milzman DP, Boulanger BR, Rodriguez A, et al. Pre-existing disease in trauma patients: a predictor
of fate independent of age and injury severity score. J Trauma 1992;32(2):236–243; discussion 243–
244.
64. Zautcke JL, Coker SB Jr, Morris RW, et al. Geriatric trauma in the State of Illinois: substance use
and injury patterns. Am J Emerg Med 2002;20(1):14–17.
65. Ellis G, Whitehead MA, Robinson D, et al. Comprehensive geriatric assessment for older adults
admitted to hospital: meta-analysis of randomised controlled trials. BMJ 2011;343:d6553.
66. Katz S, Ford A, Moskowitz RW, et al. Studies of illness in the aged. The index of ADL: a
standardized measure of biological and psychosocial function. JAMA 1963;185:914–919.
67. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and
meta-analysis: II. Cardiac and analgesic drugs. J Am Geriatr Soc 1999;47(1):40–50.
68. Hartikainen S, Lönnroos E, Louhivuori K. Medication as a risk factor for falls: critical systematic
review. J Gerontol A Biol Sci Med Sci 2007;62(10):1172–1181.
69. Kaiser MJ, Bauer JM, Rämsch C, et al. Frequency of malnutrition in older adults: a multinational
perspective using the mini nutritional assessment. J Am Geriatr Soc 2010;58(9):1734–1738.
70. Employee Benefit Research Institute Notes. Time trends in poverty for Older Americans between
2001–2009. 2012. http://www.ebri.org/pdf/notespdf/ebri_notes_04_apr-12.eldpovty.pdf. Accessed
January 10, 2015.
71. Perissinotto CM, Cenzer IS, Covinsky KE. Loneliness in older persons: a predictor of functional
decline and death. Arch Intern Med 2012;172(14):1078–1084.
72. Kelley AS, Ettner SL, Morrison RS, et al. Determinants of medical expenditures in the last 6 months
of life. Ann Intern Med 2011;154(4):235–242.
73. Pandit V, Joseph B, Rhee PM, et al. Frailty is superior to age in predicting outcomes in geriatric
trauma patients: a prospective analysis. J Am Coll Surg 2013;217(3 suppl):S59.
74. Singh M, Alexander K, Roger VL, et al. Frailty and its potential relevance to cardiovascular care.
Paper presented at: Mayo Clinic Proceedings; 2008.
75. Fried LP, Tangen CM, Walston J, et al.; Cardiovascular Health Study Collaborative Research Group.
Frailty in older adults: evidence for a phenotype. J Gerontol A Biolo Sci Med Sci 2001;56(3):M146–
M157.
76. Clegg A, Young J. The frailty syndrome. Clin Med 2011;11(1):72–75.
77. Joseph B, Pandit V, Rhee P, et al. Predicting hospital discharge disposition in geriatric trauma
patients: is frailty the answer? J Trauma Acute Care Surg 2014;76(1):196–200.
78. Moisey LL, Mourtzakis M, Cotton BA, et al.; Nutrition and Rehabilitation Investigators Consortium
(NUTRIC). Skeletal muscle predicts ventilator-free days, ICU-free days, and mortality in elderly ICU
patients. Crit Care 2013;17(5):R206
772
booksmedicos.org
79. Fairchild B, Webb T, Xiang Q, et al. Sarcopenia and frailty in elderly trauma patients. World J Surg
2015;39(2):373–379.
80. Min L, Ubhayakar N, Saliba D, et al. The vulnerable elders survey-13 predicts hospital
complications and mortality in older adults with traumatic injury: a pilot study. J Am Geriatr Soc
2011;59(8):1471–1476.
81. Matsushima K, Schaefer EW, Won EJ, et al. Positive and negative volume-outcome relationships in
the geriatric trauma population. JAMA Surg 2014;149(4):319–326.
82. Grigoryan KV, Javedan H, Rudolph JL. Ortho-geriatric care models and outcomes in hip fracture
patients: a systematic review and meta-analysis. J Orthop Trauma 2014;28(3):e49–e55.
83. Lenartowicz M, Parkovnick M, McFarlan A, et al. An evaluation of a proactive geriatric trauma
consultation service. Ann Surg 2012;256(6):1098–1101.
84. Tillou A, Kelley-Quon L, Burruss S, et al. Long-term postinjury functional recovery: outcomes of
geriatric consultation. JAMA Surg 2014;149(1):83–89.
85. Bradburn E, Rogers FB, Krasne M, et al. High-risk geriatric protocol: improving mortality in the
elderly. J Trauma Acute Care Surg 2012;73(2):435–440.
86. Bar-Or D, Salottolo KM, Orlando A, et al. Association between a geriatric trauma resuscitation
protocol using venous lactate measurements and early trauma surgeon involvement and mortality
risk. J Am Geriatr Soc 2013;61(8):1358–1364.
87. Mangram AJ, Mitchell CD, Shifflette VK, et al. Geriatric trauma service: a one-year experience. J
88. Grossman M, Scaff DW, Miller D, et al. Functional outcomes in octogenarian trauma. J Trauma
2003;55(1):26–32.
89. McGwin G Jr, MacLennan PA, Fife JB, et al. Preexisting conditions and mortality in older trauma
90. Clark DE, DeLorenzo MA, Lucas FL, et al. Initial presentation of older injured patients to high-
volume hospitals is not associated with lower 30-day mortality in Medicare data. Crit Care Med
2007;35(8):1829–1836.
91. Fleischman RJ, Adams AL, Hedges JR, et al. The optimum follow-up period for assessing mortality
outcomes in injured older adults. J Am Geriatr Soc 2010;58(10):1843–1849.
92. Davidson GH, Hamlat CA, Rivara FP, et al. Long-term survival of adult trauma patients. JAMA
2011;305(10):1001–1007.
93. Inaba K, Goecke M, Sharkey P, et al. Long-term outcomes after injury in the elderly. J Trauma
2003;54(3):486–491.
94. Kelley-Quon L, Min L, Morley E, et al. Functional status after injury: a longitudinal study of
geriatric trauma. Am Surg 2010;76(10):1055–1058.
95. Grossman MD, Miller D, Scaff DW, et al. When is an elder old? Effect of preexisting conditions on
mortality in geriatric trauma. J Trauma 2002;52(2):242–246.
96. Surgeons ACo. ST-50 Statement of Principles of Palliative Care. Vol 90. Chicago, IL: Surgeons ACo;
2005.
97. Plaisier BR, Blostein PA, Hurt KJ, et al. Withholding/withdrawal of life support in trauma patients:
is there an age bias? Am Surg 2002;68(2):159–162.
98. Goodman MD, Tarnoff M, Slotman GJ. Effect of advance directives on the management of elderly
critically ill patients. Crit Care Med 1998;26(4):701–704.
99. Barnato AE, Herndon MB, Anthony DL, et al. Are regional variations in end-of-life care intensity
explained by patient preferences?: a study of the US Medicare Population. Med Care
2007;45(5):386–393.
100. Steinhauser KE, Clipp EC, McNeilly M, et al. In search of a good death: observations of patients,
families, and providers. Ann Intern Med 2000; 132(10):825–832.
101. Siegel MD, Hayes E, Vanderwerker LC, et al. Psychiatric illness in the next of kin of patients who
die in the intensive care unit. Crit Care Med 2008;36(6):1722–1728.
102. Gries CJ, Engelberg RA, Kross EK, et al. Predictors of symptoms of posttraumatic stress and
depression in family members after patient death in the ICU. Chest 2010;137(2):280–287.
103. Wright AA, Zhang B, Ray A, et al. Associations between end-of-life discussions, patient mental
773
booksmedicos.org
health, medical care near death, and caregiver bereavement adjustment. JAMA 2008;300(14):1665–
1673.
104. Teno JM, Clarridge BR, Casey V, et al. Family perspectives on end-of-life care at the last place of
care. JAMA 2004;291(1):88–93.
105. Teno JM, Shu JE, Casarett D, et al. Timing of referral to hospice and quality of care: length of stay
and bereaved family members’ perceptions of the timing of hospice referral. J Pain Symptom
Manage 2007;34(2):120–125.
106. Obermeyer Z, Makar M, Abujaber S, et al. Association between the Medicare hospice benefit and
health care utilization and costs for patients with poor-prognosis cancer. JAMA 2014;312(18):1888–
1896.
107. Wright AA, Keating NL, Balboni TA, et al. Place of death: correlations with quality of life of
patients with cancer and predictors of bereaved caregivers’ mental health. J Clin Oncol
2010;28(29):4457–4464.
108. Kozar RA, Holcomb JB, Xiong W, et al. Are all deaths recorded equally? The impact of hospice care
on risk-adjusted mortality. J Trauma Acute Care Surg 2014;76(3):634–639.
774
booksmedicos.org
Chapter 31
Trauma in Pregnancy
Felix Y. Lui and Kimberly A. Davis
Key Points
1 Unique challenges exist in the management of the pregnant patient that need to be addressed in
order to achieve optimal outcomes for both the mother and child.
2 Anatomic and physiologic changes in the maternal trauma patient evolve over the course of
pregnancy and require modifications in management based on gestational age.
3 Patient care should be tailored for the anatomic and physiologic changes in the gravid trauma
patient, but priorities remain the same as for the nongravid patient.
4 Relative hypervolemia of pregnancy can mask large-volume hemorrhagic losses and requires rapid
identification and aggressive resuscitation.
5 Compression of the inferior vena cava (IVC) and decreased cardiac output can result from supine
positioning. Proper positioning and use of a wedge is recommended.
6 A Kleihauser–Betke test should be performed in all pregnant trauma patients with greater than 12
weeks of gestation and prophylactic anti-D immune globulin given within 72 hours for high-risk
patients.
7 Radiation exposure should be minimized in all pregnant trauma patients. Ultrasound (including
FAST) exposes the mother and fetus to no radiation and is reliable, has good negative predictive
value, and can be followed serially over time.
8 Angiography and angioembolization may be useful in life-threatening hemorrhage, recognizing the
risks of increased radiation exposure.
9 Pregnant patients are at an increased risk for deep venous thrombosis (DVT) and should be given
unfractionated subcutaneous heparin for prophylaxis.
10 Providers should have a low threshold for screening maternal trauma patients for intimate partner
violence (IPV) and substance abuse.
INTRODUCTION
Trauma is the leading cause of nonobstetric death in pregnant patients worldwide. As the risk of death
due to pregnancy-related complications has declined, trauma now accounts for nearly half of maternal
deaths in the United States annually, with an up to fourfold increase in fetal mortality in some series.1,2
Pregnant trauma patients have increased rates of preterm labor and placental abruption, and their
infants are at increased risk of respiratory distress and fetal death.3
The trauma evaluation of the pregnant patient presents unique challenges including alterations in
anatomy and physiology that evolve continuously throughout pregnancy, pregnancy-specific patterns of
injury, and pregnancy-specific challenges in critical care and surgical management.
Pregnant patients also present special social and ethical issues in trauma. Interpersonal violence
against the pregnant female is an underrecognized phenomenon worldwide and has long-lasting effects
on both mother and child. While management of the pregnant trauma patient focuses on the
resuscitation of the mother, consideration of fetal survival and outcome must be considered in the
management of these patients.
1 Trauma in the pregnant patient presents as a unique situation in which treatment is required in two
(or more) patients simultaneously. In order to provide the optimal level of care to both the mother and
child, the practitioner needs to recognize the unique anatomical and physiologic changes of the gravid
patient as the pregnancy progresses, and how they alter the treatment of these patients.
775
booksmedicos.org
EPIDEMIOLOGY OF INJURY DURING PREGNANCY
Up to 37% to 46.3% of gravid maternal deaths in the United States are attributable to trauma, resulting
in over one million deaths annually worldwide. An estimated 5% to 7% of pregnancies are complicated
by trauma, and 0.3% to 0.4% of all pregnant females required hospitalization for treatment of
injuries.4–7 The majority of trauma occurs later in pregnancy, with greater than 50% occurring during
the third trimester. Motor vehicle–related injuries are the most common cause of trauma and injury (up
to 33.6%), followed by falls and interpersonal violence.8 Although motor vehicle collisions are no more
common in pregnancy, they remain the leading cause of fetal death due to frequency of maternal
trauma.9,10 Fetal death occurs in up to 50% of life-threatening traumatic injury to the mother, but due
to the frequency of minor trauma, the majority of fetal loss occurs after minor traumatic injuries.11
Violence due to domestic abuse is an underrecognized cause of maternal and fetal injury and death.
Interpersonal violence between intimate partners occurs in up to 30% of pregnant women, with a fetal
mortality of 5%. While most common in first 18 weeks of gestation, violence is prevalent throughout
gestation. The risk of IPV is greatest immediately after delivery of a child.12–14
PATTERNS OF INJURY
2 The development of the fetus and enlargement of the uterus throughout pregnancy affects the
patterns of injury experienced depending on stage of development. Until the 12th week of gestation, the
uterus is thick walled and is well protected by the surrounding pelvis. By the 20th week of gestation,
the uterus extends out of the true pelvis up to the umbilicus and by the 34th week, the costal margins.
As the uterus grows, the protection conferred by the bony pelvis is lost and the fetus becomes
increasingly vulnerable to direct trauma and injury. Later in pregnancy the relative thickness of the
uterine wall decreases, as does the relative volume of amniotic fluid surrounding the fetus, further
limiting the protective barrier surrounding the fetus and predisposing the uterus to shear forces and
rupture.
Motor vehicle collisions remain the most common mechanism of significant blunt trauma in the
pregnant patient. Maternal seatbelt use is associated with improved outcomes and decreased fetal
mortality.15 As the growing uterus emerges out of the pelvis after the 12th week of gestation, the fetus
is increasingly exposed to direct blunt trauma by seat belt or steering wheel injuries. Trauma to the
fetus commonly results in skull fracture or intracranial hemorrhage, especially late in pregnancy.
Placental abruption, resulting from shear of the relatively inelastic placenta against the flexible uterine
wall, is the most common cause of fetal demise from trauma. Uterine rupture is fortunately rare, but
carries a rate of fetal demise near 100% and maternal mortality of 10%. Pelvic fractures are a sign of
high-energy forces and can result in severe retroperitoneal hemorrhage of the mother with hypotension,
and severe direct injury to the fetal head as it descends into the pelvic inlet late in pregnancy.
Penetrating trauma to the pregnant patient carries a high rate of fetal mortality, ranging from 40% to
80%, depending on mechanism, gestational age, and location.16–18 Up to 9.5% of trauma in pregnant
patients is intentional, with 73% of penetrating abdominal wounds in pregnancy resulting from gunshot
wounds.17 Gunshot wounds to the abdomen mandate exploratory laparotomy, whereas stab wounds
may be managed selectively depending on the presence or absence of fascial disruption.19 Fetal injury
occurs in 70% of gunshot wounds to the pregnant abdomen. Diagnostic peritoneal lavage may be useful
in evaluating these patients, though focused abdominal sonography for trauma (FAST) has largely
supplanted its use. FAST ultrasound in the pregnant patient has a sensitivity of 61% to 83% and a
specificity of 94% to 100% in detecting intraperitoneal injuries.20–22 Direct trauma to the uterus can be
associated with large-volume blood loss due to the engorged uterine vessels.
EVALUATION OF THE PREGNANT TRAUMA PATIENT

3 The evaluation of the pregnant trauma patient follows the same principles as for the nonpregnant
patient as outlined in the American College of Surgeons’ Advanced Trauma Life Support guidelines.23
The evaluation and resuscitation begins with the primary survey, utilizing a systematic ABCDE
approach, and followed by a complete assessment of injuries in the secondary survey. Basic tenets of
surgical intervention and “damage control” techniques should be followed. The best outcomes for the
fetus are achieved by the optimal evaluation, resuscitation, and treatment of the mother.
776
booksmedicos.org
Chart 31-1 Frequency of Injury in Fetal Trauma Deaths
The main priorities in prehospital care continue to be the avoidance of hypoxia and hypotension in
the mother. Maintenance of an adequate airway, as well as provision of supplemental oxygen, is
essential in avoiding fetal hypoxia. Circulatory support with crystalloids is recommended and should be
initiated early. The relative hypervolemic state of pregnancy means that a large-volume blood loss can
occur prior to the development of signs of shock. Displacement of the uterus off the inferior vena cava
(IVC) or tilting of the patient with a wedge may be required to augment cardiac return. A detailed
obstetric history including length of gestation, prenatal care, complications, and names of care providers
can be valuable information for the trauma team.
During the trauma evaluation, the priorities in patient management remain the same in the pregnant
patient as in the nonpregnant patient. Adequate oxygenation of the mother, by ensuring an adequate
maternal airway with supplemental oxygen, best ensures the adequate oxygenation of the fetus. Access
for resuscitation can be achieved with peripheral IVs or subclavian or jugular venous central access.
Blood loss should be treated with crystalloid and blood transfusion following the principles of damage
control and balanced resuscitation, with an emphasis on early use of blood and blood products in the
event of life-threatening hemorrhage.24,25
In the secondary survey, a complete physical examination is essential. In addition to a complete
examination for maternal injuries, complete examination of the fetus includes estimation of uterine size
and fundal height, examination for vaginal bleeding, rupture of membranes, presence of bulging
perineum, contractions, or abnormal fetal heart rate (FHR) or rhythm. Vaginal bleeding may be an
indicator of premature cervical dilation, early labor, abruption placentae, or placenta previa. Cloudy
white or green fluid from the cervical os may represent amniotic sac rupture. A vaginal speculum
examination should be performed to assess for cervical dilatation and bleeding from the cervical os.
Strong contractions, or bulging of the perineum (due to the presenting part of the fetus) can signal
imminent delivery (or abortion in early pregnancy).
A thorough medical and obstetric history is required for all patients in whom it can be obtained. An
accurate date of last menstrual period and expected delivery aids in measurement of uterine size,
height, and position. A history of complications of the present or previous births, such as hypertension,
preterm labor, abruption placentae, or placenta previa aids in evaluation and management, due to the
high rate of recurrence.
Options for evaluation of the fetus include Doppler FHR monitoring or ultrasound. Normal FHR
ranges from 120 to 160 beats/min. Tachycardia (>160 beats/min) is seen during stress, hypoxia, or
hypotension, however bradycardia (<120 beats/min) also indicates fetal distress and mandates
immediate maternal resuscitative efforts including supplemental oxygen, fluid, or blood administration.
Fetal heart monitoring should be performed in all potentially viable fetuses involved in a traumatic
abdominal injury.
Airway
Increased metabolic needs of the mother and fetus lead to a 30% to 60% increase in oxygen
consumption. This in combination with decreases in functional expiratory reserve volume and functional
residual capacity due to the enlarged uterus and upward pressure on the maternal diaphragms leads to
decreased overall respiratory reserve and can result in rapid onset of hypoxia of mother and fetus.
The average pregnant patient gains about 17% of body weight during pregnancy.26 This results in an
overall increase in BMI from fat and protein deposition, blood volume, interstitial fluid, and uterine
size. The resulting increase in Mallanpati scores may complicate airway management and result in
morbidity due to failed intubations.27 Raised progesterone levels also increase total-body water and
result in generalized edema, including edema of the airway. Edema of the tongue, oropharynx, and
trachea may impair visualization and intubation of the airway, further complicating intubation. These
changes progressively increase with increasing gestational age.28 Gastric compression due to increased
fundal height and lower esophageal sphincter dysmotility contribute to an increased risk of aspiration
and early intubation should be considered for at-risk patients. Preoxygenation, cricoid pressure, and
777
booksmedicos.org
avoidance of bag-mask ventilation when possible are recommended.
Cardiovascular System
4 Beginning at 10 weeks of gestation, intravascular blood volume increases steadily over the course of
pregnancy, reaching up to 50% above normal by term.29 The increase in plasma volume is relatively
greater than the approximately 15% increase in red blood cell (RBC) mass initially; therefore a relative
physiologic anemia is seen during early pregnancy. However, erythrocyte production increases later in
pregnancy, and after a nadir at 30 to 32 weeks, hematocrits are near normal by term. The relative
hypervolemia of pregnancy can mask large-volume hemorrhagic losses and up to 35% of maternal blood
loss can be lost prior to signs and symptoms of shock. Pulse rates increase by 10 to 15 beats/min and
remain elevated until delivery.
5 As the gravid uterus increases in size, supine positioning can result in “supine hypotensive
syndrome” resulting in compression of the IVC and decreased blood return to the heart, resulting in up
to a 30% decrease in cardiac output. Symptoms include lightheadedness, dizziness, pallor, tachycardia,
and hypotension. Displacing the uterus laterally to the left of the patient, either manually or by use of a
wedge to tilt the patient >15 degrees to the patient’s left can restore perfusion.
Fluid resuscitation is the first-line therapy for the unstable pregnant trauma patient. Catecholamine
release preserves the maternal blood pressure through maternal peripheral vasoconstriction, but
decreases fetal blood flow via placental vasoconstriction. Adequate access is essential in the injured
pregnant patient, as decreased fetal blood flow precedes maternal hypotension.30 Two large bore
intravenous lines, preferably above the diaphragm, should be placed initially. Adjustments must be
made for the relative hypervolemia of pregnancy and fetal distress can precede maternal instability.
Blood and blood product transfusion should be considered early in the unstable trauma patient. Type O,
Rh-negative blood should be used until type specific or cross-matched blood is available. In the
resuscitated, euvolemic patient, if pressor support is required, ephedrine and phenylephrine have the
least effect on uterine-placental vasculature and are recommended for initial pressor support in pregnant
patients. Additional pressors such as norepinephrine and epinephrine can be considered in the unstable
patient, especially in those without a viable pregnancy.31
Compression of the IVC by the gravid uterus decreases venous return to the heart and can decrease
cardiac output by up to 30%. During cardiopulmonary resuscitation (CPR), lateral displacement of the
uterus to the patient’s left can improve hemodynamics and CPR efforts. In late pregnancy (>24 weeks),
use of a foam wedge or padding to tilt the patient up to 30 degrees to her left can be helpful, though
CPR is only 80% effective in this position. Standard Advanced Cardiac Life Support (ACLS) voltage
should be used if defibrillation is required.
Pulmonary System
Increased intra-abdominal pressure from the growing uterus causes elevation of the diaphragm and
results in a decrease in total lung capacity and functional residual capacity. This results in a
compensatory chronic hyperventilation with 30% to 40% increase in minute ventilation. The resultant
chronic respiratory alkalosis facilitates transfer of fetal CO2 to the maternal circulation. Overaggressive
correction of respiratory acidosis in the mother can have deleterious effects on the fetus.32 Hypocapnia
(PaCO2 of <30 mm Hg) is common in pregnancy and a “normal” CO2 (∼40 mm Hg) may be a sign of
imminent respiratory failure. Oxygen consumption is increased approximately 20% in pregnancy and
needs to be accounted for in oxygen supplementation.
Elevation of the diaphragm late in pregnancy requires care to be taken when thoracostomy tube
placement or thoracentesis is required. Chest tubes for hemo- or pneumothoraces require higher
placement and should be inserted in the third or fourth intercostal space.
Ventilatory support, when required, should be individualized to optimize oxygenation and avoid
acidosis. There are no studies addressing the ideal way to manage ventilatory support in pregnant
patients with acute lung injury or ARDS. While lung protective strategies may be beneficial,
hypercapnea in these patients should be avoided.
Gastrointestinal System
The growing uterus causes progressive gastric compression as the pregnancy progresses. Increased
progesterone levels in pregnancy result in decreased function and tone of the lower esophageal
sphincter, as well as decreases in gastric tone and motility. This places the mother at increased risk of
778
booksmedicos.org
aspiration, especially during intubation. During intubation, rapid sequence induction is recommended
given the high risk of aspiration. High levels of progesterone decrease gallbladder contractions and lead
to bile stasis and formation of gallstones.
Genitourinary System
Renal function increases to meet the demands of increased circulatory volume during pregnancy. Renal
blood flow and glomerular filtration rates (GFRs) increase by 50% to 60% and levels of blood urea
nitrogen (BUN), creatinine, urate, and bicarbonate are decreased. Increased water retention causes
decreased plasma osmolality. Relaxation of the bladder smooth muscle increases capacity, stasis, and the
risk of development of urinary tract infections and pyelonephritis.33,34
Hematologic System
Increased intravascular volume relative to RBC production leads to a physiologic anemia with an
average hematocrit of 32 during the first two trimesters. This corrects to near normal hematocrit levels
by term. White blood cell counts (WBCs) also are relatively increased and can range from 9,800 to
15,000/mm3.
Increased estrogen levels lead to increased production of factors VII, VIII, IX, X, and XII and plasma
fibrinogen levels are elevated about 30% to 50%. Plasminogen activator levels are decreased. Protein S
activity is decreased and protein C activity is increased.35 This leads to the “hypercoagulable” state of
pregnancy and places these patients at increased risk of deep venous thrombosis (DVT) and pulmonary
embolism (PE), with slower resolution and lysis of clot. Normal levels of coagulation factors should
raise the suspicion of disseminated intravascular coagulation (DIC).
6 During trauma, entry of fetal Rh+ blood (as little as 0.07 mL) into the blood stream of an Rh−
mother results in formation of antibodies. These antibodies, while harmless to the mother, can reenter
the bloodstream of the fetus (or subsequent pregnancies) and cause hemolysis of the fetal RBCs.
Prophylactic anti-D immune globulin (RhoGAMTM) should be given within 72 hours of trauma when
significant risk of maternofetal hemorrhage exists. A Kleihauer–Betke (KB) analysis should be
performed for all pregnant patients with >12 weeks of gestation.36,37 A study out of University of
Maryland showed a positive KB was the single predictive risk factor for preterm labor with a likelihood
ratio of 20.8.38
Chart 31-2 Frequency of Injury by Mechanism
MONITORING AND EVALUATION OF THE FETUS

Pregnancies beyond 24 weeks of gestation are considered viable, and an expedient estimation of
gestational age is required. Patient history, fundal height, or ultrasonographic measurement of femur
length (in the third trimester) or biparietal measurements can be used.
Optimal management of the pregnant mother results in the best chance of survival of the fetus.
However, studies showing fetal death rates can be several fold greater than maternal deaths rates in
trauma suggest that maternal survival in itself is not sufficient. Close monitoring of the viable fetus is
necessary. Continuous fetal monitoring is the only way to identify fetal distress in the acute setting.39
The Eastern Association of Surgery for Trauma (EAST) guidelines recommend monitoring of all
pregnant female with gestation >20 weeks for at least 6 hours after significant trauma.40 Early
involvement of the neonatal intensive care staff is recommended.
779
booksmedicos.org
RADIOGRAPHIC IMAGING IN TRAUMA
The ideal diagnostic imaging test in the pregnant patient should be fast, readily available, safe, and
accurate. Selection of the appropriate test needs to balance the need for expedient diagnosis while
minimizing risk to mother and fetus. During pregnancy, radiation exposure should be avoided or
minimized whenever possible. Exposure to less than 5 rad of radiation has not been associated with fetal
anomalies or pregnancy loss, and is safe at any gestation age.41 With proper shielding, however,
minimal radiation is transmitted to the fetus with plain films (Chart 31-4).
7 Sonographic evaluation of both the mother and fetus is safe and useful in determining the extent of
injuries. FAST ultrasound has excellent specificity and negative predictive value in detecting pericardial,
pleural, and peritoneal free fluid in the hemodynamically unstable mother and poses no risk to the
fetus.42 Ultrasound is particularly useful in the evaluation of intrauterine contents, but can miss 50% to
80% of placental abruptions.43 Fetal ultrasound should be performed to assess for gestational age,
cardiac activity, and movement.
CT scans are rapid and sensitive for evaluation of traumatic injuries. CT scans of the head and neck
can be performed with minimal radiation exposure to the fetus. As radiation exposure levels from CT
scans of the chest, abdomen, and pelvis can be variable, the use of CT should be minimized whenever
possible. However, CT imaging should be performed when appropriate for complete evaluation of
traumatic injuries. Practitioners should utilize radiation reduction strategies whenever possible.44
Magnetic resonance imaging (MRI) poses minimal risk to the fetus and may have a role in the
evaluation for ligamentous injuries of the spine and spinal cord injuries. However, use of this modality
is limited due to availability and length of time required to perform. Additionally, the MRI scanner is
often remote from the resuscitation area, and ongoing resuscitative efforts may not be feasible when the
patient is undergoing MRI. Therefore, MRI should only be utilized in hemodynamically normal patients
without ongoing resuscitation requirements.
8 Angiography and angioembolization may be useful in the event of life-threatening hemorrhage, but
radiation dose increases with increasing duration and extent of evaluation. Typical exposure ranges
from 2 to 10 rad/min, and the risk versus benefit needs to be carefully weighed, and patients
appropriately counseled. Embolization of the gravid uterus is not recommended, however embolization
of the nonuterine vessels is feasible and can be life-saving in pelvic fractures with ongoing
hemorrhage.40
In counseling patients and families, healthcare providers should emphasize that the radiation exposure
from a single diagnostic test is not sufficient to cause harmful effects to the fetus, and that concerns
regarding possible effects of radiation should not prevent the use of medically indicated diagnostic
studies.45
SPECIAL CONSIDERATIONS
Pelvic Fractures
Pelvic fractures in pregnancy are associated with a high rate of hemorrhage and up to 35% fetal
mortality in trauma.46 Engorgement of the pelvic venous complex during the relative hypervolemia of
pregnancy can result in massive, life-threatening hemorrhage in the event of pelvic trauma, including
fetal death due to maternal shock.7 Direct injury to the uterus can result in placental abruption or injury
to the fetus. The most common fetal injury is traumatic brain injury, especially late in pregnancy as the
fetal head descends into the pelvic inlet. Angiography and angioembolization are useful adjuncts in the
management of life-threatening pelvic hemorrhage.
Chart 31-3 Physiologic Changes in Pregnancy
780
booksmedicos.org
Chart 31-4 Estimated Fetal Radiation Doses from Common Imaging Studies
Abruptio Placentae
Disruption of the placenta from the uterine wall is the most common cause of late maternal bleeding
and the leading cause of fetal demise after trauma.47 Fetal mortality ranges from 30% to 70%. Shearing
of the inelastic placenta off the relatively elastic uterine wall from direct trauma or deceleration leads
to separation of the placenta–uterine interface and results in maternal bleeding and disruption of blood
flow to the fetus. Disruption of greater than 50% of the placental surface is uniformly fatal to the fetus.
However, fetal distress may not manifest until greater than 30% of disruption occurs. Risk factors for
abruptio placentae include hypertension, diabetes mellitus, advanced age, multiparity, tobacco use, and
cocaine use. Symptoms include abdominal pain, intense uterine contractions, vaginal bleeding, and back
pain. Vaginal bleeding with abdominal pain after trauma mandates prompt ultrasonographic evaluation.
Massive bleeding can occur with hemodynamic collapse, but even occult bleeding can lead to
plasminogen activator–mediated fibrinolysis and DIC.48 Delayed presentation of abruptio placentae can
occur and patients with blunt injury to the abdomen should be closely monitored.49
Uterine Rupture
Traumatic rupture due to blunt trauma is uncommon, with an incidence of approximately 0.6%, but is
associated with up to 10% mortality of the mother and almost 100% mortality of the fetus.11,50 Most
result from direct high-energy trauma to the abdomen and are associated with concurrent injuries. Risk
factors include prior caesarean section or prior uterine surgery.51 Diagnosis can be challenging, as
abdominal pain, often without vaginal bleeding, can be the only sign of underlying uterine rupture.
Excellent outcomes in subsequent pregnancies can be achieved in those with prior uterine rupture who
undergo uterine repair.52 An attempt at repair and subsequent vaginal delivery should be encouraged.
781
booksmedicos.org
Amniotic Fluid Embolism
Embolism of the amniotic fluid into the maternal venous circulation is a rare, but often fatal
complication of abdominal trauma or placental abruption. Mortality rates of up to 80% have been
reported. Amniotic fluid embolization is characterized by sudden onset of hypoxemia, hypotension, and
coagulopathy. Diagnosis is mostly clinical, though chest radiography may show evidence of pulmonary
edema or bilateral scattered infiltrates characteristic of acute respiratory distress syndrome (ARDS). DIC
occurs in 30% of these patients. Treatment is supportive with optimization of hemodynamics,
oxygenation, and treatment of resulting coagulopathy.53
Preeclampsia/Eclampsia
Preeclampsia is infrequent, occurring in up to 5% of pregnancies. Risk factors include nulliparity,
diabetes mellitus, chronic hypertension, renal disease, advanced maternal age (>35 years), obesity,
prior or family history of preeclampsia.54 Signs of this syndrome include hypertension, edema,
proteinuria, and hyperactive reflexes, though patients may present only with hypertension without
other signs. Eclampsia, the onset of seizures with preeclampsia, occurs rarely in about 0.05% to 0.2% of
pregnancies, but mandates immediate treatment with magnesium sulfate, and consideration of emergent
caesarian section. An alteration in mental status in the pregnant trauma patient mandates consideration
of eclampsia as an underlying cause.
Disseminated Intravascular Coagulation

Major trauma, especially those involving massive hemorrhage, abruption, preeclampsia/eclampsia,
HELLP (hemolysis, elevated liver enzymes, low platelet count), amniotic fluid embolism, or SIRS
(systemic inflammatory response syndrome), can lead to disruption of the hemostatic cascade. In
healthy patients, tissue factor binds to factor VIIa, generating Xa. Xa binds to cofactor Va, converting
prothrombin. Regulation of this cascade is complex, involving tissue factor pathway inhibitor,
antithrombin, and activated protein C. Dysfunction of this regulatory mechanism leads to unchecked
thrombin production, with diffuse intravascular fibrin deposition (causing end-organ damage and
failure) and fibrinolysis, resulting in depletion of coagulation factors and platelets (leading to a
profound bleeding diathesis). Placental abruption can release thromboplastin into the maternal
circulation, resulting in severe DIC. Treating involves expedient correction of clotting deficits and
emptying of the uterus.
EMERGENT CAESARIAN SECTION

Vaginal delivery is preferred whenever possible, even if labor begins during evaluation and treatment
for traumatic injuries, including exploratory laparotomy and surgical intervention.55 Indications for
emergent caesarian section include maternal shock, massive exsanguination, facilitation of maternal
treatment, high risk of fetal demise, and unstable thoracolumbar spinal injuries. Perimortem caesarian
section can be considered if the estimated gestational age is over 26 weeks. However, the decision to
perform a caesarian section must be made in an expedient manner. If performed within 5 minutes of
maternal demise, survival of over 75% can be achieved in viable fetuses with fetal heart tones and >26
weeks of gestation.56,57 Case reports also show that 60% of mothers had either improved hemodynamics
or return of spontaneous circulation after performance of perimortem caesarian section. The 2010
American Heart Association guidelines recommend perimortem caesarian section for the viable fetus, in
the event of maternal cardiac arrest without return of spontaneous circulation by 4 minutes.58 These
recommendations are widely supported by national and international associations including the
American College of Obstetricians and Gynecologists and the Royal College of Obstetricians and
Gynaecologists.59,60 Early involvement of the obstetrics team facilitates the decision to perform an
emergent caesarian section and ensures the timeliest delivery of the child should one be necessary.
DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM

9 Pregnant patients are at increased risk for DVT and PE. These patients may have venous stasis from
decreased mobility, relative vena cava compression, as well as hypercoagulability due to increased
production of coagulation factors. Endothelial injury is common in trauma and adds to the increased risk
782
booksmedicos.org
in these patients (Virchow’s Triad). Unfractionated subcutaneous heparin, in addition to sequential
compression device use and early ambulation, is recommended in pregnancy and should be initiated
once stable. Low–molecular-weight heparin appears to be safe in the treatment of DVT/PE with at least
one small, randomized controlled trial showing safety and effectiveness with less bleeding
complications. Coumadin is not recommended for use in treatment of DVT/PE due to difficult regulation
of anticoagulation. When given in the first trimester, up to a 29% incidence of warfarin embryopathies
can be seen, including mental retardation, optic atrophy, ventral midline dysplasia, and central nervous
system (CNS) abnormalities. Late pregnancy administration is associated with significant risk of fetal
bleeding and mortality.61 Low–molecular-weight heparin does not cross the placenta and is not
associated with increased teratogenicity or fetal bleeding, and is recommended by the American College
of Chest Physicians for thromboembolism prophylaxis and treatment in pregnant patients.62 Placement
of a vena cava filter should be considered when the extent of thrombosis is extensive or patients at high
risk for PE.
SOCIAL AND ETHICAL CONSIDERATIONS

10 IPV affects up to 324,000 women each year, and 4% to 9.5% of all pregnancies.6,63–65 IPV affects
women across all age groups, religions, ethnic backgrounds, socioeconomic level, education, and sexual
orientation. Care providers need to have low thresholds for screening pregnant patients for IPV,
especially when patients present with multiple episodes of trauma, suspicious patterns of injury, or
injury that does not correspond to the given history. Although screening during trauma evaluation can
be challenging, even brief screening tools have found to be effective. Early detection and intervention,
with the assistance of social work and local resources, best ensures the safety of both mother and
fetus.66,67
Substance abuse is increasingly seen in pregnant trauma patients. In two major urban centers, 50% to
80% of admitted female trauma patients tested positive for cocaine and/or heroin.68 Data from the
American College of Surgeons National Trauma Data Bank showed 12.9% and 19.6% of traumas in
pregnant women were associated with alcohol and drug use, respectively.69 Alcohol abuse is associated
with decreased use of seatbelt restraint systems (22% vs. 46% in sober patients).68 While seatbelt use by
pregnant women is higher than in the general populace, improved education may improve outcomes
given half of all fetal losses could have been prevented with proper seatbelt use.15
TEAM APPROACH TO TRAUMA IN THE PREGNANT PATIENT

A coordinated approach involving prehospital providers, the Emergency Medicine team, Nursing,
Obstetrics, Obstetric Nursing, Critical Care and Surgery is key to the proper management of these
patients. Involvement of the obstetric team (even prior to arrival of the patient) can be invaluable and
consideration should be given for early notification.
SUMMARY
The optimal treatment of the pregnant patient requires special attention to the evolving anatomical and
physiologic changes that occur during pregnancy. Evaluation and management should be tailored to the
stage of pregnancy and requires a multidisciplinary, team approach. While fetal survival is best
achieved by appropriate resuscitation and care of the mother, recognition of the unique patterns and
complications of traumatic injury ensure the best possible outcome for the mother and fetus.
References
1. Fildes J, Reed L, Jones N, et al. Trauma: the leading cause of maternal death. J Trauma
1992;32:643–645.
2. El Kady D. Perinatal outcomes of traumatic injuries during pregnancy. Clin Obstet Gynecol
2007;50:582–591.
3. Schiff MA, Holt VL. Pregnancy outcomes following hospitalization for motor vehicle crashes in
783
booksmedicos.org
Washington State from 1989 to 2001. Am J Epidemiol 2005;161:503–510.
4. Peckham CH, King RW. A study of intercurrent conditions observed during pregnancy. Am J Obstet
Gynecol 1963;87:609–624.
5. Kuczkowski KM. Trauma during pregnancy: a situation pregnant with danger. Acta Anaeth Belg
2005;56:13–18.
6. Drost TF, Rosemurgy AS, Sherman HF, et al. Major trauma in pregnant women: maternal/fetal
outcome. J Trauma 1990;30:574–578.
7. Lavin JP, Polsky SS. Abdominal trauma during pregnancy. Clin Perinatol 1983;10:423–438.
8. Crosby WM. Traumatic injuries during pregnancy. Clin Obstet Gynecol 1983;26:902–912.
9. Weiss H. Pregnancy associated injury in Pennsylvania, 1995. Ann Emerg Med 1995;34:626–636.
10. Weiss HB, Songer TJ, Fabio A. Fetal deaths related to maternal injury. JAMA 2001;286:1863–1868.
11. Mattox KL, Goetzl L. Trauma in pregnancy. Crit Care Med 2005;33(suppl 10):S385–S389.
12. Weiss HB, Lawrence BA, Miller TR. Pregnancy-associated assault hospitalizations. Obstet Gynecol
2002;100(4):773–780.
13. Poole GV, Martin JN Jr, Perry KG Jr, et al. Trauma in pregnancy: the role of interpersonal
violence. Am J Ostet Gynecol 1996;174:1873–1878.
14. Rogers FB, Rozycki GS, Osler TM, et al. A multi-institutional study of factors associated with fetal
death in injured pregnant patients. Arch Surg 199;134:1274–1277.
15. Klinich KD, Flannagan CA, Rupp JD, et al. Fetal outcome in motor-vehicle crashes: effects of crash
characteristics and maternal restraint. Am J Obstet 2008;198(4):450.e1–e9.
16. Franger AL, Buschbaum HJ, Peaceman AM. Abdominal gunshot wounds in pregnancy. Am J Obstet
Gynecol 1989;160:1124–1128.
17. Petrone P, Talving P, Browder T, et al. Abdominal injuries in pregnancy:155 month study at two
level 1 trauma centers. Injury 2011;42:47–49.
18. Iliya FA, Hajj SN, Buchsbaum HJ. Gunshot wounds of the pregnant uterus: report of two cases. J
Trauma 1980;290:90–92.
19. Brooks DC, Oxford C. Chapter: The pregnant surgical patient. ACS Surg Princ Pract 2007:1–21.
20. Richards JR, Ormsby EL, Romo MV, et al. Blunt abdominal injury in the pregnant patient: detection
with US. Radiology 2004;233(2):463–470.
21. Goodwin H, Holmes JF, Wisner DH. Abdominal ultrasound examination in pregnancy blunt trauma
22. Brown MA, Sirlin CB, Farahmand N, et al. Screening sonography in pregnant patients with blunt
abdominal trauma. J Ultrasound Med 2005;24(2):175–181.
23. American College of Surgeons’ Committee on Trauma. Advanced Trauma Life Support, Student
Manual. 9th ed. Chicago: American College of Surgeons; 2012.
24. Xue X, Liu L, Rao Z. Management of postpartum hemorrhagic shock and disseminated intravascular
coagulation with damage control resuscitation. Am J Emerg Meg 2013;31:1291.e1–e2.
25. Cotton BA, Au BK, Nunez TC, et al. Predefined massive transfusion protocols are associated with a
reduction in organ failure and postinjury complications. J Trauma 2009;66:41–48.
26. Dennehy KC, Pian-Smith MC. Airway management of the Parturient. Int Anesthesiol Clin
2000;38:147–159.
27. Pilington S, Carli F, Dakin MJ, et al. Increase in Mallampati score during pregnancy. Br J Anaesth
1994;74:638–642.
28. Reisner LS, Benumof JL, Cooper SD. The difficult airway: risk, prophylaxis and management. In
Chestnut DH, ed. Obstetric Anesthesia: Principles and Practice. St. Louis, MO: Mosby;1999:590–620.
29. Hytten FE, Leitch I. The Physiology of Human Pregnancy. 2nd ed. Oxford, England: Blackwell
Scientific Publications; 1971;18.
30. Morkovin V. Trauma in pregnancy. In Farrell RG, ed. Ob/Gyn emergencies: The first 60 minutes.
Rockville, MD: Aspen Publications; 1986;71.
31. Dildy G, Belfort M, Saade G, et al. Critical Care Obstetrics. 4th ed. Malden, MA: Blackwell
Publishing; 2004:691.
32. Gordon MC. Maternal physiology in pregnancy. In Gabbe SG, Niebyl JR, Simpson JL, eds.
Obstetrics: Normal and Problem Pregnancies. 4th ed. Philadelphia, PA: Churchill Livingston; 2002:63–
784
booksmedicos.org
91.
33. Chesley LC. Renal function during pregnancy. In: Carey HM, ed. Modern trends in Human
Reproductive Physiology. Vol 1. London: Butterworths; 1963:205–214.
34. Chestnutt AN. Physiology of normal pregnancy. Crit Care Clin 2004;20:609–615.
35. Said JM, Ignjatovic V, Monagle PT, et al. Altered reference ranges for protein C and protein S
during early pregnancy: implications for the diagnosis of protein C and protein S deficiency in
pregnancy. Thromb Haemost 2010; 103:984–988.
36. Perlman MD, Tintinalli JE, Lorenz RP. A prospective controlled study of outcome after trauma
during pregnancy. Am J Obstet Gynecol 1990;162:1502–1507.
37. Muench MV, Baschart AA, Reddy UM, et al. Pregnancy is not a sufficient indicator for trauma team
activation. J Trauma 2004;57:1094–1098.
38. Muench MV, Baschat AA, Reddy UM, et al. Kleihauer-Betke testing is important in all cases of
maternal trauma. J Trauma Inj Infect Crit Care 2003;57:1094–1098.
39. Curet MJ, Schermer CR, Demarest GB, et al. Predictors of outcome in trauma during pregnancy:
identification of patients who can be monitored for less than 6 hours. J Trauma Inj Infect Crit Care
2000;49:18–25.
40. Barraco ED, Chiu WC, Clancy TV, et al. Practice management guidelines for the diagnosis and
management of injury in the pregnant patient: the EAST practice management guidelines group. J
Trauma 2010;69:211–214.
41. Brent RL. The effect of embryonic and fetal exposure to x-ray, microwaves, and ultrasound:
counseling the pregnant and nonpregnant patient about these risks. Semin Oncol 1989;16:347–368.
42. Kirkpatrick A, Ball C, D’Amours S, et al. Acute resuscitation of the unstable adult trauma patient:
bedside diagnosis and therapy. Can J Surg 2008;51:57–69.
43. Bernstein MP. Imaging of traumatic injuries in pregnancy. Am Roentgen Radiol Soc 2008;2:203–210.
44. McCollough CH, Primak AN, Braun N, et al. Strategies for reducing radiation dose in CT. Radiol Clin
North Am 2009:47:27–40.
45. ACOG Committee on Obstetric Practice. ACOG Committee Opinion #299. Guidelines for diagnostic
imaging during pregnancy. Obstet Gynecol 2004; 104;647–651.
46. Leggon RE, Wood CG, Indeck MC. Pelvic fractures in pregnancy: factors influencing maternal and
fetal outcomes. J Trauma 2002;53:796–804.
47. Crosby WM. Trauma in the pregnant patient. Conn Med 1986;50:251–258.
48. Hill C, Pickinpaugh J. Trauma and surgical emergencies in the obstetric patient. Surg Clin North Am
2008;88:421–440.
49. Higgins SD, Garite TJ. Late abruptio placentae in trauma patients: implications for monitoring.
Obstet Gynecol 1984;63:10S–12S.
50. Weintraub AY, Leron E, Manor M. The pathophysiology of trauma in pregnancy: a review. J Matern
Fetal Neonatal Med 2006;19:601–605.
51. Schrinsky DC, Benson RC. Rupture of the pregnant uterus: a review. Obstet Gynecol Surv
1978;33:217–232.
52. Fox NS, Gerber RS, Mourad M, et al. Pregnancy outcomes in patients with prior uterine rupture or
dehiscence. Obstet Gynecol 2014;123(4):785–789.
53. Judich A. Kuriansky J, Engelberg I, et al. Amniotic fluid embolism following blunt abdominal
trauma in pregnancy. Injury 1998;29:475–477.
54. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systemic review of
controlled studies. BMJ 2005;330:565.
55. Dyer I, Barclay DL. Accidental trauma complicating pregnancy and delivery. Am J Obstet Gynecol
1962;83:907.
56. Morris JA, Rosenbower TJ, Jurkovich GJ, et al. Infant survival after cesarean section for trauma.
Ann Surg 1996;223:481–491.
57. Rothengerer D, Quattlenbaum FW, Perry JF. Blunt maternal trauma: a review of 103 cases. J
Trauma 1978;18:173–179.
58. Vanden Hoek TL, Morrison LJ, Schuster M, et al. Part 12: cardiac arrest in special situations: 2010
American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency
785
booksmedicos.org
Cardiovascular Care. Circulation 2010;122:S829–S836.
59. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 100: critical care
in pregnancy. Obstet Gynecol 2009;113:443–450.
60. Royal College of Obstetricians and Gynaecologists. RCOG Green-top Guidelines No. 56: Maternal
Collapse in Pregnancy and the Puerperium. 2011. Available online at
https://www.rcog.org.uk/en/guidelines-research-services/guidelines/gtg56/. [Online]. Accessed
September 10, 2014.
61. Ginsberg JS, Hirsch J. Use of antithrombotic agents during pregnancy. Chest 1998;114:524S–530S.
62. Bates SM, Gree IA, Pabinger I, et al. Venous thromboembolism, thrombophilia, antithrombotic
therapy and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (8th Edition). Chest 2012;141(2 suppl):e691S–736S.
63. Kissinger DP, Rozycki GS, Morris JA, et al. Trauma in pregnancy: predicting pregnancy outcomes.
Arch Surg 1991;126:1079–1086.
64. Hoff WS, D’Amelio FL, Tinkoff GH, et al. Maternal predictors of fetal demise in trauma during
pregnancy. Surg Gynecol Obstet 1991;172:175–180.
65. Tinker SC, Reefhuis J, Dellinger AM, et al. Epidemiology of maternal injuries during pregnancy in a
population-based study, 1997–2005. J Womens Health 2010;19(12):2211–2218.
66. McFarlane H, Parker B, Soeken K, et al. Assessing for abuse during pregnancy. Severity and
frequency of injuries and associated entry into prenatal care. JAMA 1992;267(23):3176–3178.
67. Krimm J, Heinzer MM. Domestic violence screening in the emergency department of an urban
hospital. J Natl Med Assoc 2002;94(6):484–491.
68. Patteson SK, Snider CC, Meyer DS, et al. The consequences of high risk behaviors: trauma during
pregnancy. J Trauma 2007;62:1015–1020.
69. Ikossi DG, Lazar AA, Morabito D, et al. Profiles of mothers at risk: an analysis of injury and
pregnancy loss in 1195 trauma patients. Am Coll Surg 2005; 200:49–56.
786
booksmedicos.org
Chapter 32
Postinjury Management
Bellal Joseph and Peter Rhee
Key Points
1 Damage control resuscitation is critical to avoid the lethal triad of trauma: dilutional coagulopathy,
hypothermia, and acidosis.
2 Permissive hypotension, liberal use of blood products instead of isotonic fluids, and early correction
of coagulopathy are the principles of damage control resuscitation.
3 Massive transfusion protocols and early use of red cells, fresh frozen plasma, and platelets in a 1:1:1
ratio minimizes the risk of dilutional coagulopathy.
4 Attempts to achieve supernormal resuscitation endpoints should be avoided to prevent complications
such as abdominal compartment syndrome.
5 Traumatic brain injury (TBI) remains the leading cause of death from trauma. Neurologic
examination is a valuable tool and can replace repeat head CT scans in mild TBI. Initial laboratory
data have prognostic value in TBI outcomes.
6 Preinjury coagulopathy with home medications is common in patients with TBI and knowledge of
home medications is important.
7 Early use of enteral nutrition is desirable.
8 Organ donation is a legitimate outcome in trauma patients. Early involvement of organ procurement
networks and social services as well as aggressive resuscitation protocols improves procurement
rates.
INTRODUCTION
Trauma is now the leading cause of death for ages 46 and below in the United States.1 Hemorrhagic
shock is the most common cause of mortality during the first 6 hours following trauma and 16% to 80%
of those deaths may be preventable.2 Postinjury management predominantly focuses on two goals, early
control of bleeding and resuscitation.
ACUTE TRAUMATIC COAGULOPATHY

Coagulopathy is known to worsen posttraumatic hemorrhage and is associated with increased mortality
and worse outcomes. Interestingly, up to 25% of trauma patients are already coagulopathic upon arrival
to the hospital.3,4 Current data suggest that coagulopathy develops in the early posttraumatic period
even before resuscitation begins and is now referred to as acute traumatic coagulopathy.4–6 Diffuse
endothelial damage, activation of the protein C pathway, and massive catecholamine release are some
of the proposed mechanisms for acute traumatic coagulopathy.7 Acute traumatic coagulopathy may be
exacerbated by hypothermia, acidosis, and dilution of clotting factors.
1 Hypothermia in trauma patients results from a multitude of factors that include radiant heat losses
to the environment, failure of shivering response during anesthesia, intraoperative heat loss from
exposed peritoneal surfaces, and tissue hypoxia during hemorrhagic shock with decreased metabolism.
Another major cause of hypothermia is the use of relatively cool room temperature resuscitation fluids
or cold refrigerated blood products that were not warmed before infusion.8–10 These cumulative factors
produce qualitative and quantitative defects in platelet function and decrease coagulation factor
activity.11–13 In addition to reducing coagulation factor activity, dilutional coagulopathy from large-
volume crystalloid resuscitation and acidosis from prolonged tissue hypoxia perpetuates the bloody
vicious cycle.14,15 The combined presence of three factors, hypothermia, acidosis, and coagulopathy, is
787
booksmedicos.org
known as the “lethal triad.” Modern trauma resuscitation is defined as damage-controlled resuscitation
and aimed at reducing the iatrogenic development of this “lethal triad.”
DETECTION OF TRAUMATIC COAGULOPATHY

The early identification of acute traumatic coagulopathy remains a challenge. Conventional coagulation
assays like PT, aPTT, and INR are insensitive and unreliable in trauma patients, as they do not provide
an accurate assessment of the in vivo state of coagulation. Moreover, these assays are performed at
physiologic pH and temperature; because of this they are unable to account for the effects of
hypothermia and acidosis on coagulation.7 Acute traumatic coagulopathy involves changes in both
coagulation and fibrinolytic pathways, and detection requires a more dynamic view of all components
of the coagulation cascade, which is provided by viscoelastic tests, that is, thromboelastography and
rotational thromboelastometry. These assays rely on changes in clot strength to detect coagulation
defects and provide an in vivo picture of the coagulation and fibrinolytic processes. These tests also
assess the interaction between coagulation factors and platelets and can detect functional changes in
platelet function even with normal platelet counts. They can be performed with much more rapidity and
have been shown to detect coagulation abnormalities with higher sensitivity as compared to
conventional coagulation assays.16–18 Viscoelastic tests have also shown to be more accurate in
predicting blood product requirements and massive transfusion and can therefore guide blood
transfusion in trauma patients.19,20 Despite these advantages, viscoelastic tests come with inherent
disadvantages such as cost and the need for greater expertise in performance and interpretation.
DAMAGE CONTROL RESUSCITATION

The primary objective of resuscitation following hemorrhage is to restore effective circulating volume
to allow adequate tissue perfusion and oxygenation. Historically, the standard of practice has been to
aggressively resuscitate patients with high volumes of crystalloids to restore volume and blood
pressure. In recent years, there has been a paradigm shift away from the large-volume resuscitation.
Current strategies combine the principles of permissive hypotension, liberal use of blood products
instead of isotonic fluids, the use of hypertonic saline to pull water back into the vascular system, and
early correction of coagulopathy with blood products as well as drugs (Table 32-1).
2 Permissive hypotension aims at restoring systolic blood pressure to 90 mm Hg so that adequate
tissue perfusion can be maintained while not exacerbating blood loss, before definitive hemorrhage
control is achieved. Large-volume resuscitation with crystalloids before definitive hemostasis can raise
blood pressure which can “pop off” the clot and worsen hemorrhage.21 A target mean arterial pressure
(MAP) of around 60 mm Hg is thought to maintain adequate tissue perfusion without the potential for
increased blood loss.22,23,24,25
A brief period of hypotension with a MAP around 60 mm Hg can be safely maintained for short
periods of time without risk of irreversible damage or an increase in mortality.26 Permissive
hypotension has been shown to reduce the risk of death and development of coagulopathy.3,27 However,
in patients with hemorrhagic shock and concurrent traumatic brain injury (TBI), the safety of permissive
hypotension has not been demonstrated and thus it is not yet recommended.28
Up to 5% of civilian trauma patients require massive transfusion, defined as the need for more than
10 units of red blood cells in 24 hours. These patients are at greatest risk for developing dilutional
coagulopathy from large volumes of resuscitation even if packed red cell transfusion is used early in the
resuscitation phase. Damage control resuscitation (DCR) utilizes massive transfusion protocols and early
use of red cells, fresh frozen plasma, and platelets in a 1:1:1 ratio in an attempt to reconstitute whole
blood. The use of blood products early in the course of resuscitation is not only an attempt to combat
the coagulopathy in trauma patients requiring massive transfusion but to also minimize the use of
crystalloids and colloids.29–31
The use of predefined massive transfusion protocols has shown improved survivals and decrease in
adverse outcomes.32,33 This approach requires the ability to predict the need for massive transfusion in
trauma patients at the time of arrival which is often difficult even for experienced surgeons. Multiple
scoring systems have been developed to help define the cohort requiring massive transfusion.34,35
3 The appropriate ratios of packed red cells, fresh frozen plasma, and platelets in exsanguinating
788
booksmedicos.org
trauma patients have been debated. The concept of a 1:1:1 ratio stems from military data which show
improved survival with the use of fresh whole blood. Since civilian trauma centers do not have fresh
whole blood available, component therapy is an attempt to reconstitute whole blood by giving red cells,
fresh frozen plasma, and platelets in a nearly physiologic ratio. Most studies have shown improved
mortality with the use of high plasma and pRBC ratios with even greater survival in those with early (6
to 12 hours) use of high ratios.5,8,36–41 The use of a 1:1 ratio for pRBC and platelets has also shown
improved survival.38 Despite the survival advantage with the use of a 1:1:1 ratio for transfusion, the
potentially lethal complications of blood transfusion need to be kept in mind. The PROPPR trial which
was a multicenter prospective randomized study in hemorrhagic trauma patients demonstrated an early
survival benefit when the patients were resuscitated with a 1:1:1 ratio compared to a 2:1:1 ratio but the
28-day mortality was not statistically significantly different.
Table 32-1 Components of Damage Control Resuscitation
Hypertonic saline has many potential advantages in that it can resuscitate with low volume by pulling
water into the vascular space and thus avoids excess water during resuscitation. This concept has
advantages especially in the military field environment. Hypertonic saline is also thought to be an
immune modulator that potentially decreases inflammation associated with resuscitation injury.42
However, a multicenter prospective trial in trauma patients with hemorrhagic shock was halted before
completion as the outcome was similar between the groups. Overall there was no survival disadvantage
in the hypertonic saline arm of the study except in a small subset of patients who did not require blood
transfusion. This subset of patients had higher mortality if given hypertonic saline in the field. There
was also a subset that required ICU treatment that showed higher survival and decreased multiple organ
failure when hypertonic saline was given.43 Since 7.5% hypertonic saline is not commercially available,
an alternative is to use 5% hypertonic saline. Those who use 5% hypertonic saline administer it as a
one-time bolus in the initial phase of resuscitation. This approach may be beneficial in patients with TBI.
The safety of using 5% hypertonic saline has been shown in two studies.44,45 A caveat of using
hypertonic saline is that it causes hyperchloremic acidosis, but clinical significance has not yet been
demonstrated. Because of the capability of increasing intravascular volume, the ideal time and place for
hypertonic saline use may be in the field, especially in the military setting.46
Hyperfibrinolysis associated with traumatic coagulopathy may decrease levels of fibrinogen. High
plasma:pRBC ratios adequately replenish the fibrinogen pool required for adequate hemostasis and thus
the use of cryoprecipitate rich in fibrinogen as an adjunct to DCR is rational.8 The use of cryoprecipitate
has additional advantages as it provides particles that act as a low-volume colloid resuscitation and
draw water into the vascular system, and is an adjunct in resuscitation. Tranexamic acid is an
antifibrinolytic agent found to be safe and effective in reducing the risk of bleeding if used within 3
hours of injury.47 The military Tactical Combat Casualty Care Committee has recommended its use in
the military setting. Several other novel strategies have also been used as an adjunct in DCR including
the use of activated recombinant factor VII (rFVIIa). rFVIIa activates factor Xa at the site of tissue
injury by complexing with tissue factor on the surface of platelets. Use of rFVIIa has shown to
effectively reduce blood loss and mortality in massive trauma patients; its use is limited by high
costs.48,49 Prothrombin complex concentrate (PCC) is another cost-effective option that reverses
coagulopathy in traumatic injury.50
The discussion of DCR should also include damage control laparotomy. After injury, when a trauma
patient requires laparotomy, some patients may require abbreviated laparotomy in order to better
resuscitate the patient so that the prolonged initial surgery does not harm the patient. Although damage
control laparotomy has been widely accepted as the standard of care for trauma patients, it was adopted
without rigorous proof of concept. One hallmark study suggested that damage control laparotomy is of
benefit in trauma patients with numerous major visceral injuries that also have vascular injury; this
study also showed that damage control laparotomy in patients without major injuries was associated
with worse outcome.51 Definitive laparotomy may have survival benefit with decrease in morbidities
789
booksmedicos.org
known to accompany damage control laparotomy such as open abdomens and enterocutaneous fistulas.
Because of the decreased number of surgeries and morbidities, the cost benefits were significant.52,53
ENDPOINTS OF RESUSCITATION
The ultimate goal of resuscitation is to ensure adequate oxygen delivery to tissues. Prolonged tissue
hypoxia is associated with multiorgan dysfunction syndrome, risk of infection, and increased mortality.
Advanced Trauma Life Support guidelines define the correction of vital signs like blood pressure and
heart rate as markers of adequate resuscitation. However, up to 82% of severely injured patients with
normalized vital signs have ongoing occult ischemia that is associated with adverse outcomes.54 While
normalization of vital signs may describe the current perfusion status, they do not assess oxygen debt,
defined as ongoing oxygen deficits that have accumulated during the period of shock. Oxygen debt is
known to be associated with increased mortality.55,56 Arterial lactate and base deficit may serve as
indicators for severity of shock and may help to stratify patients. Trends in serum lactate levels indicate
adequacy of resuscitation.
Invasive monitoring with central venous pressure (CVP) and pulmonary artery catheter (PAC) have
been extensively used to guide resuscitation. CVP and pulmonary capillary wedge pressure monitoring
provide information regarding the intravascular volume, but concurrent factors like mechanical
ventilation and changes in ventricular compliance from myocardial dysfunction limit their efficacy in
accurately guiding resuscitation.57 Moreover, PAC use in critically ill trauma patients has not been
shown to improve outcomes.58
ScVO2 and SVO2 measure central venous oxygen saturation from the upper body and mixed venous
oxygen saturation from both the upper and lower body, respectively. Inadequate oxygen supply from
ongoing shock or increased oxygen demand leads to an increased tissue extraction of oxygen, which is
reflected as a decrease in the values of ScVO2 and SVO2. SVO2 of less than 65% even in the presence of
normal vital signs indicates blood loss and need for transfusion to optimize oxygen supply and
demand.59 Therefore, ScVO2 and SVO2 provide a real-time picture of tissue perfusion and are able to
detect very subtle changes in oxygen delivery. The ideal marker for resuscitation may be to determine
blood volume, but there is currently no simple way to determine ideal circulating blood volume.
ABDOMINAL COMPARTMENT SYNDROME

4 Abdominal compartment syndrome is an undesired consequence of elevated intra-abdominal pressure
and a cause of morbidity and mortality.60 The incidence of abdominal compartment syndrome is
decreasing with recent evolution in resuscitation strategy, suggesting a possible iatrogenic etiology.61
Intra-abdominal hypertension is defined as a pressure of greater than or equal to 12 mm Hg. Intra-
abdominal hypertension is graded based on increasing intra-abdominal pressure (Table 32-2).
Abdominal compartment syndrome is defined as a sustained intra-abdominal pressure greater than 20
mm Hg (with or without an abdominal perfusion pressure of less than 60 mm Hg) with new organ
dysfunction or failure.62 Experimental data indicate that hepatic arterial, portal venous, and hepatic
microcirculatory blood flow are markedly reduced when intra-abdominal pressure is increased.62,63
Typically, abdominal compartment syndrome is observed after severe abdominal trauma with intra-
abdominal hemorrhage, severe liver and kidney injuries, and in both operatively and nonoperatively
managed settings (primary abdominal compartment syndrome).64–66 Excessive large-volume
resuscitation, even in the absence of any direct abdominal trauma, can also lead to abdominal
compartment syndrome (secondary abdominal compartment syndrome).67–69 Recurrent or tertiary
abdominal compartment syndrome refers to a condition following a previously treated primary or
secondary abdominal compartment syndrome.62 Risk factors for development of abdominal
compartment syndrome include diminished abdominal wall compliance, increased intraluminal and
intra-abdominal content, crystalloid resuscitation/leak, and other risk factors such as age, shock, high
BMI, coagulopathy, and mechanical ventilation.70–80 Abdominal compartment syndrome can even
occasionally occur in patients with an open abdomen. The diagnosis often begins with findings of a
tense and distended abdomen in the presence of high end-inspiratory airway pressures and other signs
of organ dysfunction (i.e., oliguria, rising serum creatinine). Additional clinical signs consistent with
abdominal compartment syndrome are a reduced cardiac output, elevated systemic vascular resistance,
and elevated pulmonary capillary wedge pressure with simultaneous low or normal calculated estimates
790
booksmedicos.org
of end-diastolic volume. The standard for monitoring intra-abdominal pressure is bladder pressure
measurement via intravesical technique. Bladder pressure is measured in end-expiration with the patient
supine, by distending the bladder with 25 mL of sterile saline.81,82
Table 32-2 Grades of Intra-abdominal Hypertension
Surgical decompression of the abdomen is an option for established abdominal compartment

syndrome with associated organ dysfunction and persistent shock with no absolute thresholds for urine
output and airway pressure.83 Protocols on fluid resuscitation are recommended to avoid a sustained
increase in intra-abdominal pressure.84 In addition to decompressive laparotomy for abdominal
compartment syndrome, numerous medical and minimally invasive therapies have been proposed such
as sedation and analgesia for anxiety relief and brief trials of neuromuscular blockade as temporizing
measures. Body positioning and colonic/nasogastric decompression are also suggested noninvasive
treatment options.85–87 Patients with abdominal compartment syndrome may have ascites and drainage
of fluid with various catheters can be tried before performing decompressive laparotomy as a less
invasive alternative. A common factor among all cases of abdominal compartment syndrome seems to
be the use of aggressive crystalloid resuscitation causing resuscitation injury. Use of excessive
crystalloid resuscitation is discouraged in DCR and studies show decreased rates of abdominal
compartment syndrome in association with decreased rates of crystalloid resuscitation.61 Attempts to
achieve “supranormal” endpoints (cardiac index of >4 L/min/m2 or oxygen delivery index of >600
mL/min/m2), while theoretically desirable, have not been shown to be effective as this often requires
excessive resuscitation volumes that contribute to abdominal compartment syndrome.88 As resuscitation
has changed with DCR, the incidence of abdominal compartment syndrome has been decreasing. In the
trauma setting, abdominal compartment syndrome has been disappearing rapidly but in the general
surgery setting, it is more common. Sepsis as a source of inflammation can create abdominal
compartment syndrome even when resuscitation injury is minimized. Source control of the bacterial
contamination is the best treatment for abdominal compartment syndrome. End organ failure with
microcirculatory disruption and endothelial leak is another source of the syndrome.
TRAUMATIC BRAIN INJURY

5 TBI remains one of the leading causes of injury-related deaths. Initial management of TBI includes
hyperosmolar resuscitation, intracerebral pressure (ICP) monitoring, and prevention of hypoxia and
hypotension.
Secondary Brain Injury

Injury prevention and better safety are the mainstays for primary brain injury. After the initial insult,
the main goal is to prevent or minimize secondary brain injury. Secondary brain injury can be
influenced by a cascade of inflammatory responses, occurring as a consequence of the primary injury.
Secondary brain injury is also exacerbated by potentially preventable factors such as hypotension,
hyperthermia, seizure activity, hyperglycemia, and hypoxemia.
Hypotension at any point (even brief time periods) is associated with a doubling of mortality in
patients with severe TBI.89,90 Although hyperventilation temporarily reduces intracranial pressure and
may help to prevent herniation, evidence suggests that excessive hyperventilation may be harmful for
patients with TBI. Therefore, brief hyperventilation is only recommended in order to reduce ICP
temporarily until surgical decompression can be performed.
Imaging in Traumatic Brain Injury

Computed tomography (CT) scanning remains an essential tool in the initial evaluation and postinjury
management of TBI. Patients with mild and moderate TBI who are examinable and not on any
anticoagulant medications can be monitored by clinical examination without the need for routine serial
791
booksmedicos.org
CT scans of the head.91–93 With technologic improvements made to the CT scanners around the world,
the incidence of TBI has been increasing. Small insignificant intracranial radiologic findings are the main
reason for the increase in the diagnosis of TBI. With increased awareness of mild TBI and with the
increased attention to mild TBI with posttraumatic stress disorder, CT scans of the head are being
ordered more often and routinely. In trauma, the single most common reason for obtaining a CT scan of
the head has been loss of consciousness. Thus increased screening for TBI and improved technology
identifying small clinically insignificant intracranial injuries has resulted in the increase of incidence of
TBI. TBI is a clinical diagnosis and not just a radiographic diagnosis. There are patients with TBI with
normal CT scans of the head who have cognitive deficits as well as posttraumatic stress disorder and
there are many with radiographic TBI that do not have clinical deficits. Therefore, significant
deterioration in neurologic examination should be considered in the decision for whether repeat head
CT scan or consultation of a neurosurgeon is needed. CT scans and neurosurgical consultations are
valuable resources with costs to the health care system as well as to the patient. The use of routine
repeat head CT and neurosurgical consultations should be restricted to patients on prehospital
antiplatelet and anticoagulants, and those with depressed skull fractures. A Brain Injury Guideline has
been developed which helps guide when the resources should be used (Table 32-3).94–96
Progression of lesions on repeat head CT can promptly identify patients who require more invasive
neurosurgical interventions and medical therapies. Routine repeat head CT is still recommended for
those patients with GCS less than 8 and for those who do not have a reliable clinical examination such
as patients that are under general anesthesia or patients that are in the ICU under sedation.
Coagulopathy in TBI
A decreased platelet count (less than 100,000/μL) and/or impaired platelet function after TBI is
associated with progression of intracranial hemorrhage, need for neurosurgical intervention, and
mortality.97–99 Admission INR greater than 1.5 also predicts progression of intracranial hemorrhage. The
treatment of coagulopathy after TBI is multipronged due to the complexity of the problem. Therapeutic
strategies should focus on the treatment of the primary cause and controlling the progression of
intracranial bleeding. fresh frozen plasma, platelets, recombinant factor VII, and PCC can be used in
various combinations to improve outcomes.100,101
Antiplatelet and Anticoagulation Therapy in TBI

6 Antiplatelet medications, anticoagulants, and nonsteroidal anti-inflammatory drugs are among the
most frequently encountered medications in TBI patients, especially the elderly. Existing evidence
shows an increased risk of progression of intracranial bleeding in patients on high-dose aspirin and
clopidogrel, whereas low-dose aspirin and ibuprofen do not cause progression on CT or neurologic
examination.102–104 A platelet count of less than 135,000/μL in patients on antiplatelet therapy is
predictive of both radiographic and clinical worsening.105 Reversal of the effect of anticoagulants and
antiplatelets is suggested to improve the outcomes.
Table 32-3 Brain Injury Guideline
Use of newer oral anticoagulants like direct thrombin inhibitors and factor Xa inhibitors is increasing.
792
booksmedicos.org
Despite their safety advantage over coumadin, concerns for progression of intracranial bleed and
adverse outcomes exist in TBI patients.106,107 No specific reversal agents are yet available for newer oral
anticoagulants. Oral charcoal administration, hemodialysis, PCC, and rFVIIa have shown some efficacy
in the reversal of these agents.108–113
Seizure Prophylaxis after TBI

Posttraumatic seizures increase the cerebral metabolic rate, ICP, and may cause secondary brain injury.
Seizures after TBI are associated with worse outcome. It is not known if poor outcomes are due to
underlying injury which is associated with posttraumatic seizures or if posttraumatic seizures exacerbate
injury. Studies have shown that prophylactic therapy with phenytoin during the first 7 days after injury
is effective in reducing the number of early posttraumatic seizures.114 Long-term use of prophylactic
anticonvulsants has not been shown to be of benefit. Anticonvulsant prophylaxis is not indicated for late
onset posttraumatic seizures (after 7 days). Because phenytoin is cumbersome to use, as it requires
frequent drug-level monitoring and can lead to neurodepressive side effects, the use of levetiracetam
has become common. However, recent studies have shown that the seizure rate after TBI is very low
and the use of levetiracetam has not equated to reduced seizures.115
Penetrating Brain Injury

Gunshot wounds to the brain are the most lethal of all firearm injuries. Aggressive postinjury
resuscitation is associated with significant improvement in both survival and organ donor
eligibility.116,117 Early aggressive management includes blood products, hyperosmolar therapy,
vasopressors, and/ or PCC. Early aggressive T4 (levothyroxine) therapy and correction of coagulopathy
increases the organ donation rate in nonsurvivable patients.116,118
NUTRITIONAL AND METABOLIC SUPPORT

Nutritional support after injury imparts significant acute and long-term effects on outcomes.
Understanding of the nutritional and metabolic derangements following injury has increased
exponentially over the past few decades. This has resulted in a more focused and goal-oriented approach
toward nutritional support. Once patients are stabilized and recovered from shock, attention should be
directed to metabolic and nutritional support.
The route of administration and timing of initiation of nutritional support have been issues of
controversy. Current evidence supports the use of enteral nutrition in all trauma patients as soon as
possible.119–124 There are certain situations where enteral nutrition is not a feasible option; in such
patients total parenteral nutrition is an alternative. Even in cases where enteral nutrition cannot be
administered due to frequent or impending operative intervention or intolerance of enteral feeding,
total parenteral nutrition should be used as a bridging measure. The literature on nutritional support in
critically injured trauma patients consistently reports higher septic morbidity in patients on total
parenteral nutrition.122–125 Current guidelines on the nutritional support provide a level 1
recommendation on the advantages of enteral nutrition over nutritional support via the parenteral
route.126
7 Recent recommendations aim for early enteral nutrition. The definition of early varies in the
literature, ranging from a few hours after injury up to 72 hours.124,125 Although the benefits are yet to
be established, safety of early (within 24 hours of injury) enteral feeding is well documented.126 In
patients with severe burns it is recommended to initiate enteral feeding within 18 hours of injury.127
Early feeding in this group of patients reduces the risk of gastroparesis. In the case of severe TBI enteral
feeding is safe and should be administered early.128–130
Nasogastric and nasojejunal routes are the preferred modes of initial nutritional access. If long-term
nutritional support is required, the planning of feeding access should be based on individual patient
circumstances. In patients undergoing laparotomy, insertion of a surgical feeding tube either in the
stomach or small intestine is a feasible option. For patients in need of long-term nutritional support and
not requiring surgical intervention the preferred route is via endoscopically guided percutaneous
feeding tube. The percutaneous endoscopic route is increasingly popular, but the literature is not well
established on its safety and complications.131,132 While choosing one route over the other, special
consideration should be given to individual patient factors as there is no single feeding access that
stands out among the others for safety and efficacy.133–136
793
booksmedicos.org
The goal of nutritional support during postinjury phase is twofold, first to provide enough calories to
meet basal energy expenditure and second to complement the special micronutrient requirements of
ongoing inflammation. Basal energy expenditure during postinjury phase ranges from 30 to 35
kcal/kg/day. Basal energy expenditure is higher in TBI patients and lower in spinal cord injury patients.
The estimation of basal energy expenditure in critically ill patients remains challenging and current
calculators frequently overestimate caloric requirements. A high-caloric dietary supplementation is
associated with hyperglycemia, hypercapnia, and higher in-hospital complications.137 While
underfeeding is also a concern in critically ill patients, a more balanced approach is permissive
underfeeding. Permissive underfeeding focuses more on maintaining nitrogen balance than meeting
caloric requirements alone. Diets containing higher protein content and lower caloric value than target
serve such a purpose. Permissive underfeeding results in better glycemic control, rapid recovery, and
overall better in-hospital patient outcomes.138–140
In the setting of trauma and critical illness, the ongoing catabolic response demands special
micronutrients and dietary considerations along with standard protein and caloric replacement.
Nonessential amino acids such as arginine and glutamine become conditionally essential. Addition of
these amino acids along with omega-3 fatty acids to standard dietary formulas has been shown to
improve outcomes and immune function. Enhanced diets containing higher protein content, and
including a combination of arginine, glutamine, omega-3 fatty acids, minerals (zinc, copper, etc.),
nucleic acids, and vitamins have shown to improve overall immune function.141–144
The assessment of nutritional requirement in critically ill patients is primarily done by the indirect
calorimetry method. The standard measure of nutritional requirement uses a metabolic cart, but this is
expensive and cumbersome.145 An alternative approach uses predictive equations but these are
imprecise and often over- or underestimate the nutritional requirement.146 In recent years, several hand-
held indirect calorimeters have been marketed. They provide ease of use as they are portable and
relatively accurate.147 To assess the adequacy of nutritional supplementation, anthropometric
measurements and biochemical data can be utilized. While there is no single measure which accurately
predicts adequacy of nutritional support, prealbumin levels provide a reliable estimate compared to
albumin, transferrin, and retinol-binding protein.148
ORGAN DONATION
Trauma donors are the major contributor in the organ donation pool.149 There remains great potential
to enhance the conversion rate in this group of trauma donors. Over the past decade significant changes
occurred in resuscitation protocols in general and specifically in potential organ donors. These changes
in resuscitation have resulted in better organ donation in this group of potential donors.
Wide spread acceptance of DCR has led to better end-organ preservation, which not only improves
outcomes in surviving patients but can improve overall organ donation rates in patients who become
brain dead. The guidelines defining organ donor management recommend continuation of this
aggressive resuscitative support even after declaration of brain death.118,150
A feasible goal for resuscitating any potential donors is to follow a rule of 100’s that is, maintaining a
systolic blood pressure of >100 mm Hg, heart rate of <100 bpm, urinary output >100 mL/hr, and
paO2 >100 mm Hg. Along with hemodynamic resuscitation, focus should also be given to pulmonary
edema, coagulopathy, and hypothermia. Coagulopathy and hypothermia are not only associated with
adverse outcomes in trauma patients but also render them ineligible for organ donation.151
The focus of resuscitative efforts after declaration of brain death shifts from cerebral preservation to
organ preservation. The shift in resuscitation focus is a continuum of ongoing resuscitation.152 Donors
should be managed in a critical care setting and attention should be directed toward moderation of
postbrain death physiologic changes. Along with ongoing resuscitation, initiation of a T4 protocol
should ensue. T4 protocol or hormone replacement therapy takes into account the disruption of
hypothalamic–pituitary axis.153 The essential components of the T4 protocol include
methylprednisolone, triiodothyronine (T3)/levothyroxine (T4), arginine, vasopressin, and insulin. The
goal of this resuscitative cocktail is to prevent potential cardiac arrhythmias, diabetes insipidus,
hypotension, and metabolic acidosis. Early initiation of hormonal therapy has shown improved organ
donation rates and should be considered in all brain-dead potential organ donors.154–156
8 Organ donation is a legitimate outcome in trauma patients. As aggressive resuscitation protocols for
trauma patients closely align with donor management goals, the spectrum of care in potential organ
794
booksmedicos.org
donors can easily be extended to address organ preservation. Trauma patients presenting with
previously fatal neurologic injuries provide an excellent cohort where aggressive resuscitation can not
only improve survival rates but also the organ donation rates.118,157 The care of a potential organ donor
is a multidisciplinary task. Involvement of organ procurement networks and social services can improve
the communication between the treatment team, procurement agency, and the donor’s relatives.
Bridging this gap is of utmost importance as family decline still remains a major cause of loss of
potential donors.
References
1. Rhee P, Joseph B, Pandit V, et al. Increasing trauma deaths in the United States. Ann Surg
2014;260:13–21.
2. Spinella PC, Holcomb JB. Resuscitation and transfusion principles for traumatic hemorrhagic shock.
Blood Rev 2009;23:231–240.
3. Maegele M, Lefering R, Yucel N, et al. Early coagulopathy in multiple injury: an analysis from the
German Trauma Registry on 8724 patients. Injury 2007;38:298–304.
4. MacLeod JB, Lynn M, McKenney MG, et al. Early coagulopathy predicts mortality in trauma. J
Trauma 2003;55:39–44.
5. Maegele M, Lefering R, Paffrath T, et al. Red-blood-cell to plasma ratios transfused during massive
transfusion are associated with mortality in severe multiple injury: a retrospective analysis from the
Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie. Vox Sang 2008;95:112–119.
6. Brohi K, Singh J, Heron M, et al. Acute traumatic coagulopathy. J Trauma 2003;54:1127–1130.
7. Palmer L, Martin L. Traumatic coagulopathy–part 1: pathophysiology and diagnosis. J Vet Emerg
Crit Care (San Antonio) 2014;24:63–74.
8. Duchesne JC, Hunt JP, Wahl G, et al. Review of current blood transfusions strategies in a mature
level I trauma center: were we wrong for the last 60 years? J Trauma 2008;65:272–276; discussion
6–8.
9. Burch JM, Denton JR, Noble RD. Physiologic rationale for abbreviated laparotomy. Surg Clin North
Am 1997;77:779–782.
10. Kirkpatrick AW, Chun R, Brown R, et al. Hypothermia and the trauma patient. Can J Surg
1999;42:333–343.
11. Rohrer MJ, Natale AM. Effect of hypothermia on the coagulation cascade. Crit Care Med
1992;20:1402–1405.
12. Valeri CR, Feingold H, Cassidy G, et al. Hypothermia-induced reversible platelet dysfunction. Ann
Surg 1987;205:175–181.
13. Vella MA, Jenner C, Betteridge DJ, et al. Hypothermia-induced thrombocytopenia. J Royal Soc Med
1988;81:228–229.
14. Meng ZH, Wolberg AS, Monroe DM 3rd, et al. The effect of temperature and pH on the activity of
factor VIIa: implications for the efficacy of high-dose factor VIIa in hypothermic and acidotic
patients. J Trauma 2003;55:886–891.
15. Dirkmann D, Hanke AA, Gorlinger K, et al. Hypothermia and acidosis synergistically impair
coagulation in human whole blood. Anesth Analg 2008;106:1627–1632.
16. Doran CM, Woolley T, Midwinter MJ. Feasibility of using rotational thromboelastometry to assess
coagulation status of combat casualties in a deployed setting. J Trauma 2010;69(Suppl 1):S40–S48.
17. Levrat A, Gros A, Rugeri L, et al. Evaluation of rotation thrombelastography for the diagnosis of
hyperfibrinolysis in trauma patients. Br J Anaesth 2008;100:792–797.
18. Martini WZ, Cortez DS, Dubick MA, et al. Thrombelastography is better than PT, aPTT, and
activated clotting time in detecting clinically relevant clotting abnormalities after hypothermia,
hemorrhagic shock and resuscitation in pigs. J Trauma 2008;65:535–543.
19. Cotton BA, Faz G, Hatch QM, et al. Rapid thrombelastography delivers real-time results that predict
transfusion within 1 hour of admission. J Trauma 2011;71:407–414; discussion 14–17.
20. Plotkin AJ, Wade CE, Jenkins DH, et al. A reduction in clot formation rate and strength assessed by
thrombelastography is indicative of transfusion requirements in patients with penetrating injuries. J
Trauma 2008;64:S64–S68.
795
booksmedicos.org
21. Alam HB. An update on fluid resuscitation. Scand J Surg 2006;95:136–145.
22. Kentner R, Safar P, Prueckner S, et al. Titrated hypertonic/hyperoncotic solution for hypotensive
fluid resuscitation during uncontrolled hemorrhagic shock in rats. Resuscitation 2005;65:87–95.
23. Sondeen JL, Coppes VG, Holcomb JB. Blood pressure at which rebleeding occurs after resuscitation
in swine with aortic injury. J Trauma 2003;54:S110–S117.
24. Alam HB, Koustova E, Rhee P. Combat casualty care research: from bench to the battlefield. World
J Surg 2005;29:S7–S11.
25. Alam HB, Rhee P. New developments in fluid resuscitation. Surg Clin North Am 2007;87(1):55–72.
26. Palmer L, Martin L. Traumatic coagulopathy–part 2: resuscitative strategies. J Vet Emerg Crit Care
(San Antonio) 2014;24:75–92.
27. Mapstone J, Roberts I, Evans P. Fluid resuscitation strategies: a systematic review of animal trials.
J Trauma 2003;55:571–589.
28. Chesnut RM, Marshall LF, Klauber MR, et al. The role of secondary brain injury in determining
outcome from severe head injury. J Trauma 1993; 34:216–222.
29. Alam HB, Stanton K, Koustova E, et al. Effect of different resuscitation strategies on neutrophil
activation in a swine model of hemorrhagic shock. Resuscitation 2004;60:91–99.
30. Rhee P, Koustova E, Alam HB. Searching for the optimal resuscitation method: recommendations
for the initial fluid resuscitation of combat casualties. J Trauma 2003;54(5):S52–S62.
31. Koustova E, Stanton K, Gushchin V, et al. Effects of lactated Ringer’s solutions on human
leukocytes. J Trauma 2002;52:872–878.
32. Cotton BA, Au BK, Nunez TC, et al. Predefined massive transfusion protocols are associated with a
reduction in organ failure and postinjury complications. J Trauma 2009;66:41–48; discussion 8–9.
33. Cotton BA, Gunter OL, Isbell J, et al. Damage control hematology: the impact of a trauma
exsanguination protocol on survival and blood product utilization. J Trauma 2008;64:1177–1182;
discussion 82–83.
34. Yucel N, Lefering R, Maegele M, et al. Trauma Associated Severe Hemorrhage (TASH)-Score:
probability of mass transfusion as surrogate for life threatening hemorrhage after multiple trauma.
J Trauma 2006;60:1228–1236; discussion 36–37.
35. Nunez TC, Voskresensky IV, Dossett LA, et al. Early prediction of massive transfusion in trauma:
simple as ABC (assessment of blood consumption)? J Trauma 2009;66:346–352.
36. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects
mortality in patients receiving massive transfusions at a combat support hospital. J Trauma
2007;63:805–813.
37. Gunter OL Jr, Au BK, Isbell JM, et al. Optimizing outcomes in damage control resuscitation:
identifying blood product ratios associated with improved survival. J Trauma 2008;65:527–534.
38. Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios
improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008;248:447–
458.
39. Snyder CW, Weinberg JA, McGwin G Jr, et al. The relationship of blood product ratio to mortality:
survival benefit or survival bias? J Trauma 2009;66:358–362; discussion 62–64.
40. Sperry JL, Ochoa JB, Gunn SR, et al. An FFP:PRBC transfusion ratio ≥1:1.5 is associated with a
lower risk of mortality after massive transfusion. J Trauma 2008;65:986–993.
41. Teixeira PG, Inaba K, Shulman I, et al. Impact of plasma transfusion in massively transfused trauma
patients. J Trauma 2009;66:693–697.
42. Junger WG, Coimbra R, Liu FC, et al. Hypertonic saline resuscitation: a tool to modulate immune
function in trauma patients? Shock 1997;8:235–241.
43. Bulger EM, May S, Kerby JD, et al. Out-of-hospital hypertonic resuscitation after traumatic
hypovolemic shock: a randomized, placebo controlled trial. Ann Surg 2011;253:431–441.
44. DuBose JJ, Kobayashi L, Lozornio A, et al. Clinical experience using 5% hypertonic saline as a safe
alternative fluid for use in trauma. J Trauma 2010;68(5):1172–1177.
45. Joseph B, Aziz H, Snell M, et al. The physiologic effects of hyperosmolar resuscitation: 5% vs. 3%
hypertonic saline. Am J Surg 2014;208(5):697–702.
46. Rhee P. Noncolligative properties of intravenous fluids. Curr Opin Crit Care 2010;16(4):317–322.
796
booksmedicos.org
47. Williams-Johnson JA, McDonald AH, Strachan GG, et al. Effects of tranexamic acid on death,
vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage
(CRASH-2) a randomised, placebo-controlled trial. West Indian Med J 2010;59:612–624.
48. Perkins JG, Schreiber MA, Wade CE, et al. Early versus late recombinant factor VIIa in combat
trauma patients requiring massive transfusion. J Trauma 2007;62:1095–1099; discussion 9–101.
49. Spinella PC, Perkins JG, McLaughlin DF, et al. The effect of recombinant activated factor VII on
mortality in combat-related casualties with severe trauma and massive transfusion. J Trauma
2008;64:286–293; discussion 93–94.
50. Joseph B, Hadjizacharia P, Aziz H, et al. Prothrombin complex concentrate: an effective therapy in
reversing the coagulopathy of traumatic brain injury. J Trauma Acute Care Surg 2013;74:248–253.
51. Rotondo MF, Schwab CW, McGonigal MD, et al. ’Damage control’: an approach for improved
survival in exsanguinating penetrating abdominal injury. J Trauma 1993;35:375–382; discussion 82–
83.
52. Hatch QM, Osterhout LM, Ashraf A, et al. Current use of damage-control laparotomy, closure rates,
and predictors of early fascial closure at the first take-back. J Trauma 2011;70:1429–1436.
53. Hatch QM, Osterhout LM, Podbielski J, et al. Impact of closure at the first take back: complication
burden and potential overutilization of damage control laparotomy. J Trauma 2011;71:1503–1511.
54. Abou-Khalil B, Scalea TM, Trooskin SZ, et al. Hemodynamic responses to shock in young trauma
patients: need for invasive monitoring. Crit Care Med 1994;22:633–639.
55. Bishop MH, Shoemaker WC, Appel PL, et al. Prospective, randomized trial of survivor values of
cardiac index, oxygen delivery, and oxygen consumption as resuscitation endpoints in severe
trauma. J Trauma 1995;38:780–787.
56. Shoemaker WC, Appel PL, Kram HB. Tissue oxygen debt as a determinant of lethal and nonlethal
postoperative organ failure. Crit Care Med 1988;16:1117–1120.
57. Trauma TEAftSo. Resuscitation Endpoints - Practice Management Guideline. 2014.
58. Barmparas G, Inaba K, Georgiou C, et al. Swan-Ganz catheter use in trauma patients can be reduced
without negatively affecting outcomes. World J Surg 2011;35(8):1809–1817.
59. Scalea TM, Hartnett RW, Duncan AO, et al. Central venous oxygen saturation: a useful clinical tool
in trauma patients. J Trauma 1990;30:1539–1543.
60. Ivatury RR, Porter JM, Simon RJ, et al. Intra-abdominal hypertension after life-threatening
penetrating abdominal trauma: prophylaxis, incidence, and clinical relevance to gastric mucosal pH
and abdominal compartment syndrome. J Trauma 1998;44(6):1016–1021.
61. Joseph B, Zangbar B, Pandit V, et al. The conjoint effect of reduced crystalloid administration and
decreased damage-control laparotomy use in the development of abdominal compartment
syndrome. J Trauma Acute Care Surg 2014;76(2):457–461.
62. Kirkpatrick AW, Roberts DJ, De Waele J, et al. Intra-abdominal hypertension and the abdominal
compartment syndrome: updated consensus definitions and clinical practice guidelines from the
World Society of the Abdominal Compartment Syndrome. Intensive Care Med 2013;39(7):1190–
1206.
63. Diebel LN, Wilson RF, Dulchavsky SA, et al. Effect of increased intra-abdominal pressure on hepatic
arterial, portal venous, and hepatic micro-circulatory blood flow. J Trauma 1992;33(2):279–282.
64. Morris JA Jr, Eddy VA, Blinman TA, et al. The staged celiotomy for trauma. Issues in unpacking
and reconstruction. Ann Surg 1993;217(5):576–584.
65. Chen RJ, Fang JF, Chen MF. Intra-abdominal pressure monitoring as a guideline in the
nonoperative management of blunt hepatic trauma. J Trauma 2001;51(1):44–50.
66. Yang EY, Marder SR, Hastings G, et al. The abdominal compartment syndrome complicating
nonoperative management of major blunt liver injuries: recognition and treatment using
multimodality therapy. J Trauma 2002;52(5):982–986.
67. McKinley BA, Kozar RA, Cocanour CS, et al. Normal versus supranormal oxygen delivery goals in
shock resuscitation: the response is the same. J Trauma 2002;53(5):825–832.
68. Hobson KG, Young KM, Ciraulo A, et al. Release of abdominal compartment syndrome improves
survival in patients with burn injury. J Trauma 2002;53(6):1129–1133.
69. Biffl WL, Moore EE, Burch JM, et al. Secondary abdominal compartment syndrome is a highly
lethal event. Am J Surg 2001;182(6):645–648.
797
booksmedicos.org
70. Balogh ZJ, Martin A, van Wessem KP, et al. Mission to eliminate postinjury abdominal
compartment syndrome. Arch Surg 2011;146:938–943.
71. Reintam Blaser A, Parm P, Kitus R, et al. Risk factors for intra-abdominal hypertension in
mechanically ventilated patients. Acta Anaesthesiol Scand 2011;55:607–614.
72. Dalfino L, Tullo L, Donadio I, et al. Intra-abdominal hypertension and acute renal failure in
critically ill patients. Intensive Care Med 2008;34:707–713.
73. Balogh Z, McKinley BA, Holcomb JB, et al. Both primary and secondary abdominal compartment
syndrome can be predicted early and are harbingers of multiple organ failure. J Trauma
2003;54:848–859 (discussion 859–861).
74. Madigan MC, Kemp CD, Johnson JC, et al. Secondary abdominal compartment syndrome after
severe extremity injury: are early, aggressive fluid resuscitation strategies to blame? J Trauma
2008;64:280–285.
75. Kirkpatrick AW, Pelosi P, De Waele JJ, et al. Clinical review: intra-abdominal hypertension: does it
influence the physiology of prone ventilation? Crit Care 2010;14:232.
76. Hering R, Vorwerk R, Wrigge H, et al. Prone positioning, systemic hemodynamics, hepatic
indocyanine green kinetics, and gastric intramucosal energy balance in patients with acute lung
injury. Intensive Care Med 2002;28:53–58.
77. Hering R, Wrigge H, Vorwerk R, et al. The effects of prone positioning on intraabdominal pressure
and cardiovascular and renal function in patients with acute lung injury. Anesth Analg
2001;92:1226–1231.
78. Vidal MG, Ruiz Weisser J, Gonzalez F, et al. Incidence and clinical effects of intra-abdominal
hypertension in critically ill patients. Crit Care Med 2008; 36:1823–1831.
79. Ke L, Ni HB, Sun JK, et al. Risk factors and outcome of intra-abdominal hypertension in patients
with severe acute pancreatitis. World J Surg 2012;36:171–178.
80. Kim IB, Prowle J, Baldwin I, et al. Incidence, risk factors and outcome associations of intra-
abdominal hypertension in critically ill patients. Anaesth Intensive Care 2012;40:79–89.
81. Lui F, Sangosanya A, Kaplan LJ. Abdominal compartment syndrome: clinical aspects and
monitoring. Crit Care Clin 2007;23(3):415–433.
82. Malbrain ML, Cheatham ML, Kirkpatrick A, et al. Results from the International Conference of
Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrome. I. Definitions.
83. Hong JJ, Cohn SM, Perez JM, et al. Prospective study of the incidence and outcome of intra-
abdominal hypertension and the abdominal compartment syndrome. Br J Surg 2002;89(5):591–596.
84. Cheatham ML, Safcsak K. Is the evolving management of intra-abdominal hypertension and
abdominal compartment syndrome improving survival? Crit Care Med 2010;38:402–407.
85. Ouellet JF, Leppaniemi A, Ball CG, et al. Alternatives to formal abdominal decompression. Am Surg
2011;77(Suppl 1):S51–S57.
86. De Keulenaer BL, De Waele JJ, Malbrain ML. Nonoperative management of intra-abdominal
hypertension and abdominal compartment syndrome: evolving concepts. Am Surg 2011;77(Suppl
1):S34—S34.
87. Cheatham ML. Nonoperative management of intraabdominal hypertension and abdominal
compartment syndrome. World J Surg 2009;33:1116–1122.
88. Sperry JL, Minei JP, Frankel HL, et al. Early use of vasopressors after injury: caution before
constriction. J Trauma 2008;64(1):9–14.
89. Winchell RJ, Simons RK, Hoyt DB. Transient systolic hypotension. A serious problem in the
management of head injury. Arch Surg 1996;131(5):533–539.
90. Manley G, Knudson MM, Morabito D, et al. Hypotension, hypoxia, and head injury: frequency,
duration, and consequences. Arch Surg 2001;136(10):1118–1123.
91. Joseph B, Sadoun M, Aziz H, et al. Repeat head computed tomography in anticoagulated traumatic
brain injury patients: still warranted. Am Surg 2014;80(1):43–47.
92. Joseph B, Aziz H, Pandit V, et al. A three-year prospective study of repeat head computed
tomography in patients with traumatic brain injury. J Am Coll Surg 2014;219(1):45–51.
93. Aziz H, Rhee P, Pandit V, et al. Mild and moderate pediatric traumatic brain injury: replace routine
repeat head computed tomography with neurologic examination. J Trauma Acute Care Surg
798
booksmedicos.org
2013;75(4):550–554.
94. Joseph B, Friese RS, Sadoun M, et al. The BIG (brain injury guidelines) project: defining the
management of traumatic brain injury by acute care surgeons. J Trauma Acute Care Surg
2014;76(4):965–969.
95. Joseph B, Aziz H, Sadoun M, et al. Acute care surgery model: managing traumatic brain injury
without an inpatient neurosurgical consultation. J Trauma Acute Care Surg 2013;75(1):102–105.
96. Joseph B, Pandit V, Aziz H, et al. Mild traumatic brain injury defined by Glasgow Coma Scale: is it
really mild?Brain Inj 2015;29:11–16.
97. Schnüriger B, Inaba K, Abdelsayed GA, et al. The impact of platelets on the progression of
traumatic intra-cranial hemorrhage. J Trauma 2010;68:881–885.
98. Nekludov M, Bellander BM, Blombäck M, et al. Platelet dysfunction in patients with severe
traumatic brain injury. J Neurotrauma 2007;24:1699–1706.
99. Joseph B, Aziz H, Zangbar B, et al. Acquired coagulopathy of traumatic brain injury defined by
routine laboratory tests: which laboratory values matter? J Trauma Acute Care Surg
2014;76(1):121–125.
100. Joseph B, Aziz H, Pandit V, et al. Prothrombin complex concentrate versus fresh-frozen plasma for
reversal of coagulopathy of trauma: is there a difference? World J Surg 2014;38(8):1875–1881.
101. Joseph B, Hadjizacharia P, Aziz H, et al. Prothrombin complex concentrate: an effective therapy in
reversing the coagulopathy of traumatic brain injury. J Trauma Acute Care Surg 2013;74(1):248–
253.
102. Zangbar B, Pandit V, Rhee P, et al. Clinical outcomes in patients on preinjury ibuprofen with
traumatic brain injury. Am J Surg 2015;209:921–926.
103. Joseph B, Pandit V, Aziz H, et al. Clinical outcomes in traumatic brain injury patients on preinjury
clopidogrel: a prospective analysis. J Trauma Acute Care Surg 2014;76(3):817–820.
104. Joseph B, Aziz H, Pandit V, et al. Low-dose aspirin therapy is not a reason for repeating head
computed tomographic scans in traumatic brain injury: a prospective study. J Surg Res
2014;186(1):287–291.
105. Joseph B, Pandit V, Meyer D, et al. The significance of platelet count in traumatic brain injury
patients on antiplatelet therapy. J Trauma Acute Care Surg 2014;77(3):417–421.
106. Schaefer JH, Leung W, Wu L, et al. Translational insights into traumatic brain injury occurring
during dabigatran or warfarin anticoagulation. J Cereb Blood Flow Metab 2014;34:870–875.
107. Joseph B, Ditillo M, Pandit V, et al. Dabigatran therapy: minor trauma injuries are no longer minor.
Am Surg 2014;80(4):116–118.
108. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by
prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy
subjects. Circulation 2011;124:1573–1579.
109. Godier A, Miclot A, Le Bonniec B, et al. Evaluation of prothrombin complex concentrate and
recombinant activated factor VII to reverse rivaroxaban in a rabbit model. Anesthesiology
2012;116:94–102.
110. Marlu R, Hodaj E, Paris A, et al. Effect of nonspecific reversal agents on anticoagulant activity of
dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb
Haemost 2012;108:217–224.
111. Solbeck S, Meyer MA, Johansson PI, et al. Monitoring of dabigatran anticoagulation and its
reversal in vitro by thrombelastography. Int J Cardiol 2014;176:794–799.
112. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate–a novel, reversible, oral direct
thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity.
Thromb Haemost 2010;103:1116–1127.
113. Warkentin TE, Margetts P, Connolly SJ, et al. Recombinant factor VIIa (rFVIIa) and hemodialysis
to manage massive dabigatran-associated postcardiac surgery bleeding. Blood 2012;119:2172–2174.
114. Temkin NR, Dikmen SS, Wilensky AJ, et al. A randomized, double-blind study of phenytoin for the
prevention of posttraumatic seizures. N Engl J Med 1990;323(8):497–502.
115. Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam
versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg
2013;74(3):766–771.
799
booksmedicos.org
116. Joseph B, Aziz H, Pandit V, et al. Improving survival rates after civilian gunshot wounds to the
brain. J Am Coll Surg 2014;218(1):58–65.
117. Gressot LV, Chamoun RB, Patel AJ, et al. Predictors of outcome in civilians with gunshot wounds to
the head upon presentation. J Neurosurg 2014;121(3):645–652.
118. Joseph B, Aziz H, Sadoun M, et al. Fatal gunshot wound to the head: the impact of aggressive
management. Am J Surg 2014;207(1):89–94.
119. Peterson VM, Moore EE, Jones TN, et al. Total enteral nutrition versus total parenteral nutrition
after major torso injury: attenuation of hepatic protein reprioritization. Surgery 1988;104:199–207.
120. Moore FA, Moore EE, Jones TN, et al. TEN versus TPN following major abdominal trauma–reduced
septic morbidity. J Trauma 1989;29:916–922; discussion 22–23.
121. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral,
reduces postoperative septic complications. The results of a meta-analysis. Ann Surg 1992;216:172–
183.
122. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic
morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503–511; discussion
11–13.
123. Mochizuki H, Trocki O, Dominioni L, et al. Mechanism of prevention of postburn hypermetabolism
and catabolism by early enteral feeding. Ann Surg 1984;200:297–310.
124. Kompan L, Kremzar B, Gadzijev E, et al. Effects of early enteral nutrition on intestinal permeability
and the development of multiple organ failure after multiple injury. Int Care Med 1999;25:157–161.
125. Moore EE, Jones TN. Benefits of immediate jejunostomy feeding after major abdominal trauma–a
prospective, randomized study. J Trauma 1986;26:874–881.
126. Jacobs DG, Jacobs DO, Kudsk KA, et al. Practice management guidelines for nutritional support of
the trauma patient. J Trauma 2004;57:660–678; discussion 79.
127. Raff T, Hartmann B, Germann G. Early intragastric feeding of seriously burned and long-term
ventilated patients: a review of 55 patients. Burns 1997;23:19–25.
128. Hadley MN, Grahm TW, Harrington T, et al. Nutritional support and neurotrauma: a critical review
of early nutrition in forty-five acute head injury patients. Neurosurgery 1986;19:367–373.
129. Borzotta AP, Pennings J, Papasadero B, et al. Enteral versus parenteral nutrition after severe closed
head injury. J Trauma 1994;37:459–468.
130. Klodell CT, Carroll M, Carrillo EH, et al. Routine intragastric feeding following traumatic brain
injury is safe and well tolerated. Am J Surg 2000; 179:168–171.
131. Blomberg J, Lagergren J, Martin L, et al. Complications after percutaneous endoscopic gastrostomy
in a prospective study. Scand J Gastroenterol 2012;47:737–742.
132. Glazer ES, Kulvatunyou N, Green DJ, et al. Contemporary acute care surgery percutaneous
endoscopic gastrostomy tube placement: an extreme bumper height and complications. J Trauma
Acute Care Surg 2013;75:859–863.
133. Adams GF, Guest DP, Ciraulo DL, et al. Maximizing tolerance of enteral nutrition in severely
injured trauma patients: a comparison of enteral feedings by means of percutaneous endoscopic
gastrostomy versus percutaneous endoscopic gastrojejunostomy. J Trauma 2000;48:459–464;
discussion 64–65.
134. Kortbeek JB, Haigh PI, Doig C. Duodenal versus gastric feeding in ventilated blunt trauma patients:
a randomized controlled trial. J Trauma 1999;46:992–996; discussion 6–8.
135. Singh N, Sharma B, Sharma M, et al. Evaluation of early enteral feeding through nasogastric and
nasojejunal tube in severe acute pancreatitis: a noninferiority randomized controlled trial. Pancreas
2012;41:153–159.
136. Gómez AM. Testing the cycle of violence hypothesis: child abuse and adolescent dating violence as
predictors of intimate partner violence in young adulthood. Youth Soc 2010;43(1):171–192.
137. Dickerson RN. Optimal caloric intake for critically ill patients: first, do no harm. Nutr Clin Pract
2011;26:48–54.
138. Arabi YM, Haddad SH, Aldawood AS, et al. Permissive underfeeding versus target enteral feeding
in adult critically ill patients (PermiT Trial): a study protocol of a multicenter randomized
controlled trial. Trials 2012;13:191.
139. Arabi YM, Tamim HM, Dhar GS, et al. Permissive underfeeding and intensive insulin therapy in
800
booksmedicos.org
critically ill patients: a randomized controlled trial. Am J Clin Nutr 2011;93:569–577.
140. Owais AE, Kabir SI, Mcnaught C, et al. A single-blinded randomised clinical trial of permissive
underfeeding in patients requiring parenteral nutrition. Clinical Nutrition 2014;33(6):997–1001.
141. Moore FA, Moore EE, Kudsk KA, et al. Clinical benefits of an immune-enhancing diet for early
postinjury enteral feeding. J Trauma 1994;37:607–615.
142. Taylor SJ, Fettes SB, Jewkes C, et al. Prospective, randomized, controlled trial to determine the
effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients
suffering head injury. Crit Care Med 1999;27:2525–2531.
143. Kudsk KA, Minard G, Croce MA, et al. A randomized trial of isonitrogenous enteral diets after
severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg 1996;224:531.
144. Marimuthu K, Varadhan KK, Ljungqvist O, et al. A meta-analysis of the effect of combinations of
immune modulating nutrients on outcome in patients undergoing major open gastrointestinal
surgery. Ann Surg 2012; 255:1060–1068.
145. Davis KA, Kinn T, Esposito TJ, et al. Nutritional gain versus financial gain: the role of metabolic
carts in the surgical ICU. J Trauma 2006;61:1436–1440.
146. Mueller C, Compher C, Ellen DM. A.S.P.E.N clinical guidelines nutrition screening, assessment, and
intervention in adults. JPEN J Parenter Enteral Nutr 2011;35:16–24.
147. Hipskind P, Glass C, Charlton D, et al. Do handheld calorimeters have a role in assessment of
nutrition needs in hospitalized patients? A systematic review of literature. Nutr Clin Pract
2011;26:426–433.
148. Beck FK, Rosenthal TC. Prealbumin: a marker for nutritional evaluation. Am Fam Phys
2002;65:1575–1580.
149. Saidi RF, Markmann JF, Jabbour N, et al. The faltering solid organ donor pool in the United States
(2001–2010). World J Surg 2012;36:2909–2913.
150. Salim A, Velmahos GC, Brown C, et al. Aggressive organ donor management significantly increases
the number of organs available for transplantation. J Trauma 2005;58:991–994.
151. Joseph B, Khalil M, Pandit V, et al. Hypothermia in organ donation: A friend or foe? J Trauma
Acute Care Surg 2014;77:559–563.
152. McKeown DW, Bonser RS, Kellum JA. Management of the heartbeating brain-dead organ donor. Br
J Anaesth 2012;108(Suppl 1):i96–i107.
153. Novitzky D, Cooper DK, Morrell D, et al. Change from aerobic to anaerobic metabolism after brain
death, and reversal following triiodothyronine therapy. Transplantation 1988;45:32–36.
154. Joseph B, Aziz H, Pandit V, et al. Levothyroxine therapy before brain death declaration increases
the number of solid organ donations. J Trauma Acute Care Surg 2014;76:1301–1305.
155. Salim A, Martin M, Brown C, et al. Using thyroid hormone in brain-dead donors to maximize the
number of organs available for transplantation. Clin Transplant 2007;21:405–409.
156. Rosendale JD, Kauffman HM, McBride MA, et al. Aggressive pharmacologic donor management
results in more transplanted organs. Transplantation 2003;75:482–487.
157. Croezen DH, Van Natta TL. Presentation and outcomes for organ donation in patients with cerebral
gunshot wounds. Clin Transplant 2001;15(Suppl 6):11–15.
801
booksmedicos.org
Chapter 33
Environmental Injuries
J. Patrick Walker and Gregory J. Jurkovich
Key Points
1 Of the 3,000 species of snakes worldwide, only 600 are venomous, with approximately 6 deaths per
year in the United States caused by snakebite. In contrast, there are over 150,000 species of
Hymenoptera in the world that cause approximately 40 deaths per year, mostly as a result of severe
anaphylactic reactions.
2 Snakebite morbidity depends on the type of snake and the degree of envenomation. Venoms consist
of numerous polypeptides that can disrupt endothelial cells and blood flow, produce neuromuscular
blockade, or generate a coagulopathy via procoagulants. Some snakes (particularly Elapids
[represented by the coral snakes in North America]) also have direct neurotoxins and cardiotoxins.
3 Snakebite produces immediate pain, edema, and erythema at the site. Spread of the swelling greater
than 30 cm/hr indicates severe envenomation. Initial incision and suction and the use of a proximal
tourniquet are contraindicated. Use of purified ovine antivenin is effective for serious Crotalidae
envenomation and has replaced equine antivenin with its associated risk of serum sickness. Because
of the presumed safety of the newer antivenom, overuse is more likely.
4 Spider bites produce toxicity by local tissue necrosis (brown recluse and hobo spiders) and painful
muscle contractions (black widow spider). Death may be caused by stinging Hymenoptera, including
bees (particularly aggressive Africanized bees), fire ants, and scorpions. The death is usually
secondary to anaphylaxis, but occasionally massive envenomation occurs – especially with
Africanized honeybees. The estimated lethal dose is approximately 20 stings/kg in most mammals.
5 Hypothermia risk is high in the severely injured patient as a result of exposure, loss of normal
protective metabolism (i.e., shivering), rapid massive infusion of cold fluids/blood, and open
thoracic and abdominal cavities.
6 The initial response to hypothermia is an intensive sympathetic type reaction with tremulousness,
profound vasoconstriction, marked increase in oxygen consumption, and accelerated heart rate and
minute ventilation. As core temperature falls to 33°C and 30°C this response is lost, and deeper core
hypothermia rapidly develops.
7 Hypothermia increases risk of mortality at every level of traumatic injury. There is no improvement
in outcome when applied to the severe TBI, and patients rapidly rewarmed require less resuscitation
volume and have improved survival.
8 Treating hypothermia begins by preventing further heat loss and allowing endogenous rewarming.
Active rewarming has many adjuncts, including warm blankets, heating pads and lights, and
immersion in warm water or internally by core rewarming. Internal core rewarming is more
effective, and includes heated intravenous fluids; heated body cavity lavage; heated moist inhaled
air; extracorporeal circulatory rewarming (ECMO or CPB) or closed circuit intravascular
countercurrent heat-exchange devises.
9 Frostbite involves ice crystal formation and unpredictable loss of tissue. Early definitive rewarming
(avoiding refreezing) by submersion in 40°C to 42°C water is preferable with subsequent meticulous
care, awaiting demarcation, and avoidance of early débridement to optimize outcomes and tissue
salvage.
10 Early thrombolytic therapy might be beneficial in select frostbite patients.
Although most of us will not suffer a gunshot wound or a small bowel obstruction, we will all receive
insect bites and those of us who frequent the outdoors will be exposed to many other facets of the
environment. This chapter is about those encounters – the heat, the cold, venomous bites and stings. It
is essential that all physicians know the basics of care for injuries produced in this manner.
802
booksmedicos.org
ENVENOMATION
Snakebite
The legends and lore of snakes are spread across history; with serpents mentioned in 42 Bible verses,
implicated in the death of Cleopatra, and the medical field – the snake is essential to the rod of
Aesculapius and the Caduceus. Few emergencies have been surrounded with as many types of treatment
(some very innovative – electrical shock and TASER, tourniquets with ice emersion, crosscut of the bite
with suction of the wound) and little scientific fact as a snakebite. We will attempt to address the
management of envenomation with as much evidence as possible.
There are over 1.8 million poisonous snakebites in the world annually with almost 100,000 deaths.1
In the United States, the CDC estimates there are 7,000 to 8,000 bites per year with 5 to 6 deaths.2 Most
of the deaths are secondary to Rattlesnake envenomation, with only two fatalities from Copperhead
snakebite in the past 5 years.
1 More than 3,000 species of snakes exist in the world of which approximately 600 are venomous.
They range in size from 10 cm to greater than 9 m.3 Nonvenomous snakes predominate on all continents
with the exception of Australia. There are five families of poisonous snakes worldwide: Colubridae,
Elapidae, Hydrophidae, Viperidae, and Atractaspididae. The boomslang and the bird snake represent the
Colubridae – found mostly in Africa. The Elapids are found throughout the world and include snakes,
such as mambas, kraits, adders, and cobras. The only Elapids in North America are the coral snakes. The
Hydrophidae are the sea snakes. The Viperids have long hinged fangs. They include the pit vipers that,
like the Boidae family (boas and pythons), have infrared sensors in a nasal pit that is located between
the nose and the eye (Fig. 33-1). These are excellent sensitive organs that can differentiate a
temperature differential of 0.003°C. All venomous snakes in North America with the exception of the
coral snakes are in this family. Poisonous snakes in North America are therefore of the phylum
Chordata, class Reptilia, order Squamata, suborder Serpentes, and of the Crotalidae (subfamily
Crotalinae) or Elapidae family. Venomous snakes are distributed throughout the United States with at
least one species in every state with the exception of Hawaii, Alaska, and Maine. Water moccasins are
found primarily in the Southeastern United States. Copperheads are found from Massachusetts westerly
to Illinois and to the south from Florida to Texas. Rattlesnakes are found coast to coast. The genus
Crotalus – the true rattlesnakes – are found only in the New World.
Figure 33-1. Heat sensor – nasal pit. (Photo courtesy of Ronny Stewart, MD.)
Snakes are easily identifiable reptiles, marked anatomically by the large number (greater than 120) of
precloacal vertebral bodies. They also have a reduced (almost absent) left lung, a single ventricle (no
ventricular septum), and no muscles in the ciliary body of the eye. Despite the absence of a ventricular
septum, oxygenated and deoxygenated blood channels fairly separately though the heart.4 All snakes are
strictly carnivores. The size of the snake dictates the size of the prey.
The pit vipers (the genus Crotalus, Sistrurus, and Agkistrodon) are morphologically distinguished by
elliptical pupils, a triangular head, (Fig. 33-2) and retractable fangs. The fangs are tubular; injecting
venom similar to a hypodermic needle. This is in contradistinction to the Elapids in which the fangs are
fixed and grooved – wicking the venom into the victim. Venomous snakes have a single row of caudal
plates distal to the anal plate, whereas harmless snakes have a double row of caudal plates. There are 32
species of rattlesnakes in the New World, ranging from southern Alberta to central Argentina.5–7
803
booksmedicos.org
Rattlesnakes are only found in the Americas. All true rattlesnakes have a rattle (with the exception of an
endangered species in Mexico – the Santa Catalina rattlesnake, which has only a vestigial rattle). The
rattle is a series of interlocking segments. A new segment is added with each shedding of the skin,
which may occur 2 to 3 times per year. There are two genus of rattlesnakes; Crotalus – the true
rattlesnakes and Sistrurus – the pigmy rattlers. There are 14 species of Crotalus (Table 33-1) in North
America. The largest species of rattlesnake in North America is the eastern diamondback (Crotalus
adamanteus), which is slightly larger than its cousin the western diamondback (Crotalus atrox). There are
eight members of the Agkistrodon genus – moccasins and copperheads (Table 33-2).
Figure 33-2. Triangular shape of pit viper head. (Photo courtesy of Ronny Stewart, MD.)
By far the most critical step in management of snakebite is identification of the offending species. The
majority of snakebites are nonvenomous and require no treatment. Some bites, such as those of
copperheads (Fig. 33-3) and pigmy rattlers (Table 33-3), are almost always self-limiting and require
little more than observation. Others such as the diamondback (Fig. 33-4) and Mojave rattlers can
require intense medical management, occasional surgical management, and even rarely cause death.
Identification of the species by the patient is notoriously invalid; however, a detailed description of the
offending snake should be taken. The only snake where color is useful in identifying is the coral snake–
red and yellow kill a fellow, red and black venom lack (Fig. 33-5). Note that this is true only in North
America, as there are venomous coral snakes in Central and South America that have red bands touching
black bands. Other clues, such as geography and topography (proximity to water), can also at least help
with identification of the genus. All snakebites should, at least initially, be considered an event with
potential morbidity and possible mortality.
Table 33-1 Crotalus Species
804
booksmedicos.org
Table 33-2 Agkistrodon Species
As snakes are cold-blooded animals, snakebites generally occur in the warm months, with a particular
increase in incidence in the spring and fall. The majority of snakebites occur in young men, with up to
60% of bites occurring in victims that were deliberately provoking the snakes.
2 Venom is produced in Duvernoy glands on the dorsal sides of the head (corresponding to parotid
glands) enhancing the triangular appearance. During envenomation the venom is forced through the
fangs by the palantine muscles. If a fang is broken off, it will be replaced by the next in a row of “proto-
fangs.” Any clothing may limit the amount and depth of envenomation. The purpose of the venom is to
immobilize or kill the prey and begin digestion. Pit viper venoms are complex – with up to 50 different
proteins and enzymes identified.8–10 Over 90% of the dry weight of venom is proteinaceous in nature.
Although it is common to classify the venoms as neurotoxic or digestive in nature, all snakes have
varying compositions of venoms. The Crotalids will have a higher percentage of digestive/enzymatic
type proteins than the Elapids, which will contain a higher percentage of neurotoxins. Common
enzymes are phospholipases, metalloproteases, collagenase, and hyaluronidase (Table 33-4). These
peptides and polypeptides act by damaging vascular endothelium and other cellular membranes.
Compliment is activated, fibrin is degraded, and platelets are activated. The increased permeability of
the membranes leads to peripheral and pulmonary edema, hemorrhage, and hypotension. L-amino acid
oxidase splits fibrinogen contributing to the induction of DIC. The Elapids in particular contain a higher
percentage of proteins that block acetylcholine receptor sites. This can lead to dysphagia, slurred
speech, seizures, coma, and death. Despite the very high toxicity of coral snake venom, only one fatality
has been recorded in the United States in the past 50 years.
805
booksmedicos.org
Figure 33-3. Copperhead. (Photo courtesy of Ronny Stewart, MD.)
Table 33-3 Sistrurus Species
3 When evaluating the snakebite victim, it is important to document both local and systemic signs
and symptoms. Vital signs should be recorded, and repeated at intervals guided by the clinical response.
Pain, edema, and erythema at the site are common. Secondary symptoms include muscle twitching,
perioral paresthesias, and a metallic taste in the mouth. Marking lines at the site of documented
discoloration (Fig. 33-6) can help the clinician follow the progression of the envenomation. Swelling in
the affected digit or limb should be measured (circumference) and followed closely. The amount of local
tissue destruction is an accurate marker of the degree of envenomation. It is probable that if there is no
pain or erythema by the time that the patient arrives in the ED, no envenomation has occurred.
Intravenous access should be obtained. Laboratory evaluation should include a CBC with platelet count,
PT, PTT, CPK, fibrinogen level, creatinine, BUN, and urinalysis. Up to 30% of Crotalid envenomations
will show an abnormality in the coagulation profile, although clinical bleeding is exceedingly rare.11 In
Lovonas 2004 review of 400 copperhead bites from the Carolinas: no hypotension, no respiratory
failure, and no deaths occurred.15 Eight patients did have laboratory abnormalities, but none developed
bleeding complications. However, in severe envenomation by one of the larger rattlesnakes, diffuse
capillary leakage can lead to pulmonary edema, hypotension, and shock.12 A consumptive coagulopathy
may rapidly develop. Such patients may bleed spontaneously from any site. Acute renal failure may
result from directs nephrotoxins as well as myoglobinuria. An electrocardiogram, or at least continuous
cardiac monitoring should be considered. If there appears to be no evidence of envenomation, the
patient may be observed in the emergency department for several hours and discharged home. With
evidence of envenomation our recommendation is for admission to the hospital, preferably a monitored
bed, for observation and possible intervention for at least 24 hours.
806
booksmedicos.org
Figure 33-4. Western diamondback.
Figure 33-5. Coral snake.
Table 33-4 Composition of Venom
807
booksmedicos.org
Figure 33-6. Demarcation of hemolysis after bite.
As noted above treatment is largely dictated by the species of snake and the initial clinical
presentation. Although a number of series have noted the appropriate treatment of Agkistrodon
(copperhead and moccasin) bite is observation only,13–15 extrapolation of this data to rattlesnakes could
be misleading. In the rattlesnake bite victim with a moderate or severe envenomation, early use of
antivenom is appropriate, and should be strongly considered (see below). Although there are a number
of snakebite severity indices (grading systems) published, a modification of the simple system proposed
by Dart in 1996 is probably the most useful.16 A grade 1 envenomation is limited to the immediate bite
site, a grade 2 envenomation extends onto less than a full extremity and may have non–life-threatening
symptoms such as nausea, vomiting, mild tachycardia, and mild hypotension. A grade 3 envenomation
involves more than an extremity and includes systemic signs such as severe hypotension/tachycardia or
blood dyscrasias or clinically significant clotting abnormalities. Although enzyme-linked immunosorbent
assays (ELISAs) have been developed that can directly measure serum venom antigens as well as
identify the offending snake, clinical applicability of these types of tests are limited.17
Initial first aid on the scene should involve immobilization and splinting. Although there are no data
to confirm this will limit the spread of venom, it might be more comfortable. The application of ice or
heat seems to have little effect on results. A number of historical treatments should specifically be
avoided. Incision and suction, advocated for years, is no longer recommended.18 A surgical incision in
the field by a nonsurgeon can possibly involve vessels, tendons, and nerves and increase morbidity, and
only a small amount of venom can actually be extracted with suction. Limited cooling of the extremity
may have some benefit, although a version of this – ligation cryotherapy – is associated with a high rate
of amputation.19,20 Although placement of a constrictor band may be of benefit in Australia (where
Elapids predominate) to prevent rapid dissemination of a deadly neurotoxin, it is probably of little
benefit in North America where the offending species is almost certainly a Crotalid. The use of a
compression bandage has been shown to slow the systemic absorption of venom.21,22 This may make it
the treatment of choice in the field for a nonnecrotizing envenomation, such as produced by an Elapid.
It may however increase local necrosis when used to treat the bite of a pit viper.
The wound should be cleansed and the location of the puncture sites documented. The distance
between the two fang marks is related to the size of the snake. The tetanus immunization status of the
patient should be reviewed and updated. Steroids have no benefit in humans although these are often
used by veterinarians.23,24 Steroids do have a role in treating the infrequent acute allergic as well as
delayed-onset serum sickness that may occur after the use of sheep-derived antivenom, as noted below.
The prophylactic use of antibiotics has been evaluated by several studies and does not seem to reduce
infection rates.25–28 Infection after snakebite is surprisingly uncommon and while patients are often
given an antibiotic, there is no good clinical evidence for their use. Although many patients will have
erythema, edema, and tissue necrosis and will appear infected, these are usually sterile; culture-proven
infection occurring after snakebite should be treated appropriately. Culture of organisms in the mouth
of the rattlesnake include Pseudomonas, Enterobacteracie, Staphylococcus, and Clostridia.29
If the species is a coral snake or a nonindigenous Elapid, the administration of cholinergic agonists
should occur at the first sign of symptoms. Calcium infusion may reduce the onset of seizures.
Certainly the most controversial decision point in management of snakebite is the administration of
antivenom. Although hundreds of antivenoms are available worldwide for various species, for all
practical purposes in North America we are only dealing with envenomation by Crotalids. Snakebite by
coral snakes are uncommon, and while the venom is exceedingly toxic, the treatment is only supportive
as antivenom is no longer available. Prior to 2000, the primary antivenom available in the United States
for the bite of a Crotalid was a hyperimmune serum produced by envenomation of horses. Its use was
associated with a high incidence of side effects: anaphylaxis, hypersensitivity, and delayed serum
sickness.30 In 2000, CroFab (Crotalidae Polyvalent Immune Fab [Ovine]) was introduced obviating the
use of now unavailable horse serum products.12,31
CroFab is truly an elegant drug. It is produced by immunizing sheep with the venom from the
western diamondback rattlesnake (Crotalus atrox), the eastern diamondback rattlesnake (Crotalus
adamanteus), the Mojave rattlesnake (Crotalus scutulatus) or the cottonmouth water moccasin
(Agkistrodon). The monovalent immunoglobulin from the sheep is prepared by fractionation of the
immunoglobulin from the serum, digesting it with papain, and then utilizing ion exchange and affinity
chromatography to separate the Fab fragments specific to each species.32 The Fc portion of IgG is
generally thought to be responsible for high rates of hypersensitivity and serum sickness seen with the
808
booksmedicos.org
horse serum product developed by Wyeth in 1954, and hence this ovine (sheep) version is generally
considered safer. The four different monospecific antivenins are then mixed (Table 33-5). In a murine
model there is good antigenic crossover in treating other North American Crotalid envenomations.33
Utilizing CroFab to treat Crotalid envenomation is somewhat controversial, primarily because of the
cost/benefit ratio. The cost of this drug is a significant factor with wholesale prices up to $2,000 per
vial. Certainly any patient with life-threatening symptoms should immediately be given 4 to 6 vials of
the antivenom.34 Treatment is not based on the body mass of the patient – as the antivenom neutralizes
the poison that is injected – this will vary with each envenomation. The lyophilized powder is
reconstituted with 18 mL of normal saline, followed by dilution in 250 mL. Each dose is given over 1
hour. It is thought that venom is rapidly tissue bound, therefore the earlier the antivenom can be given,
the more likely a favorable response. The packaging information states that treatment should begin
within 6 hours of the bite. There is however at least one report of effective use of antivenom after
significant delay.35 Thus is the conundrum – there are certainly snakebites that initially appear
innocuous that later become life-threatening. This has lead physicians in the emergency room to over
treat large numbers of patients who do not require therapy, and why it is so important that every
attempt be made to identity the offending species. If one can ascertain that the snake is one of the less
virulent types (Agkistrodon or Sistrurus species) the patient can almost certainly be treated without the
use of antivenom.14,36 However, in the patient with a deteriorating clinical condition, treatment should
always be given. Repeated dosing should be given until clinical stability is achieved; although this is
highly unlikely after 30 to 40 vials. The patient should be monitored for recurrence of symptoms and
retreated if necessary.37 CroFab has an estimated half-life of 12 to 23 hours.
Table 33-5 Components of Antivenom–CroFab Antibodies
Immediate adverse drug reactions will occur in 6% to 8% of patients.38,39 This may be related to the
rate of infusion.40 Although anaphylaxis would occur in up to 50% of patients treated with the older
equine antivenin, it is an uncommon occurrence with CroFab – maybe up to 14% of patients.41 It should
be treated aggressively when occurring: The antivenin infusion should be stopped and a combination of
antihistamines (diphenhydramine), epinephrine, and steroids administered, depending on the severity of
the response. The airway should be assessed and secured if necessary. Appropriate volume resuscitation
should be instituted. Steroid dosing ranges from a single 125 mg intravenous bolus of
methylprednisolone to short-course prednisone pulse dosing (60 mg daily for 5 days).40
Serum sickness will occur in 13% to 16%39,41 of patients treated with ovine antivenom (CroFab),
certainly less common than with the older Wyeth equine antivenom.30 Serum sickness is a type III
hypersensitivity reaction in which soluble antigen–antibody complexes are deposited diffusely in the
presence of antigen excess. Symptoms such as urticaria, itching, nephritis, and arthralgia can occur for
weeks after the infusion. The treatment for serum sickness is a pulse of corticosteroids tapered over 7 to
14 days.
There is no question that the purified ovine antivenin (CroFab) is much safer than the older horse
product.8,42 This has led to some indiscriminate usage in emergency departments across the country. It
should be recognized that the vast majority of snakebite victims will recover uneventfully with only
supportive treatment. Each patient must be individually clinically evaluated and limit antivenom use to
those in whom the potential benefits outweighs the risk of side effect.
CroFab has been used extensively in children as young as 14 months.43–45 There are beginning to be
reports of overuse of CroFab in children as well as adults.46 A special consideration should be use of
antivenom in the pregnant patients. Certainly coagulopathy could be lethal to the mother and fetus.
There have been limited reports of use of CroFab in pregnancy.47 Reports of fetal loss of up to 20% are
noted in the worldwide literature with snakebites of a variety of species. This seems to be improved
with the use of antivenom.47,48 Certainly the risk/benefit ratio must be carefully weighed, but the
general recommendation is to treat pregnant women with CroFab when indicated.
In the rare patient that develops clinical bleeding; such as hemoptysis, intracranial hemorrhage, or
809
booksmedicos.org
gastrointestinal bleeding, correction of the coagulopathy should be undertaken with appropriate blood
products. Antivenom should be given in these patients as initial therapy. Do not routinely treat
thrombocytopenia or severe coagulopathy in the absence of bleeding. Coagulopathy can recur up to 2
weeks late.37
Figure 33-7. Hemorrhagic bullae.
The use of surgery in the management of snakebite has a limited role. Although historically snakebite
has been treated with various surgical procedures,19,49 it should be in an unusual patient that more than
simple debridement is needed. Crosscut and aspiration of the puncture sites was utilized for years, but
this is no longer recommended. Several studies have shown the limitations of this practice. In dogs, up
to one-half of the venom can be removed if incision and suction are begun within 3 minutes.17 In rabbits
up to 37% of antivenom can be removed. However, in human studies only about 11% of the venom may
be removed.50,51 It is rapidly bound to tissues and is difficult to be removed by suction. Laceration of
vessels and nerves by well-meaning people at the scene is likely to increase morbidity as well as
increase the risk of infection. Both partial and radical surgical excision of the involved bite area has
likewise been attempted with no proven benefit.52–55 A common finding is a local cytolytic response
(Fig. 33-7), that produces a hemolytic bullae and requires debridement (Figs. 33-8 and 33-9). This can
be expected to heal by secondary intention with a satisfactory cosmetic response (Fig. 33-10).
Another use of CroFab is in the patient with impending compartment syndrome. The great majority of
snakebites deposit venom in the subcutaneous tissues, not subfascial. It can sometimes be difficult to
differentiate a swollen painful extremity from a true compartment syndrome. When in doubt
compartment pressures should be measured.55,56 With rising pressures (greater than 30 to 40 mm),
antivenom therapy should be initiated (or repeated). With failure of response to adequate dosing of
antivenom, appropriate surgical fasciotomy can save extremities. Prophylactic fasciotomy has no role in
treatment. Stewart and colleagues at the University of Texas Health Science Center in San Antonio have
an extensive experience with rattlesnake bites.57 They have randomized animals to receive an
intracompartmental injection of venom from the western diamondback rattlesnake. The animals
received fasciotomy with debridement alone, antivenom alone, or antivenom with fasciotomy and
debridement. Antivenom therapy prevented muscle loss and improved survival. Surgery alone did not.
It was noted that muscle that had been debrided would have survived if treated with antivenom alone.
Fasciotomy may increase the severity of local tissue loss.58,59 When fasciotomy is required because of
rising compartment pressures that do not respond to antivenom, consideration for postoperative
negative-pressure wound therapy should be given.
810
booksmedicos.org
Figure 33-8. First debridement.
Figure 33-9. Second debridement.
Creative attempts at treating envenomation have even included the use of electrical current to
neutralize the venom.60 The use of current from the generator of an outboard motor and an automotive
battery has even been attempted. As innovative and entertaining as these efforts may be, there is no
improved outcome.61 The TASER® or conductive electrical weapon (stun gun) is a small hand-held
device that produces a very high voltage with a low current. It is used primarily by law enforcement
agencies to temporarily immobilize attackers. A group of physicians practicing in Ecuador reported a
series of 34 patients in letters to the editor of Lancet.62,63 They claimed an immediate improvement
with no mortality. The snakebites were most likely Bothrops atrox – the Fer-de-lance – a pit viper.
Unfortunately this reported treatment was not a controlled study. Several animal studies have since
proven electrical shock therapy to be ineffective in snakebite.64–66
Figure 33-10. Healed wound.
Special Consideration of Elapid Envenomation

As noted there are only three species of Elapids in the United States – the eastern coral snake, the Texas
coral snake, and the Arizona coral snake. The Eastern coral snake (Micrurus fulvius) is found in the
811
booksmedicos.org
southeastern United States up to Kentucky and North Carolina. The Texas coral snake (Micrurus tener) is
found in west of the Mississippi across Arkansas, through Louisiana into eastern Texas. The Eastern and
Texas coral snakes inhabit forests and shrubbery. The Arizona coral snake (Micruroides euryxanthus) is
found in the desert climates of the southwestern United States into Mexico. Coral snakes are more
active at night and hide under ground cover. Their behavior is elusive and they will generally try to flee
when disturbed. This family of snakes has a common feature – bilateral upper maxillary fangs that are
fixed into position and angled down and back. The fangs are grooved for instillation of the venom,
which is predominately a neurotoxin. The snakes are oviparous and have round pupils. Their head is
flat, with a smooth tapered tale and of course no rattles. They have characteristic coloration which is
mimicked by several other nonvenomous species (such as the king snake and the scarlet king snake) in a
biologic phenomenon referred to as Batesian mimicry.67 Although the North American coral snakes are
relatively small (less than 5 ft), some Elapids from other continents are very large; the Black mamba is
14 to 15 ft and the King Cobra can be up to 18 ft and weigh 25 lb. Although nonnative elapids bites
have a substantial risk for death, only one known death from a Coral snake has occurred in the United
States in the last 50 years (Bonita Springs Florida 2006).68
The bite of an Elapid is likely to produce much less tissue injury than the bite of a Crotalid.69 There
may be minimal pain. Envenomation may result in immediate neurotoxicity (within 15 to 30 minutes in
the case of the mamba or Australian brown snake) or be delayed a bit (2 to 5 hours with coral snakes).
There is no longer any antivenom available for North American coral snakes, but local zoos may be able
to provide antivenom for more exotic Elapidae. First aid should involve a compression bandage over the
wound. The poison generally spreads by lymphatics; therefore field compression to occlude lymph flow
at the site of envenomation can slow toxicity. Symptoms will be related to the neurotoxicity –
confusion, muscle spasm, nausea, vomiting, and dizziness. Blurred vision and difficulty with speech will
occur. Finally, respiratory paralysis of the diaphragm occurs with resultant death. Cardiovascular and
pulmonary support is essential to salvage patients that progress to this state.70 It should be noted that
venom of an Elapid is incredibly toxic. The Taipan and Belcher sea snakes have an LD50 in mice of as
little as 0.025 mg/kg of venom.71 Any suspected Elapid bite should be managed with the possibility of
rapid demise of the patient. If the bite is of a nonnative Elapid, antivenom (if it can be found) should be
administered promptly at the first sign of clinical demise. Death rates for untreated nonnative Elapids
varies from 20% to 30% for cobras to nearly 100% for the mambas.72 Antivenom for exotic snakebites
may be obtained from the local zoo or through their national organization – the Association of Zoos and
Aquariums (https://www.aza.org) or through the Poison Control Center at 1-800-222-1222.
Figure 33-11. Gila monster.
Venomous Lizards
There are two venomous lizards in North America: the Gila monster (Heloderma suspectum) and the
Mexican beaded lizard (Heloderma horridum). Both species have heavy bodies with large heads. The Gila
monster is found in the southwestern United States, ranging primarily in Arizona, extending into
southeastern California, southwestern Utah and New Mexico, and into northern Mexico. There are two
subspecies: the banded Gila monster (Fig. 33-11) that is found in the northern portion of the habitat and
the reticulated that exists in the southern portion of the range. It is the largest lizard in the United
States with a length of up to 56 cm. The Gila monster has generated substantial lore in the southwestern
United States, because of its characteristic appearance and apparent fetid breath. It lives below ground
and spends most of its life in or near its burrow. It is primarily seen in the spring, in the morning hours
during breeding season. It has powerful jaws and the bite is characterized by the tendency to hang on
with the animal difficult to dislodge. The lizard has eight labial glands on either side of the lower jaw.
The venom is secreted into the floor of the mouth where it is wicked into the victim via grooved lower
812
booksmedicos.org
canine teeth. Envenomation is limited and deaths are virtually unknown.73 The morbidity is usually
secondary to local effects from the toxins present: serotonin, phospholipase A, amine oxidases,
hyaluronidase, and proteases.74 These produce pain at the site that usually resolves in less than 24
hours. Hypotension, coagulopathy, and myocardial infarction have been reported.75 Nausea and
vomiting can occur. Malaise may persist for several days. The patient should be admitted for
observation and a low threshold for surgical exploration/debridement be given because the teeth often
shed into the bite and can serve as a nidus for infection.76
The Mexican beaded lizard is found from Sonora to Guatemala and is represented by four subspecies.
They are larger than the North American Gila monster; with a maximum size of up to 91 cm. They have
similar venom as the Gila monster and bites should be managed in a supportive fashion.
Insect Bites and Stings

4 Although the bite of a venomous snake will certainly draw more attention in the emergency
department, in fact insects kill many more Americans (greater than 100 deaths per year)77 than snakes
(about 5 deaths per year). Although most of these deaths are from anaphylactic reactions, some are
from overwhelming envenomation, particularly from those of the Africanized honey bee (the “killer”
bee). Most of the treatment recommendations below are from expert opinion; few randomized trials
have been performed.
Spiders
There are six genera of spiders in the United States that can produce painful bites, tissue necrosis, and
rarely death. These fall into three groups – the brown recluse (Fig. 33-12), the black widow (Fig. 33-
13), and the hobo spiders.78
Figure 33-12. Brown recluse.
Brown Recluse
There are 13 species of Loxosceles, of which 5 have been known to produce tissue necrosis. Probably the
species producing the most pathology is the brown recluse (Loxosceles reclusa). Envenomation by the
hobo spiders (Tegenaria agresis) produces a similar wound. The brown recluse is generally found in the
southern states.79 Hobo spiders are found in the Pacific Northwest.80 Bites from these two species
generally are initially painless and the victim may not recall being bit. Pain and erythema develop over
the next 6 hours. The venom can produce a painful, necrotic, slow healing wound over the next 48 to 72
hours.79,81 Two to 7 days after the bite an eschar develops with surrounding soft tissue induration. The
eschar can conceal an underlying tissue necrosis that can persist for months.79,82 These can require
extensive debridement leading to skin grafting and even amputation.
The venom is both hemolytic and cytotoxic. The enzyme that is thought to produce the
“desmonecrotic arachnidosis” is sphingomyelinase D. The venom also contains hyaluronidase, lipase,
arachidonic acid, and prostaglandins.83,84 Systemic symptoms occur in less than 10% of victims, more
commonly in children. Rarely hemolysis, hemodynamic instability, and death have occurred.85 Initial
treatment should include analgesia, wound care, and tetanus prophylaxis. Antibiotics should be reserved
for infection/cellulitis. Early debridement should be withheld. Consideration for oral dapsone therapy
should be given. Dapsone is thought to work as an inhibitor of polymorphonuclear leukocyte
chemotaxis. It has significant side effects and can produce hemolysis in G6PD-deficient patients. Its use
is somewhat controversial. It has been shown to reduce the size of the skin lesion and lessen the amount
of surgical debridement, but these are not prospective studies.86 A controlled study of dapsone,
813
booksmedicos.org
electroshock therapy and no treatment in guinea pigs showed some improvement with dapsone, but
none with the electrical therapy.87 Hyperbaric oxygen has been studied in rabbits and pigs and failed to
demonstrate significant improvement.88 A trial of hyperbaric oxygen, dapsone, and cyproheptadine in
rabbits failed to show any improvement.89 Systemic steroids and antihistamines likewise have not been
shown to help. Initial surgical excision of the lesion has no clear benefit.90 Delayed excision of the area
of necrosis with skin grafting can be necessary. Recurrent necrosis in the same site can return even
years later.
Figure 33-13. Black widow.
Black Widow Spiders

There are 31 species of the genus Lactrodectus, the Black Widow spider, of which 4 are found in North
America. These are marked by a prominent red hourglass figure on the ventral aspect of the thorax.
Although both the male and the female possess venom, only the bite of the female can penetrate human
skin. The female is four times the size of the male. The female of the species is known for eating the
male after mating, which may or may not occur. The bite may produce only minimal local symptoms,
with only a small area of redness, or a “target” appearance. The venom contains alpha-latrotoxin, which
is neurotoxic. This produces chest and abdominal pain, and the patient’s presentation may be confused
as an acute surgical abdomen.91 Marked cramping and abdominal rigidity may be present. Fasciculations
of facial muscles with ptosis and spasm may occur producing a particular facie. Hyperreflexia,
paresthesia, cutaneous hyperesthesia, and nausea may also occur. Symptoms may occur within an hour
and resolve over several days.92 The muscle spasm should initially be treated with benzodiazepines.
Antivenin is available, and should be considered in the very young or ill patient. The dose is one ampule
given in 50 mL of saline. The antivenom is equine and hypersensitivity testing should be done prior to
giving the antivenom.93,94 A 1-mL test dose of horse serum is included with the antivenom for topical
conjunctival testing. Calcium gluconate was often given in the past, but is no longer recommended.
Mortality is exceedingly rare.
Hymenoptera
More than 100,000 species of Hymenoptera exist. This includes bees, wasp, hornets, and fire ants. The
venom injected by these insects is at least as toxic as that of the rattlesnake, but the volume is much
less. The venom is primarily a hemolysin and neurotoxin. Anaphylaxis is a common clinical problem
produced by the envenomation. Approximately 0.4% of the human population is at risk of anaphylaxis
from Hymenoptera stings.95 The anaphylaxis is modulated by preformed IgE that activates mast cells
leading to massive histamine release. This leads to laryngeal edema, pulmonary edema, and
cardiovascular collapse. This must be treated aggressively with intravenous diphenhydramine and
epinephrine as well as with management of the airway and supplemental oxygen. Most stings are mild,
however, resulting in only dermal reactions – pain, erythema, and edema. The stinger should be
removed and ice applied to the site. Application of meat tenderizer might be of some benefit. Patients
with a history of insect sting anaphylaxis should be given a prescription for an epinephrine pen and be
considered for venom immunotherapy. This is almost 100% successful in desensitization, but can take
up to 3 years.
Killer Bees
Africanized honeybees (killer bees) are hybrids of the African honeybee and the European honeybee, the
one commonly found in the United States. The Africanized honeybee was originally brought from
Tanzania to Brazil in 1957, with the hope of better honey production. The bees have spread up through
Central America, Mexico, and into Texas. They are continuing to advance at about 100 miles per
814
booksmedicos.org
year.96,97 Africanized honeybees are indistinguishable from the European honeybee, so DNA (usually
mitochondrial DNA) analysis is necessary to differentiate the subspecies.98 They are termed “killer bees”
because of increased aggressive traits. They show greater defensiveness of the hive, they have a bigger
“alarm” area, and they deploy in greater numbers and will pursue perceived threats over much greater
distances. Although their venom is of the same potency as the European bees, the number of stings
received will usually be much greater. With more than 50 stings, nausea, vomiting, shock, hemolysis,
rhabdomyolysis, coagulopathy, coma, and death may occur. Usually most patients will just complain of
pain, but delayed toxic reactions – 6 to 48 hours – may also occur. It is recommended that any patient
presenting with more than 50 stings be hospitalized and observed.99 Laboratory evaluation with
coagulation studies, platelet count, and liver function studies should be obtained.
Fire Ants
Fire ants are wingless members of the Hymenoptera order. They were brought to the United States from
South America around 1918.100 The red imported fire ants appear to have come over on a ship through
Mobile, Alabama. Shipments of infested nursery stock and other agricultural products, natural mating
flights, and floating on flood waters have contributed to their spread. Two species of imported fire ant
now infect large areas of the Gulf Coast states.101 Fire ants aggressively attack any perceived danger to
themselves or their mound.102 Each ant can produce multiple stings. The venom is a dialkylpiperidine
that induces the release of histamine from increased mast cell reactivity. The fire ant sting produces a
sterile pustule, which does not usually require antibiotic therapy. Infectious complications can occur at
the site that may be more common in diabetic or immunocompromised individuals. Fire ant venom
shares at least four antigenic proteins with bees and wasps. More than 80 fatalities have been reported
from fire ant anaphylaxis, notably in Australia and southern United States. The treatment is the same as
with bee/wasp sting anaphylaxis.77
Scorpions
More than 1,500 species of scorpions can be found worldwide. Only about 20 or 25 are considered
dangerous. They are in the class Arachnidia; close relatives of ticks, mites, and spiders. Their
characteristic shape makes them readily identifiable. Scorpions prefer dry habitats but may be found
throughout the southern United States. Scorpions are nocturnal, hiding during the day and becoming
active at night. This behavior helps them manage their temperature and water balance, important for
survival in their dry habitats. The scorpion’s body has a 5-segmented tail that can be arched over the
back and becomes more slender toward the end. On the end of the tail is the bulb-like poison
gland/stinger. Between the last pair of legs are comb like structures called the pectines – sensory organs
used to sense surface textures and detect prey. The venom toxicity varies greatly depending on the
species, season, and age of the scorpion. Stings from dangerous species may cause paralysis, severe
convulsions, cardiac irregularities, breathing difficulties, and death. In the United States most scorpion
bites are not life-threatening and only result in local effects. In parts of Brazil, Mexico, North Africa, and
Israel, however, the sting may be lethal. In Brazil the mortality rate is as high as 12% for adults and
60% in children.103 In India, of 34 children admitted to a hospital for a scorpion sting, 14 had
hypertension, 9 had acute pulmonary edema, 5 had a myocardial infarction, and 4 died.104 Antivenins
are typically available in area where dangerous species are found, either from a local zoo or state or
university agricultural extension departments. One species in the North America is particularly
venomous – the Arizona bark scorpion (Centuroides sculpturatus) (Fig. 33-14). The sting produces a
dramatic neuromotor syndrome and respiratory insufficiency. It has produced several deaths in the
United States and hundreds in Mexico. An antivenin is available in Mexico, but not in the United States.
815
booksmedicos.org
Figure 33-14. Arizona bark scorpion.
Centipedes and Millipedes

There are approximately 3,000 species of centipedes in the world. They are arthropods with a single set
of legs on each body segment. The front pair of legs are modified to deliver venom. One of the largest
members of this class is the giant desert centipede (Scolopendra gigantea). It can grow to 26 cm in
length. Significant morbidity, including EKG changes and rhabdomyolysis, can occur from centipede
bites, but death is exceedingly rare. The most common symptoms include erythema, swelling, and
pain.105 Treatment is largely symptomatic, with reports of both ice and heat improving symptoms.106
There are approximately 7,000 species of millipedes. They have 2 pairs of legs on each body segment.
Millipedes do not have a mechanism to inject a venom, but instead secrete an irritating liquid from
pores covering their body.107 This can produce a superficial burn that is self-limiting. Only symptomatic
therapy is indicated.
Asp Caterpillars
The asp is a venomous caterpillar found in the southern United States. It is the larval stage of the
Southern Flannel Moth (Megalopyge opercularis) (Fig. 33-15). It has the appearance of soft furry ball,
encouraging the unwary to touch it. The long hairs of the asp conceal shorter spikes that discharge
venom. Typically an intense throbbing and pain occurs almost immediately. Erythematous spots occur
at the site of envenomation. Symptoms include headache, nausea, vomiting, and the development of
lymphadenopathy. Chest pain occurs occasionally. Rarely shock and respiratory distress have been
reported. Death is exceedingly rare and is almost certainly because of a hypersensitivity reaction.108–110
A similar caterpillar found in South America – Lonomia – has a death rate of 1.7%. The initial treatment
should be to apply adhesive tape and pull it off to remove the spines. Ice packs and antihistamines may
provide symptomatic relief. Intravenous calcium and steroids have been suggested as a treatment
regimen.111
816
booksmedicos.org
Figure 33-15. Asp caterpillar.
Hypothermia
5 Humans will always attempt to maintain a constant body temperature despite changes in
environmental temperature. Normal body temperature is 37°C sublingually, 38°C in the rectum, 32°C at
the skin, and 38.5°C deep in the liver, with normal daily (circadian) variation of about 0.5°C to 1°C; we
tolerate poorly even minor deviations from these norms.112 Although humans have a remarkable
capacity to dissipate heat by evaporating body water, our tropical evolutionary heritage has provided us
with far less ability to cope with cold conditions. As a result, hypothermia can occur in a variety of
clinical settings and from a number of causes (Table 33-6).
Table 33-6 Clinical Definitions of Hypothermia and Examples of Settings in

Which They Occur
Figure 33-16. Number of hypothermia-related deaths by year in the United States, 1979–2002. (After Hypothermia-related deaths
—United States, 2003–2004. MMWR Morb Mortal Wkly Rep 2005;54:173–175.)
Hypothermia is considered to be present in humans if the core temperature drops below 35°C (95°F).
Hypothermia is usually classified by temperature zones: mild (32°C to 35°C); moderate (28°C to 32°C);
or severe (<28°C). Primary accidental hypothermia is defined as a decrease in core temperature that
occurs as a result of overwhelming environmental cold stress, such as recreational misadventures that
lead to cold-water immersion or prolonged environmental exposure. Secondary accidental hypothermia
occurs in patients with abnormal heat production or thermoregulation, who become cold despite only
mild cold stress. The most significant risk factors are advanced age, mental impairment, and substance
abuse (alcohol, primarily), although hypothyroidism, hypoadrenalism, trauma, and hypoglycemia are
other risk factors.113,114 Chronic hypothermia develops in patients with impaired heat generation (i.e.,
the elderly and infirm) who live in unheated apartments, are under continual cold stress, and after a
time are found to have a chronically low temperature as if they have autoregulated to a new, lower-set
core temperature.
A multicenter review of 428 cases of accidental hypothermia reported an overall mortality rate of
17%,115 although other reports document mortality rates as high as 80%, primarily a result of infection
817
booksmedicos.org
and underlying illness. Treatment of accidental hypothermia remains highly variable. A report from an
academic medical center in Amsterdam highlights this, as they reported that over an 8-year period
(2000 to 2008) a total of 84 patients with accidental hypothermia were treated with 14 different
rewarming techniques, with an overall mortality of 28.6%.116 It is estimated that each year about 1,500
patients in the United States have hypothermia listed on their death certificate, although the exact
incidence of primary and secondary hypothermia and the associated morbidity and mortality remain
uncharacterized.114 From 1979 to 2002, the CDC reported that a total of 16,555 deaths in the United
States, an average of 689 per year (range 417 to 1,021), were attributed to exposure to excessive
natural cold (Fig. 33-16).113 From 1999 to 2002, a total of 4,607 death certificates in the United States
had hypothermia-related diagnoses listed as the underlying cause of death for an annual incidence of 4
per 1,000,000 population.113 Most reported hypothermia-related deaths (67%) occurred in males (Fig.
33-17), but the overall death rate is the same for both males and females. Notable is that deaths occur in
all states, even those that generally are considered to have warm climates. Hypothermia-related deaths
are reported by states with characteristically milder climates that experience rapid temperature changes
and by western states that have high elevations and experience considerable changes from daytime to
nighttime temperatures. States with the greatest overall death rates caused by hypothermia are Alaska,
New Mexico, Wyoming, and Montana (Fig. 33-18).
Figure 33-17. Number and rate (per 100,000 population) of hypothermia-related deaths, by age group and gender, in the United
States, 1979–2002. (After Hypothermia-related deaths United States, 2003–2004. MMWR Morb Mortal Wkly Rep 2005;54:173–175.)
6 The physiologic response to hypothermia is one of transitional changes, with few exact
temperature-dependent responses (Fig. 33-19). Broadly speaking, the transition from a “safe zone” of
hypothermia (in which physiologic adaptations to heat loss are working) to a “danger zone” of
hypothermia (in which shivering is abolished, metabolism decreases, and heat loss is passively accepted)
occurs between 33°C and 30°C. The initial effects of hypothermia mimic intense sympathetic
stimulation, with tremulousness, profound vasoconstriction, tremendous increases in oxygen
consumption, and acceleration of heart rate and minute ventilation.77 When core body temperature
cannot be measured, a four-stage hypothermia classification based on vital signs and level of
consciousness has been developed by Swiss clinicians.114,117 It should be emphasized that the purpose of
the Swiss clinical grading is to direct treatment in the absence of the ability to actually measure core
body temperature, so it should have its primary purpose in the austere or field care environment.
The cardiovascular response to hypothermia begins with tachycardia, but followed by progressive
bradycardia, which starts at approximately 34°C and results in a 50% heart rate decrease at 28°C.
Cardiac output initially increases with the tachycardia, and then progressively decreases, with a
concomitant fall in blood pressure. The conduction system is particularly sensitive to hypothermia: the
PR interval, then the QRS complex, and finally the QT interval become progressively prolonged.118 As
temperature falls below 30°C, atrial fibrillation, bradycardia, and ventricular dysrhythmia become
common, with asystole occurring at temperatures below 25°C. Perhaps the most challenging
management of an accidental hypothermia patient is the one with temperatures between 28°C and 32°C
(Swiss stage 2), as these patients are prone to develop poorly perfusing arrhythmias, yet they often can
be rewarmed with active external and environmental rewarming if such arrhythmias do not occur.
Hence gentle manipulation of such patients is required. Because palpating pulses or measuring blood
pressure in cold, stiff, hypothermic patients is difficult, the presence of an organized cardiac electrical
rhythm should be taken as a sign of life that contraindicates cardiopulmonary resuscitation chest
compressions, despite the absence of a palpable pulse. Such a rhythm may provide diminished but
sufficient circulation in patients with severely reduced metabolism, and it is likely that vigorous chest
818
booksmedicos.org
compressions will convert this perfusing rhythm to fibrillation. Rewarming should occur with close
monitoring of rhythm, pulse, and blood pressure. If cardiac arrest occurs (Swiss stage 3 or 4),
extracorporeal cardiopulmonary bypass (CPB) or extracorporeal membrane oxygenation (ECMO) for
perfusion and rewarming is indicated.114,119,120 Among patients with what is likely Swiss stage 4, those
treated with ECMO or CPB have a reported survival rate without neurologic impairment of 47% to
63%, compared to 37% for similar patients treated without active core rewarming and oxygenation
techniques.114 One report noted excellent long-term functional outcomes in 15 of 32 young patients
successfully rewarmed with CPB.119 All patients were intubated and ventilated and had received
ongoing cardiac massage during transportation, and all 15 survivors had documented circulatory arrest
(ventricular fibrillation or asystole) and fixed, dilated pupils. The mean interval from discovery of the
patient to rewarming with cardiopulmonary bypass was 141 ± 50 minutes; the mean temperature was
21.8°C ± 2.5°C. A report from Finland documents a 61% (14 of 23) survival to hospital discharge for
adults undergoing cardiopulmonary bypass after a mean of 70 minutes of cardiopulmonary resuscitation
following hypothermic arrest primarily from cold-water immersion or exposure.121
Figure 33-18. Average annual rate per 100,000 of hypothermia-related deaths by state, 1999–2002.
819
booksmedicos.org
Figure 33-19. Zones of hypothermia and corresponding physiologic responses. Wide biologic variability accounts for physiologic
changes rarely occurring at the exact temperatures noted. (After Jurkovich GJ. Hypothermia in the trauma patient. Adv Trauma
1989;4:111–140.)
7 Respiratory drive is increased during the early stages of hypothermia, but below 33°C progressive
respiratory depression occurs, resulting in a decrease in minute ventilation. This decrease is not usually
a significant problem until temperatures below 29°C is reached. Occasionally, hypothermia results in the
production of a large amount of mucus (cold bronchorrhea).122 This development predisposes to
atelectasis and aspiration as ciliary action and the cough reflex are also depressed. Noncardiogenic
pulmonary edema is also occasionally reported, especially in elderly patients and especially after
prolonged periods of hypothermia.123
The effect of core hypothermia on arterial blood gas interpretation warrants a comment. Arterial
blood gas samples are typically warmed to 37°C before measurement. A nomogram of Severinghaus
mathematical corrections is then used to estimate the blood gas values at the patient’s actual body
temperature. With each 1°C temperature reduction, the PCO2 decreases by 4.4% and the PO2 decreases by
7.2%. As an example, lets say a blood gas from a hypothermic 32°C patient is measured at 37°C showing
a PCO2 of 40 mm Hg and a PO2 of 70 mm Hg; using the above correction techniques results in a reported
PCO2 of 32 mm Hg and a PO2 of 48 mm Hg. The decrease in partial pressure is related to the increased
solubility of gases in cold fluids and is not a result of a change in carbon dioxide content, oxygen
content, or serum bicarbonate level. Clinicians often assume that the normal PCO2 and PO2 at 37°C are
the values that should be attained at all temperatures. However, if normothermic endpoints for PCO2
were attained in a hypothermic patient, they would have increased total-body CO2 stores, which would
manifest by a rising PCO2 and a falling pH during rewarming. Likewise, attempts at increasing a PO2 that
reflects normal oxygen content at a lower temperature are also inappropriate. A far simpler strategy is
to assess the blood gases at 37°C without temperature correction. Values that are normal and acceptable
when reported at 37°C (without temperature correction) correspond to normal values and contents
when “corrected” for hypothermic temperatures.
Temperature correction of blood gases for pH management is also unnecessary.124 A pH of 7.40 at
37°C would be temperature corrected to 7.47 in a 32°C patient. At 37°C, the acid–base balance of water
820
booksmedicos.org
is neutral (pH is equal to pOH) when the pH is 6.8, and the body functions optimally when its pH is
offset 0.6 pH units above the neutral point of water and has a relatively alkaline pH of 7.40. The pH of
water rises with cooling, causing the pH of blood to rise by 0.015 pH units/°C, without a change in
bicarbonate content.125 Treating a patient with a temperature of 30°C with a pH of 7.40 instead of 7.47
fails to maintain the normal pH offset above the neutral point of water (relative alkalinity) and results
in an acidotic cellular and chemical environment that has a multiplicity of effects on enzyme systems.
Because blood with a pH of 7.40 assessed at 37°C is reported as having a pH of 7.47 when temperature
corrected to 32°C, the simplest strategy when confronted with a patient with a temperature of 32°C is to
assess the blood gas at 37°C only and to use the 37°C uncorrected pH value for management.126–128
The neurologic response to hypothermia is heralded by progressive loss of lucidity and deep tendon
reflexes and, eventually, by flaccid muscular tone. Patients are often amnestic below 32°C, and between
31°C and 27°C they usually lose consciousness. Pupillary dilatation and loss of cerebral autoregulation
occur at temperatures below 26°C, and electroencephalography becomes silent at 19°C to 20°C.129 These
findings, combined with an unobtainable pulse and apparent rigor mortis, may cause the patient to
appear dead. It is important to remember that patients have been revived from core temperatures as
low as 14°C130 and hence the saying “No one is dead until warm and dead.”131 An exception to this
admonition probably includes the patient who has sustained an anoxic event while still normothermic
and has a serum potassium level greater than 10 mmol/L, although the Bernese criteria for trauma and
hypothermia have picked a level of 12 mmol/L as being nonsalvageable.114,117,121,132 The role of
hypothermia in brain death determination remains controversial. Brain death is a medically and legally
accepted mechanism of death in the United States and worldwide. Yet significant variability in
individual institutional policies regarding the determination of brain death occurs. In 2010 the American
Academy of Neurology (AAN) issued guidelines on the determination of brain death.133 A recent study
examined how well 52 organ procurement organizations and 508 unique hospitals have adopted these
guidelines, determining that among other variables in policy, only 181 of 228 policies (80%) required
the absence of hypothermia (temperature >36°C) in brain death determination.134
In classic surgical physiology research, Moyer and Debakey showed that with hypothermia, reduction
in blood pressure and cardiac output decreases glomerular filtration rate, but urinary output is
maintained because of impairment in renal tubular Na+ reabsorption (cold diuresis).135,136
Vasoconstriction also results in an initial increase in central blood volume that prompts a diuresis. Ileus,
bowel wall edema, depressed hepatic drug detoxification, punctate gastric erosions (Wischnevsky
ulcers), hyperamylasemia, and, rarely, hemorrhagic pancreatitis are hallmarks of the intestinal response
to hypothermia. Hypothermia inhibits insulin release and insulin uptake at receptor sites, making
hyperglycemia a relatively common finding, especially at temperatures below 30°C.137 Exogenous
insulin administration is unwarranted because it may result in rebound hypoglycemia during
rewarming. Serum electrolyte changes are unpredictable, but serum potassium is often slightly
increased in hypothermic patients because of renal tubular dysfunction, acidosis, and the breakdown of
liver glycogen.138 Hypothermia also appears to affect endothelial cell adhesion molecule function, which
may partially explain increased infectious complications in hypothermic patients.139 One study
demonstrated a drop of 1.9°C core hypothermia triples the incidence of surgical wound infection
following colon resection and increases the duration of hospitalization by 20%, leading to the now
standard perioperative checklist monitoring of body temperature during surgery.140
Body temperature has a significant effect on oxygen uptake. Oxygen consumption (VO2) initially
increases dramatically with any fall in body temperature. When involuntary muscle contractions in the
form of shivering occur, oxygen consumption increases by as much as three- to fivefold.141,142 This
process is inefficient because shivering produces heat near the surface of the body, causing most of the
heat to be lost to the environment, with less than 45% being retained by the patient. As core
temperatures fall to between 33°C and 30°C, shivering is abolished, and the patient will rapidly sink to
ambient temperature.
The thermoregulatory drive is such a powerful one that it takes precedence over many other
homeostatic functions. The resultant increase in oxygen utilization may result in anaerobic metabolism,
acidosis, and significant cardiopulmonary stress. One study noted a 35% increase in oxygen
consumption and a 65% increase in CO2 production in postoperative patients after resolution of
anesthesia, when the thermostatic drive reappeared.143,144 In another study, a core temperature
decrease of as little as 0.3°C in postoperative patients was associated with a 7% increase in VO2, and
temperature reductions between 0.3°C and 1.2°C were associated with a 92% increase in VO2, with
proportional increases in minute ventilation. Shivering can be iatrogenically abolished with low doses of
821
booksmedicos.org
meperidine (Demerol®) and possibly ondansetron (Zofran®, Zuplenz®). Further details of the specific
organ system responses to hypothermia are beyond the scope of this chapter, but the interested reader
is referred to several excellent indepth monographs.112,145,146
Hypothermia in Trauma Patients

Mild hypothermia is very common after traumatic injury. The thermoneutral environment for humans is
a humid and warm 28°C (82.5°F) (think tropical islands). When ambient temperature falls below the
thermoneutral temperature (i.e., the temperature at which no thermogenesis or heat dissipation is
necessary), an increase in heat production is required to maintain a normal body temperature.
Combustion is the only source of endogenous heat production, and this process requires an increase in
oxygen utilization. After shock or injury, however, oxygen supplies are often limited and further heat
loss occurs owing to cold emergency department and operating room environments, cold fluid
resuscitation, and open thoracic and abdominal cavities. Anesthetic and neuromuscular blocking agents
that prevent the heat-producing shivering response further aggravate this. Thus, the occurrence of
hypothermia in surgical or critically injured patients is most often a form of secondary accidental
hypothermia.
One study found that 57% of trauma patients admitted to a level 1 trauma center were hypothermic
at some time and that temperature loss was most significant in the emergency department.147 Another
study reported that the average initial temperature for 94 intubated major trauma victims was 35°C,
with no seasonal variation.148 Of patients in this study, 66% were hypothermic on admission; 43% were
mildly hypothermic (34°C to 36°C), and 23% had temperatures below 34°C. Likewise, Jurkovich and
Luterman reported that 42% of 71 adult trauma victims with an injury severity score (ISS) of 25 or
higher had core temperatures below 34°C and in 13% the core temperature fell below 32°C.149
Importantly, there were no survivors when core body temperature was below 32°C. Inaba reported that
of 118 patients requiring emergent surgery following traumatic injury, hypothermia (<35°C) was
present in nearly 30% of patients upon presentation to the operating room, and that a continued
decrease in core temperature was associated with increased mortality. This mortality rose to 50% if
temperature fell below 32°C.150 Both mortality rate and the incidence of hypothermia increase with
higher ISS, massive fluid resuscitation, and the presence of shock, but controlling for these variables still
demonstrates that the mortality rate of the hypothermic trauma patient is greater than that of the warm
trauma patient.151 Although the mortality rate for moderate (28°C to 32°C) degrees of primary
accidental hypothermia is approximately 20%,114,115 moderate levels of hypothermia in trauma and
critically ill patients are associated with a much higher mortality rate. Rutherford et al.152 reported that
9.4% of surgical intensive care unit patients had a core body temperature less than 35°C; the mortality
rate of the hypothermic trauma patients was 53%. In fact, compared with other patient populations, the
mortality rate associated with hypothermia in the trauma victim is so high that the definition of mild,
moderate, and severe hypothermia in the trauma patient warrants special classification (Table 33-7).112
CLASSIFICATION
Table 33-7 Zones of Severity for Hypothermia
Hypothermia appears to occur primarily in victims of relatively severe trauma. Little and Stoner,153
while reporting on a heterogeneous group of 82 trauma patients, observed that hypothermia occurred
only in those patients with an ISS greater than 12. Skin temperature fell from 32.0°C to 31.7°C, whereas
core temperature fell from 37.3°C to 36.5°C. Hypothermia did not occur in less severely injured
patients, and shivering, which should be expected, was noted in only one of the hypothermic patients.
Mild degrees of injury have, in fact, been associated with small elevations in core body temperature,
particularly when the shivering response mechanism has not been abated.112,154 It is notable that over
the past two decades, considerable attention has been given to preventing hypothermia in trauma
patients. Prior to the 1993 version of Advanced Trauma Life Support, the student and instructor course
books did not include the prevention of hypothermia in the primary survey. The recognition that
hypothermia can be prevented has resulted in substantial changes in the management of the acute
822
booksmedicos.org
injured patient. As a result, the “lethal triad” of coagulopathy, acidosis, and hypothermia is much less
frequently observed.155
The detrimental effect of hypothermia in the human trauma victim is contrasted by a large body of
experimental evidence in animals suggesting that hypothermia has a protective role in shock. This
extensive body of literature is reviewed elsewhere,112 but in general, animals subjected to combined
hypothermia and shock (hemorrhage, burn, and blunt trauma) usually survive longer than similarly
injured but actively warmed animals. Blalock and Mason (1941) were among the first in modern times
to recognize the ability of hypothermia to prolong survival times after shock,156 but they emphasized
that the overall survival rate was unchanged, an observation reaffirmed in 2003.157 However, increases
in both survival times and survival rates have been shown in a number of animal models of induced
hypothermia after hemorrhagic shock.158,159 The protective effects of hypothermia in preventing
ischemia–reperfusion injury have been described in a number of models, including muscle, intestine,
and rabbit ear.160–162 These observations have prompted some to suggest that there is a role for
iatrogenic-induced hypothermia in severe trauma patients, with the goal being a reduction of oxygen
consumption in the setting of limited oxygen delivery (hypovolemic shock) to allow surgeons time to
repair injured structures and then rewarm and resuscitate the patients.163–165
Hypothermia has also utilized in attempts to protect the traumatically injured brain. The use of
therapeutic hypothermia in a patient with traumatic brain injury was first reported in 1943166 and
sporadically over the ensuing 2 decades120 in 2001, Clifton et al. reported a randomized, multicenter,
controlled trial of core body hypothermia in trauma patients with severe closed head injury.167 Select
trauma patients (GCS 3 to 7) were intentionally cooled within 6 hours of injury to 32°C to 33°C for 48
hours after injury and then rewarmed. The outcome was poor (defined as severe disability, a vegetative
state, or death) in 57% of the patients in both groups. Mortality was 28% in the hypothermia group and
27% in the normothermia group (p = 0.79). The patients in the hypothermia group had more hospital
days with complications than the patients in the normothermia group. This study has led most
authorities to conclude that treatment with total-body hypothermia is not effective in improving
outcomes in patients with severe brain injury. Other authors have also reported higher rates of
pneumonia and diabetes insipidus in patients with severe head injury and induced hypothermia.168
Evidence further supporting the harmful effect of hypothermia in the trauma patient is provided by a
prospective, randomized trial of rapid rewarming versus conventional rewarming of 57 multiple-trauma
patients.168 In this study, trauma patients who were rapidly rewarmed with continuous arteriovenous
rewarming (CAVR) from less than 34.5°C to greater than 36°C required less resuscitation fluid volume
and had a lower early mortality rate than those rewarmed more slowly. Failure to rewarm in either
group was uniformly fatal. The survival rate at 3 days after injury was 82% in the rapid rewarm group
versus 62% in conventionally managed patients. Approximately 50% of the patients in both groups had
a severe head injury, defined as a head abbreviated injury severity score of 3 or greater. In this well-
controlled study, maintenance of hypothermia not only failed to confer an advantage but also was
detrimental to early survival.
The use of hypothermia in the treatment of acute cardiac arrest is beyond the scope of this chapter. It
is discussed in Chapter 20. However, the principle of this increasingly common technique is the same as
the principle of organ preservation for transplantation – cooling of the body decreased oxygen
consumption and may allow for a longer period of relative anoxia with good recovery.169–171 The
advantage in these patients, or rather the difference between the acute care arrhythmia patient and the
patient with trauma is likely the total-body tissue injury and its effect in coagulation and the
inflammatory response. But the attraction for the concept of “suspended animation” with induced
hypothermia in trauma remains seductive.
The role of hypothermia in the injured patient remains complex. It is apparent that the physiologic
consequence of severe trauma is a drop in core body temperature, either as a protective response to
shock or the result of diminished heat production caused by failing metabolism. The frequent presence
of lactic acid accumulation in cold, seriously injured patients supports the latter hypothesis. Clinical
studies indicate that even mild hypothermia in the trauma patient is predictive of a poor outcome, given
our current capabilities of surgical repair of injured organs. Hypothermia does diminish metabolic
demands and oxygen consumption, but the price appears to be malfunction of enzymes and physiologic
systems necessary to recover from injury.
The systems most affected by hypothermia in victims of injury are those involved in clotting. Focused
attention on the coagulation mechanisms in trauma patients over the past decade has exposed the lack
of a comprehensive understanding of the complex relationship between injury, inflammation, and
823
booksmedicos.org
coagulopathy.172 Temperature is yet another variable in this complexity. Reports of coagulation
abnormalities in patients with apparently normal clotting factor levels surfaced shortly after the
introduction of hypothermic cardioplegia for cardiac surgery.173,174 Although hemodilution with volume
expanders deficient in clotting factors and platelets is the usual cause of nonsurgical bleeding, cold
platelets are known to undergo morphologic changes that affect adherence, including loss of shape,
cytoplasmic swelling, and dissolution of cytoplasmic microtubules necessary for normal motility.175
Platelet activation is also associated with activation of cell membrane phospholipases that hydrolyze
phospholipids to arachidonic acid, a precursor to prostaglandin endoperoxides and thromboxane A2, a
potent vasoconstrictor necessary for normal platelet aggregation176 Valeri et al.177 induced systemic
hypothermia to 32°C in baboons, but kept one forearm warm using heating lamps and a warming
blanket. Simultaneous bleeding time measurements in the warm and cold arm were 2.4 and 5.8 minutes,
respectively. This effect, which was reversible with rewarming, appeared to be mediated by cold-
induced slowing of the enzymatic reaction rate of thromboxane synthetase, which resulted in decreased
production of thromboxane A2. Bleeding observed at mildly reduced temperatures (33°C to 37°C) results
primarily from a platelet adhesion defect and not reduced enzyme activity or platelet activation;
however, at temperatures below 33°C, both reduced platelet function and enzyme activity likely
contribute to the coagulopathy,178 perhaps helping to explain why 32°C is such a critical temperature in
the coagulopathic injured patient.
As with blood gases, clinical tests of coagulation are temperature standardized to 37°C. Fibrometers
contain a thermal block that heats the plasma and reagents to 37°C before initiating the assay. Thus,
tests of coagulation reflect clotting factor deficiencies but are corrected for any potential effect of
hypothermia on clotting factor function. A detailed study of the kinetic effects of hypothermia on
clotting factor function has been undertaken by Reed et al.179 He performed clotting tests (PT, PTT, and
thrombin time) on reference human plasma–containing normal clotting factor levels at temperatures
ranging from 25°C to 37°C. The results showed a significant slowing of all coagulation tests at
temperatures below 35°C that was proportional to the degree of hypothermia. The prolongation of clot
formation occurred at clinically relevant levels of hypothermia and was equivalent to that seen in
normothermic patients with significant clotting factor depletion. For example, assays conducted at 35°C,
33°C, and 31°C prolonged the PTT to the same extent as would occur in a euthermic patient with
reductions in factor IX levels to 66%, 32%, and 7% of normal, respectively.
Clotting factor supplementation is not the answer to a hypothermia-induced coagulopathy; rewarming
is. However, in many seriously injured patients, clotting factor depletion exists in conjunction with
hypothermia. A potentiating effect of hypothermia on coagulation dysfunction occurs in plasma of
patients with deficient clotting factor levels, although there does not appear to be synergy between the
two conditions.180 Hypothermic, coagulopathic trauma patients still benefit from coagulation profile
testing. If prolongation of PT and PTT is evident in plasma warmed to 37°C, clotting factor replacement
is indicated. If PT and PTT are near normal, rewarming alone reverses the clinically apparent
coagulopathy.
Treatment
8 Rewarming techniques are usually classified as passive external rewarming, active external
rewarming, or active core rewarming.181 Passive external rewarming simply implies allowing
spontaneous rewarming to occur with the patient removed from a hypothermic environment and is
usually used only for the mildly hypothermic patient. Active external rewarming techniques include
surrounding the patient with warm blankets or heating pads, infrared heating lights, and immersion in
warm water. Active core rewarming includes heated intravenous fluids, as well as heated peritoneal or
thoracic lavage; heated gastric, bladder, or colonic lavage; heated and water-saturated inhaled air; and
extracorporeal circulatory rewarming. Blood rewarming is currently limited to a maximum temperature
of 42°C by the American Association of Blood Banks, but rewarming to 49°C with inline microwave
blood rewarmers has been reported as safe, as has intravenous fluid rewarming to 65°C.182,183
The advantages and disadvantages of each technique are regularly debated, particularly regarding the
role of external versus core rewarming. It is clear, however, that the rate of heat transfer to the
hypothermic patient is greatest using active core rewarming, particularly extracorporeal circulation
rewarming. This may be a critical factor in surgical patients for whom rapid restoration of clotting and
cardiac function is necessary.
The technique of rewarming the hypothermic victim by extracorporeal circulation has been described
by numerous authors, initially based on small personal experiences and using cardiopulmonary bypass
824
booksmedicos.org
techniques of open-heart surgery.119–121 This technique has appeal in cases of primary accidental
hypothermia, in which maintenance of circulation, correction of hypoxia, and replenishment of
intravascular volume may play a role as large as correcting the temperature change itself. The need for
systemic anticoagulation has, however, generally limited the usefulness of full cardiopulmonary bypass
rewarming in the trauma patient. More recently the use of ECMO for core hypothermia rewarming has
been the subject of numerous publications as more centers become more experienced with this tool.184
A simplified technique of extracorporeal active core rewarming is CAVR.185 This technique makes use
of the patient’s own blood pressure to drive an extracorporeal circuit through an efficient, but small
countercurrent heat-exchange device. Systemic anticoagulation is not necessary if the tubing is heparin-
bonded and trauma patients are relatively anticoagulated. The relative ease of use made this device
widely applicable in rewarming severely hypothermic patients with an intact circulation and, in a
prospective, randomized trial of rewarming trauma patients, demonstrated its efficacy by improved
survival.168 Unfortunately, the product used in that referenced study by Gentilello et al. is no longer in
commercial production.
Direct intracirculation rewarming can be accomplished with commercially available devises that
employ either an intra–vena caval countercurrent heat-exchange devise (InnerCool RTx®, Phillips
Healthcare, Best, The Netherlands) or balloon catheters with large surface areas (Alsius/Zoll Medical
Irvine, CA). The ownership and design of these devises change rapidly, as the clinical need is limited.
Although initially developed to cool patients for neurosurgical procedures, they are now used primarily
for inducing and maintaining hypothermia following sudden cardiac arrest; rewarming can be
accomplished by simply changing the temperature of the closed-loop circulating fluid. Requirements are
the commercial bedside console and the specialized endovascular temperature control catheter, inserted
via the femoral vein to the vena cava, usually with a larger size introducer (10 to 12 Fr). Data on
rewarming cold patients suggest that rewarming can occur up to 3°C per hour compared to 6°C to 9°C
per hour with ECMO or CPB.114,186
The use of body cavity lavage with warm solutions is a simple, less invasive method of accomplishing
active core rewarming; however, rewarming rates with body cavity lavage vary greatly based on initial
core temperature, dialysate temperature, infusion rate, and dwell time. Several studies support the
notion that active core rewarming by peritoneal lavage is preferable to active external rewarming.187
Moss examined three techniques of rewarming hypothermic and cardiac-arrested dogs, concluding that
both peritoneal lavage (55°C dialysate) and partial extracorporeal circulation were faster than active
external rewarming with a heating blanket.188 A frequently stated disadvantage of external rewarming
is that the peripheral tissues are rewarmed in advance of the still cool “core,” resulting in peripheral
vasodilation. In the presence of inadequate volume resuscitation, this rewarming method may result in
vascular collapse (“rewarming shock”) and a subsequent fall in central temperature (“afterdrop”) as the
cold peripheral blood returns to the core. Whether this process is the mechanism of the core afterdrop is
debatable because a core afterdrop has been noted to occur in animal models even during complete
circulatory arrest. Volume contraction caused by vasoconstriction, cold diuresis, and cellular swelling
coupled with inadequate fluid resuscitation may be a more appropriate explanation for circulatory
collapse during rewarming.
The thermodynamic principles of heat transfer to the hypothermic patient are reviewed in greater
detail elsewhere, but a sense of rewarming rates and quantity of heat transferred by various techniques
is instructional.181,189 Ventilating a patient with a core temperature of 32°C with water-saturated air at
41°C results in a maximum heat transfer rate of 9 kcal/hr. For comparison, basal metabolic heat
generation produces approximately 70 kcal/hr, and shivering produces up to 250 kcal/hr. Given the
specific heat of the body (0.083 kcal/kg/°C), 58 kcal is required to raise the temperature of a 70-kg
patient by 1°C. Thus, more than 6 hours would be required to warm a 32°C patient using 41°C
humidified inspired air.
Heat transfer rates using body cavity lavage can be similarly calculated based on the specific heat of
water (1 kcal/kg/°C). If 1 L of 44°C water infused into a body cavity dwells long enough to exit at 40°C,
4 kcal of heat will have been transferred to the patient. Thus, over 14 L of fluid is needed to increase
core temperature by 1°C. However, warming becomes less efficient as the patient rewarms because a
longer dwell time is required to reduce the temperature of the infusate to 40°C.
Warming by cardiopulmonary bypass or ECMO or CAVR is the most efficient method of core heating.
With flow rates of 15 to 30 L/hr, it is possible to deliver 120 to 240 kcal/hr if the reinfused blood is
heated to 40°C, a rate of heat transfer over 10 times that of the other methods. In any case, the urgency
with which rewarming must be accomplished depends on how adversely the hypothermia is affecting
825
booksmedicos.org
the patient. With the exception of extracorporeal circulatory methods, most rewarming techniques serve
primarily to prevent loss of endogenously generated heat and are ineffective in circumstances in which
rapid rewarming is indicated. Early and direct attention to preventing heat loss is therefore essential in
surgical patients. With more widespread adoption of ECMO capabilities for treating severe lung disease,
centers are starting to report on the use of this modality as a rewarming technique. The combination of
injury and hypothermia represents a particular challenge. Swiss physicians with experience in treating
injured and hypothermia avalanche victims have developed the Bernese Hypothermia Algorithm, a
detailed approach to rewarming techniques and injury care priorities in this population.190
Cold Injury and Frostbite

9 Frostbite is a cold injury limited to digits, extremities, or exposed surfaces that is the result of direct
tissue freezing. Chilblain (aka pernio) and trenchfoot are the result of more chronic exposure to an
environment just above freezing. Both of these types of cold injury have been a major cause of
morbidity during war experiences. They resulted in more than 7 million lost soldier fighting days by
Allied forces in World War II and were reportedly the most common major injury sustained by British
soldiers in the Falklands expedition.138
The terms chilblain and pernio describe a form of local cold injury characterized by pruritic, red-purple
papules, macules, plaques, or nodules on the skin. The lesions are often associated with edema or
blistering and are caused by a chronic vasculitis of the dermis191; this entity does not appear to be
related to hereditary protein C or S deficiency.192 This pathologic process is provoked by repeated
exposure to cold, but not freezing, temperatures. This injury typically occurs on the face, the anterior
surface of the tibia, or the dorsum of the hands and feet, areas poorly protected or chronically exposed
to the environment. With continued exposure, ulcerative or hemorrhagic lesions may appear and
progress to scarring, fibrosis, and atrophy. Treatment consists of sheltering the patient, elevating the
affected part on sheepskin, and allowing gradual rewarming at room temperature. Rubbing and massage
are contraindicated because they can cause further damage and secondary infection.
Trench foot or cold immersion foot (or hand) describes a nonfreezing injury of the hands or feet,
typically in sailors, fishermen, or soldiers, that is caused by chronic exposure to wet conditions and
temperatures just above freezing.193 It appears to involve an alternating arterial vasospasm and
vasodilatation, with the affected tissue first cold and anesthetic and then hyperemic after 24 to 48 hours
of exposure. With the hyperemia comes an intense, painful burning and dysesthesia, and tissue damage
is characterized by edema, blistering, redness, ecchymosis, and ulceration. Complications of local
infection or cellulitis, lymphangitis, and gangrene may occur. A posthyperemic phase occurs 2 to 6
weeks later and is characterized by tissue cyanosis with increased sensitivity to cold. Treatment is best
started during or before the reactive hyperemia state and consists of immediate removal of the
extremity from the cold, wet environment with exposure of the feet (or hands) to warm, dry air.
Elevation to minimize edema, protection of pressure spots, and local and systemic measures to combat
infection are indicated. Massage, soaking of the feet, or rapid rewarming is not indicated.
Demyelination of nerves, muscle atrophy, fallen arches, and osteoporosis may all present long-term
complications, and a tendency toward marked vasospasm during subsequent exposure to cold develops
in some patients.194
Frostnip is the mildest form of cold injury. It is characterized by initial pain and pallor, with
subsequent numbness of the affected body part. Skiers and other winter outdoor enthusiasts are most
likely to experience this cold injury to the nose, ears, or tips of digits. The injury is reversible and
warming of the cold tissue results in return of sensation and function with no tissue loss.
Frostbite is a more severe and common form of cold injury. Frostbite damage is caused by direct ice
crystal formation at the cellular level with cellular dehydration and microvascular occlusion. Frostbite is
traditionally classified into four grades of injury severity (Table 33-8).
The affected body part nearly always initially appears hard, cold, white, and anesthetic, regardless of
the depth of injury. Because the appearance of the lesion changes frequently during the course of
treatment and because the initial treatment regimen is applicable for all degrees of insult, some
authorities suggest discarding this classification as a prognostic impossibility and simply classifying
frostbite as either superficial or deep.195
Weather conditions, altitude, degree of protective clothing, duration of exposure, and degree of tissue
wetness are all contributing external factors to the development of frostbite injury. Because sensory
nerve activity is abolished at 7°C to 9°C, the disappearance of pain is an early warning sign of cold
injury. Acclimation to cold may be protective, whereas a previous history of frostbite probably
826
booksmedicos.org
predisposes to another cold tissue injury. Smoking and a history of arterial disease also are contributing
factors. In urban environments, more than 50% of frostbite injuries are alcohol-related and in one
report, 16% of these patients also had a significant underlying psychiatric illness.196
Evidence suggests that frostbite injury has two components – the initial freeze injury and a
reperfusion injury that occurs during rewarming. The initial response to tissue cooling is
vasoconstriction and arteriovenous shunting, intermittently relieved (every 5 to 7 minutes) by
vasodilation, the so-called hunting response.197 With prolonged exposure, this response fails, and the
temperature of the freezing tissue approximates ambient temperature until –2°C. At this point,
extracellular ice crystals form, and as these crystals enlarge, the osmotic pressure of the interstitium
increases resulting in movement of intracellular water out of cells and into the interstitium. Cells begin
to shrink and become hyperosmolar, disrupting cellular enzyme function. If freezing is rapid
(>10°C/min), intracellular ice crystal formation will occur, resulting in immediate cell death.198 In
addition, endothelial cell disruption and red cell sludging associated with freezing result in cessation of
circulation.
CLASSIFICATION
Table 33-8 Classification of Frostbite
During rewarming, red cell, platelet, and leukocyte aggregation occurs and results in patchy
thrombosis of the microcirculation. These accumulated blood elements are thought to release, among
other products, the toxic oxygen free radicals and the arachidonic acid metabolites PGF2a and
thromboxane A2, which further aggravate vasoconstriction and platelet and leukocyte
aggregation.199,200 However, the exact mechanism of tissue destruction and death after freeze injury
remains poorly defined. Animal studies suggest that vascular injury in the form of endothelial cell
damage and subsequent interstitial edema, but not vessel thrombosis, predominate as initial events in
rewarming injury.201 A substantial component of severe cold injury may be neutrophil mediated, as
suggested by the observation that a monoclonal antibody to neutrophil–endothelial and neutrophil–
neutrophil adherence can markedly ameliorate the pathologic process of a severe cold injury.202 In this
rabbit model, animals treated with anti-CD11/CD18 adhesion molecule after cold injury (30 minutes at
–15°C) but before rewarming (39°C water bath) had significantly less tissue loss and edema. The
implication of these observations is that much of the injury of severe frostbite occurs during rewarming
or reperfusion, although the efficacy of intra-arterial thrombolytic therapy suggests that endovascular
clotting does occur and can be reversed.203–206
Treatment
Prehospital or field care of the victim of cold injury should focus on removing the patient from the
hostile environment and protecting the injured body part from further damage. Rubbing or exercising
the affected tissue does not augment blood flow and risks further cold injury or mechanical trauma.
Because repeated bouts of freezing and thawing worsen the injury, it is preferable for the patient with
frostbite of the hands or feet immediately to seek definitive shelter and care rather than rewarm the
tissue in the field and risk refreezing. Although the initial symptoms may be mild and overlooked by the
patient, severe pain, burning, edema, and even necrosis and gangrene may appear with rewarming.
With severe injury the range of motion progressively decreases and edema becomes prominent. The
injury may progress to numbness and, eventually, to loss of all sensation in the affected tissue.
The emergency room treatment of a frostbite victim should first focus on the basic ABCs (airway,
breathing, and circulation) of trauma resuscitation and then systemic hypothermia should be identified
and corrected. Most patients are dehydrated, and resuscitation with warm fluids is an important part of
827
booksmedicos.org
early management. Fractures are often accompanied by frostbite in mountaineers, and although
manipulation may be required to treat vascular compromise, open reduction is hazardous, and
application of traction should be delayed until after postthawing edema has been assessed.
Rapid rewarming is the goal. Gradual, spontaneous rewarming is inadequate, particularly for deeper
injuries, and rubbing the injured part in ice or snow often delays warming and results in marked tissue
loss.207 Rapid rewarming should be achieved by immersing the tissue in a large water bath of 40°C to
42°C (104°F to 108°F). The water should feel warm, but not hot, to the normal hand. The bath should be
large enough to prevent rapid loss of heat, and the water temperature should be maintained. Dry heat is
not advocated because it is difficult to regulate, and the result of using excessive heat is often
disastrous. The rewarming process should take approximately 30 to 45 minutes for digits, with the
affected area appearing flushed when rewarming is complete and good circulation has been
reestablished. Narcotics are required because the rewarming process can be quite painful.
The skin should be gently but meticulously cleansed and air-dried and the affected area elevated to
minimize edema. A tetanus toxoid booster should be administered as indicated by immunization history.
Sterile cotton is placed between toes or fingers to prevent skin maceration and extreme care taken to
prevent infection and avoid even the slightest abrasion. The affected tissue should be protected by a
tent or cradle, and pressure spots must be prevented. In one review, infection developed in 13% of
urban frostbite victims, but one-half of these infections were present at the time of admission.196 Most
clinicians reserve antibiotics for identified infections.208
After rewarming, the treatment goals are to prevent further injury while awaiting the demarcation of
irreversible tissue destruction. All patients should be hospitalized and affected tissue gently cleansed
once or twice a day in warm (38°C) whirlpool baths, with some clinicians adding an antiseptic such as
chlorhexidine or an iodophor to the bath. Based on the findings of arachidonic acid metabolites in the
blisters of frostbite victims, some authors advocate the use of topical aloe vera (thromboxane inhibitor)
and systemic ibuprofen or aspirin. Heggers et al. report in a nonrandomized trial in which 56 patients
treated with these agents, plus prophylactic penicillin, had less tissue loss, a lower amputation rate, and
a shorter hospital stay than 98 patients treated with warm saline, silver sulfadiazine, or sulfamylon
dressings (Bertek Pharmaceuticals, Research Triangle Park, NC).209 Another report on frostbite
treatment in rabbits demonstrated improved tissue viability when systemic pentoxifylline and topical
aloe vera cream were used.210 Uninfected blebs should be left intact because they provide a sterile
biologic dressing for 7 to 10 days and protect underlying epithelialization. After resolution of edema,
digits should be exercised during the whirlpool bath and physical therapy begun. Tobacco, nicotine, and
other vasoconstrictive agents must be withheld. Weight bearing is prohibited until complete resolution
of edema.
Numerous adjuvants have been tried in an effort to restore blood supply to frostbitten areas. The
intense vasoconstrictive effect of cold injury has focused attention on increased sympathetic tone.
Sympathetic blockade and even surgical sympathectomy continues to be advocated by some authors
based on the theory that it releases the vasospasm that precipitates thrombosis in the affected
tissue.211,212 This method of treatment has produced inconsistent results and is difficult to evaluate
clinically, with no prospective, randomized trials available. Although sympathectomy appears to mollify
the pain and hyperhidrosis and vasospasm of cold injuries, it may increase vascular shunting and
adversely affect healing. In one series, a more proximal demarcation of injury in sympathectomized
limbs was noted than in nonsympathectomized ones, despite apparently equal bilateral injury.207
Experience with intra-arterial vasodilatory drugs, such as reserpine, tolazoline, and papaverine, has
also been unrewarding. For example, Bouwman et al.212 demonstrated in a controlled clinical study that
immediate (mean 3 hours) ipsilateral intra-arterial reserpine infusion coupled with early (mean 3 days)
ipsilateral operative sympathectomy failed to alter the natural history of acute frostbite injury
compared with the contralateral limb. Iloprost, a synthetic analog of prostacyclin PGI2 has also been
used in an effort to vasodilate microvascular arcades.206 Low–molecular-weight dextran has been shown
to alleviate postthawing circulatory obstruction as late as 2 hours after thawing and markedly reduced
tissue loss in rabbit feet,213 but similar results in humans has not been demonstrated. Heparin,
thrombolytic agents, and hyperbaric oxygen have also failed to demonstrate any substantial treatment
benefit, but hyperbaric enthusiasts continue to tout its role.214 None of these adjuncts is considered
routine care.
828
booksmedicos.org
Figure 33-20. Digital angiography of a 19-year-old woman who sustained bilateral lower extremity frostbite following vehicle
breakdown. A: The image demonstrates poor distal perfusion to the left toes. B: Following administration of tissue plasminogen
activator via bilateral femoral catheters, angiography demonstrates return of perfusion. All 10 of her toes were saved. (Reproduced
with permission from Bruen KJ, Ballard JR, Morris SE, et al. Reduction of the incidence of amputation in frostbite injury with
thrombolytic therapy. Arch Surg 2007;142:546–553.)
10 The most recent adjunct to the management of frostbite is the intra-arterial infusion of tissue
plasminogen activator (tPA). In a nonrandomized study of a small number (n = 7) of patients who
received intra-arterial tPA, the burn team at the University of Utah demonstrated that tPA infusion
improved tissue perfusion and reduced amputations (10% vs. 41%) when administered within 24 hours
of injury (6 of the 7), as compared with 25 patients managed in a more traditional fashion.203 Since this
2007 report, isolated case reports have also suggested that this therapy is effective.205,215 Candidates for
this therapy should have minimal risk of bleeding from other injuries, have the tPA administered (intra-
arterial or intravenously) within 24 hours of frostbite, with no episodes of rewarming or refreezing
between injury and treatment, and have clear evidence of full-thickness tissue involvement, as well as
abnormal perfusion on either angiogram or pyrophosphate scanning (Fig. 33-20, Table 33-9).
The difficulty in determining the depth of tissue destruction in cold injury has led to a conservative
approach to the care of frostbite injuries.208,216 For digit frostbite, the Hennepin score may provide a
useful way to track progress and compare experimental therapies.217 As a general rule, amputation and
surgical débridement are delayed for 2 to 3 months unless infection with sepsis intervenes, hence the
adage: “frostbite in January, amputate in June.” The natural history of a full-thickness frostbite injury is
the gradual demarcation of the injured area with dry gangrene or mummification clearly delineating
nonviable tissue. Often the permanent tissue loss is much less than originally suspected. In an Alaskan
series, only 10.5% of patients required amputation, usually involving only phalanges or portions of
phalanges.193 The need for emergency surgery is unusual, but vigilance should be maintained during the
rewarming phase for the development of a compartment syndrome requiring fasciotomy. Open
amputations are indicated in patients with persistent infection and sepsis that is refractory to
débridement and antibiotics. Mills convincingly demonstrated that of all the factors in the treatment of
frostbite that may influence outcome, premature surgical intervention by any means, in any amount,
was by far the greatest contributor to poor results.218
Table 33-9 Amputation Outcomes of Patients Treated With Tissue Plasminogen

Activator (tPA) Compared With All Other Patients by Frostbite
829
booksmedicos.org
The use of technetium-99m methylene diphosphonate bone scanning has shown some promise in the
early detection of eventual bone and soft tissue viability219 as has the use of magnetic resonance
imaging.220,221 Technetium-99m “triple-phase” scanning (at 1 minute, 2 hours, and 7 hours) performed
beginning 48 hours after admission has been used to assess early tissue perfusion and viability, in an
attempt to define the extent of fatally damaged tissues and to allow for early débridement and wound
closure.222,223 The utility of this diagnostic modality continues to evolve, however, with one recent
study suggesting that the moderate to severe frostbite lesion identified by technetium-99m scans can be
“hibernating” (viable) tissue, which can show improvement up to 6 months following injury.208,224
Frostbitten tissues seldom recover completely. Some degree of cold insensitivity invariably remains.
Hyperhidrosis (in up to 72% of patients), neuropathy, decreased nail and hair growth, and a persistent
Raynaud phenomenon in the affected part are frequent sequelae to cold injury.204,224,225 The affected
tissue remains at risk for reinjury and should be carefully protected during any cold exposure. As
mentioned previously, chilblain (or chronic pernio) is a specific form of a dermopathy secondary to
cold-induced skin vasculitis. Treatment with antiadrenergic agents (prazosin hydrochloride, 1 to 2
mg/d) or calcium channel blockers (nifedipine, 30 to 60 mg/d) and careful protection from further
exposure is often helpful.191,224 However, few therapies afford significant relief to the chronic
symptoms after tissue freeze injury, although β- and α-adrenergic blocking agents, calcium channel
blockers, topical and systemic steroids, and a host of home remedies have been tried with occasional
individual success.
References
1. Estimation of the global burden of snakebite [Internet]. 2008 [cited March 1, 2016]. Available at:
http://www.cdc.gov/niosh/topics/snakes.
2. Centers for Disease Control and Prevention. Necrotic arachnidism–Pacific Northwest, 1988–1996.
JAMA 1996;275(24):1870–1871.
3. Mattison C. Snake: The essential visual guide to the world of snakes. New York, NY: Dorling
Kindersley Ltd; 2006.
4. Pough F. Herpetology. Upper Saddle River, NJ: Pearson/Prentice Hall; 2004.
5. Conant R, Collins J. Peterson field guide: Reptiles and amphibians: Eastern and central North
American. Boston, MA: Houghton Mifflin; 1998.
6. Stebbins R. Peterson field guides: Western reptiles and amphibians. New York, NY: Houghton
Mifflin; 2003.
7. Tennant A, Salmon G, King R. Snakes of North America: Eastern and Central Regions. Lanham, MD:
Lone Star; 2003.
8. Gold BS, Dart RC, Barish RA. Bites of venomous snakes. N Engl J Med 2002;347(5):347–356.
9. Ruha AM, Curry SC, Albrecht C, et al. Late hematologic toxicity following treatment of rattlesnake
envenomation with crotalidae polyvalent immune Fab antivenom. Toxicon 2011;57(1):53–59.
10. Ownby C. Structure, function, and biophysical aspects of the myotoxins from snake venoms. J
Toxicol - Toxin Rev 1998;172(2):213–238.
11. Hutton RA, Warrell DA. Action of snake venom components on the haemostatic system. Blood Rev
1993;7(3):176–189.
12. Lavonas EJ, Gerardo CJ, O’Malley G, et al. Initial experience with Crotalidae polyvalent immune
Fab (ovine) antivenom in the treatment of copperhead snakebite. Ann Emerg Med 2004;43(2):200–
206.
13. Burch JM, Agarwal R, Mattox KL, et al. The treatment of crotalid envenomation without antivenin.
J Trauma 1988;28(1):35–43.
14. Walker JP, Morrison RL. Current management of copperhead snakebite. J Am Coll Surg
2011;212(4):470–474; discussion 474–475.
15. Whitley RE. Conservative treatment of copperhead snakebites without antivenin. J Trauma
1996;41(2):219–221.
16. Dart RC, Hurlbut KM, Garcia R, et al. Validation of a severity score for the assessment of crotalid
snakebite. Ann Emerg Med 1996;27(3):321–326.
17. Bucher B, Canonge D, Thomas L, et al. Clinical indicators of envenoming and serum levels of
830
booksmedicos.org
venom antigens in patients bitten by Bothrops lanceolatus in Martinique. Research Group on Snake
Bites in Martinique. Trans R Soc Trop Med Hyg 1997;91(2):186–190.
18. Stewart ME, Greenland S, Hoffman JR. First-aid treatment of poisonous snakebite: Are currently
recommended procedures justified? Ann Emerg Med 1981;10(6):331–335.
19. McCullough N, Gennaro J Jr. Treatment of venomous snake bites in the United States. Clin Toxicol
1970;3:483–500.
20. Stahnke HL, McBride A. Snake bite and cryotherapy. J Occup Med 1966;8(2):72–76.
21. Anker RL, Straffon WG, Loiselle DS, et al. Retarding the uptake of “mock venom” in humans:
Comparison of three first-aid treatments. Med J Aust 1982;1(5):212–214.
22. Meggs WJ, Courtney C, O’Rourke D, et al. Pilot studies of pressure-immobilization bandages for
rattlesnake envenomations. Clin Toxicol (Phila) 2010;48(1):61–63.
23. Clark R. Cryotherapy and corticosteroids in the treatment of rattlesnake bite. Mil Med 1971;136:42–
44.
24. Schottler WH. Antihistamine, ACTH cortisone, hydrocortisone and anesthetics in snake bite. Am J
Trop Med Hyg 1954;3(6):1083–1091.
25. Blaylock RS. Antibiotic use and infection in snakebite victims. S Afr Med J 1999;89(8):874–876.
26. Clark RF, Selden BS, Furbee B. The incidence of wound infection following crotalid envenomation.
J Emerg Med 1993;11(5):583–586.
27. Kularatne SA, Kumarasiri PV, Pushpakumara SK, et al. Routine antibiotic therapy in the
management of the local inflammatory swelling in venomous snakebites: results of a placebo-
controlled study. Ceylon Med J 2005;50(4):151–155.
28. LoVecchio F, Klemens J, Welch S, et al. Antibiotics after rattlesnake envenomation. J Emerg Med
2002;23(4):327–328.
29. Ledbetter E, Kutscher A. The aerobic and anaerobic flora of rattlesnake fangs and venom:
therapeutic implications. Arch Environ Health 1969; 50(4):151–155.
30. Jurkovich GJ, Luterman A, McCullar K, et al. Complications of Crotalidae antivenin therapy. J
Trauma 1988;28:1032–1037.
31. Dart RC, Seifert SA, Boyer LV, et al. A randomized multicenter trial of crotalinae polyvalent
immune Fab (ovine) antivenom for the treatment for crotaline snakebite in the United States. Arch
Intern Med 2001; 161(16):2030–2036.
32. Chippaux JP, Goyffon M. Venoms, antivenoms and immunotherapy. Toxicon 1998;36(6):823–846.
33. Consroe P, Egen NB, Russell FE, et al. Comparison of a new ovine antigen binding fragment (Fab)
antivenin for United States Crotalidae with the commercial antivenin for protection against venom-
induced lethality in mice. Am J Trop Med Hyg 1995;53(5):507–510.
34. Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the management of
crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC
Emerg Med 2011;11:2.
35. Bebarta V, Dart RC. Effectiveness of delayed use of crotalidae polyvalent immune Fab (ovine)
antivenom. J Toxicol Clin Toxicol 2004;42(3):321–324.
36. White RR 4th, Weber RA. Poisonous snakebite in central Texas. Possible indicators for antivenin
treatment. Ann Surg 1991;213(5):466–471; discussion 71–72.
37. Bogdan GM, Dart RC, Falbo SC, et al. Recurrent coagulopathy after antivenom treatment of crotalid
snakebite. South Med J 2000;93(6):562–566.
38. Holstege CP, Wu J, Baer AB. Immediate hypersensitivity reaction associated with the rapid infusion
of Crotalidae polyvalent immune Fab (ovine). Ann Emerg Med 2002;39(6):677–679.
39. Schaeffer TH, Khatri V, Reifler LM, et al. Incidence of immediate hypersensitivity reaction and
serum sickness following administration of Crotalidae polyvalent immune Fab antivenom: a meta-
analysis. Acad Emerg Med 2012;19(2):121–131.
40. Clark RF, McKinney PE, Chase PB, et al. Immediate and delayed allergic reactions to Crotalidae
polyvalent immune Fab (ovine) antivenom. Ann Emerg Med 2002;39(6):671–676.
41. Cannon R, Ruha AM, Kashani J. Acute hypersensitivity reactions associated with administration of
crotalidae polyvalent immune Fab antivenom. Ann Emerg Med 2008;51(4):407–411.
42. Corneille MG, Larson S, Stewart RM, et al. A large single-center experience with treatment of
831
booksmedicos.org
patients with crotalid envenomations: outcomes with and evolution of antivenin therapy. Am J Surg
2006;192(6):848–852.
43. Pizon AF, Riley BD, LoVecchio F, et al. Safety and efficacy of Crotalidae Polyvalent Immune Fab in
pediatric crotaline envenomations. Acad Emerg Med 2007;14(4):373–376.
44. Farrar HC, Grayham T, Bolden B, et al. The use and tolerability of Crotalidae Polyvalent Immune
FAB (Ovine) in pediatric envenomations. Clin Pediatr (Phila) 2012;51(10):945–949.
45. Goto CS, Feng SY. Crotalidae polyvalent immune Fab for the treatment of pediatric crotaline
envenomation. Pediatr Emerg Care 2009;25(4):273–9; quiz 280–282.
46. Correa JA, Fallon SC, Cruz AT, et al. Management of pediatric snake bites: Are we doing too much?
J Pediatr Surg 2014;49(6):1009–1015.
47. Lin HL, Lin TY, Lee WC. Snakebite: use of antivenom in a pregnant woman. Am J Emerg Med
2011;29(4):457.
48. Langley RL. Snakebite during pregnancy: a literature review. Wilderness Environ Med
2010;21(1):54–60.
49. Glass T. Early debridement in pit viper bites. JAMA 1976;235(23):2513–2516.
50. Alberts M, Shalit M, LoGalbo F. Suction for venomous snakebite: a study of “mock venom”
extraction in a human model. Ann Emerg Med 2004;43(2):181–186.
51. Bush SP, Hegewald KG, Green SM, et al. Effects of a negative pressure venom extraction device
(Extractor) on local tissue injury after artificial rattlesnake envenomation in a porcine model.
Wilderness Environ Med 2000;11(3):180–188.
52. Huang T, Lynch J, Larson D. The use of excisional therapy in management of snakebite. Ann Surg
1974;179(35):598–607.
53. Lawrence W, Giannopoulos A, Hansen A. Pit viper bites: rational management in locales in which
copperheads and cottonmouths predominate. Ann Plast Surg 1996;36:276–285.
54. McCullough N, Gennaro J. Evaluation of venomous snake bite in southern United States. J Fla Med
Assoc 1963;40:959–967.
55. Garfin S. Rattlesnake bites and surgical decompression: results using a laboratory model. Toxicon
1984;22:177–184.
56. Curry S, Kraner J, Kunkel D, et al. Noninvasive vascular studies in management of rattlesnake
envenomations to extremities. Ann Emerg Med 1985;14:1081–1084.
57. Stewart RM, Page CP, Schwesinger WH, et al. Antivenin and fasciotomy/debridement in the
treatment of the severe rattlesnake bite. Am J Surg 1989;158(6):543–547.
58. Hall EL. Role of surgical intervention in the management of crotaline snake envenomation. Ann
Emerg Med 2001;37(2):175–180.
59. Tanen DA, Danish DC, Grice GA, et al. Fasciotomy worsens the amount of myonecrosis in a porcine
model of crotaline envenomation. Ann Emerg Med 2004;44(2):99–104.
60. Osborn C. Multiple HVDC shocks as first aid or therapy for venomous bites and stings. J Okla State
Med Assoc 1992;85:331–343.
61. Dart RC, Lindsey D, Schulman A. Snakebites & shocks. Ann Emerg Med 1988;17(11):1262.
62. Guderian R, MacKenzie C, Williams J. High voltage shock treatment for snake bite. Lancet
1986;2:229–231.
63. Pearson CA. High-voltage shock treatment for snake bite. Lancet 1986; 2(8504):461.
64. Howe N, Meisenheimer J. Electric shock does not save snakebitten rats. Ann Emerg Med
1988;17(3):22–124.
65. Johnson EK, Kardong KV, Mackessy SP. Electric shocks are ineffective in treatment of lethal effects
of rattlesnake envenomation in mice. Toxicon 1987;25(12):1347–1349.
66. Ben Welch E, Gales BJ. Use of stun guns for venomous bites and stings: a review. Wilderness Environ
Med 2001;12(2):111–117.
67. Pfennig DW, Harcombe WR, Pfennig KS. Frequency-dependent Batesian mimicry. Nature
2001;410(6826):323.
68. List of fatal snake bites in the United States. Wikipedia; 2016. Available at:
https://en.wikipedia.org/wiki/List_of_fatal_snake_bites_in_the_United_States. Accessed September 5,
2016.
832
booksmedicos.org
69. Kitchens CS, Van Mierop LH. Envenomation by the Eastern coral snake (Micrurus fulvius fulvius). A
study of 39 victims. JAMA 1987;258(12):1615–1618.
70. Parrish H. Incidence of treated snakebites in the United States. Public Health Rep 1966;81:269–276.
71. Chippaux J. Snake bites: appraisal of the global situation. Bull World Health Organ 1998;76(5):515–
524.
72. WHO/SEARO. Guidelines for the clinical managment of snake bites in the Southeast Asian region.
Southeast Asian J Trip Med Public Health 1999;30(suppl 1):1.
73. Strimple PD, Tomassoni AJ, Otten EJ, et al. Report on envenomation by a Gila monster (Heloderma
suspectum) with a discussion of venom apparatus, clinical findings, and treatment. Wilderness
Environ Med 1997; 8(2):111–116.
74. Hooker KR, Caravati EM, Hartsell SC. Gila monster envenomation. Ann Emerg Med
1994;24(4):731–735.
75. Preston C. Hypotension, myocardial infarction, and coagulopathy following Gila monster bite. J
Emerg Med 1989;7:37–40.
76. Cantrell FL. Envenomation by the Mexican beaded lizard: A case report. J Toxicol Clin Toxicol
2003;41(3):241–244.
77. Health NIfOSa. Insects and Scorpions: Centers for Disease Control. 2016. Available at:
http://www.cdc.gov/niosh/topics/insects/. Accessed September 5, 2016.
78. Saucier JR. Arachnid envenomation. Emerg Med Clin North Am 2004;22(2):405–22, ix.
79. Swanson DL, Vetter RS. Bites of brown recluse spiders and suspected necrotic arachnidism. N Engl J
Med 2005;352(7):700–707.
80. Necrotic arachnidism–Pacific Northwest, 1988–1996. MMWR Morb Mortal Wkly Rep
1996;45(21):433–436.
81. Walker JS, Hogan DE. Bite to the left leg. Necrotic ulcer from a brown recluse spider bite. Acad
Emerg Med 1995;2(3):223; 231; 234–237.
82. Wilson DC, King LE, Jr. Spiders and spider bites. Dermatol Clin 1990; 8(2):277–286.
83. Futrell JM. Loxoscelism. Am J Med Sci 1992;304(4):261–267.
84. Patel KD, Modur V, Zimmerman GA, et al. The necrotic venom of the brown recluse spider induces
dysregulated endothelial cell-dependent neutrophil activation. Differential induction of GM-CSF, IL-
8, and E-selectin expression. J Clin Invest 1994;94(2):631–642.
85. Sams HH, Dunnick CA, Smith ML, et al. Necrotic arachnidism. J Am Acad Dermatol 2001;44(4):561–
573; quiz 573–576.
86. Bryant SM, Pittman LM. Dapsone use in Loxosceles reclusa envenomation: Is there an indication?
Am J Emerg Med 2003;21(1):89–90.
87. Barrett SM, Romine-Jenkins M, Fisher DE. Dapsone or electric shock therapy of brown recluse
spider envenomation?Ann Emerg Med 1994;24(1):21–25.
88. Strain GM, Snider TG, Tedford BL, et al. Hyperbaric oxygen effects on brown recluse spider
(Loxosceles reclusa) envenomation in rabbits. Toxicon 1991;29(8):989–996.
89. Phillips S, Kohn M, Baker D, et al. Therapy of brown spider envenomation: a controlled trial of
hyperbaric oxygen, dapsone, and cyproheptadine. Ann Emerg Med 1995;25(3):363–368.
90. Rees RS, Altenbern DP, Lynch JB, et al. Brown recluse spider bites. A comparison of early surgical
excision versus dapsone and delayed surgical excision. Ann Surg 1985;202(5):659–663.
91. Clark RF, Wethern-Kestner S, Vance MV, et al. Clinical presentation and treatment of black widow
spider envenomation: a review of 163 cases. Ann Emerg Med 1992;21(7):782–787.
92. Muller GJ. Black and brown widow spider bites in South Africa. A series of 45 cases. S Afr Med J
1993;83(6):399–405.
93. Suntorntham S, Roberts JR, Nilsen GJ. Dramatic clinical response to the delayed administration of
black widow spider antivenin. Ann Emerg Med 1994;24(6):1198–1199.
94. Antivenin Latrodectus Mactans (Black Widon Spider Antivenin). Food and Drug Administration.
2014.
95. Reisman RE. Stinging insect allergy. Med Clin North Am 1992;76(4):883–894.
96. Kim KT, Oguro J. Update on the status of Africanized honey bees in the western states. West J Med
1999;170(4):220–222.
833
booksmedicos.org
97. Schumacher MJ, Egen NB. Significance of Africanized bees for public health. A review. Arch Intern
Med 1995;155(19):2038–2043.
98. Szalanski A, Magnus R. Mitochondrial DNA characterization of Africanized honey bee (Apis
mellifera L.) populations from the USA. J Apicult Res Bee 2010;49(2):177–185.
99. Kolecki P. Delayed toxic reaction following massive bee envenomation. Ann Emerg Med
1999;33(1):114–116.
100. Kemp SF, deShazo RD, Moffitt JE, et al. Expanding habitat of the imported fire ant (Solenopsis
invicta): a public health concern. J Allergy Clin Immunol 2000;105(4):683–691.
101. Stafford CT. Fire ant allergy. Allergy Proc 1992;13(1):11–16.
102. Goddard J, Jarratt J, de Castro FR. Evolution of the fire ant lesion. JAMA 2000;284(17):2162–
2163.
103. Yarom R. Scorpion venom: a tutorial review of its effects in man and experimental animals. Clin
Toxicology 1970;3(4):561–569.
104. Bawaskar HS, Bawaskar PH. Cardiovascular manifestations of severe scorpion sting in India
(review of 34 children). Ann Trop Paediatr 1991;11(4):381–387.
105. Bush SP, King BO, Norris RL, et al. Centipede envenomation. Wilderness Environ Med
2001;12(2):93–99.
106. Chaou CH, Chen CK, Chen JC, et al. Comparisons of ice packs, hot water immersion, and analgesia
injection for the treatment of centipede envenomations in Taiwan. Clin Toxicol (Phila)
2009;47(7):659–662.
107. Radford AJ. Millipede burns in man. Trop Geogr Med 1975;27(3):279–287.
108. Foot NC. Pathology of the dermatitis caused by megalopyge opercularis, a Texan caterpillar. J Exp
Med 1922;35(5):737–753.
109. Neustater BR, Stollman NH, Manten HD. Sting of the puss caterpillar: an unusual cause of acute
abdominal pain. South Med J 1996;89(8):826–827.
110. Norris R. Caterpillar envenomations 2014. Available at:
http://emedicine.medscape.com/article/772949-overview. Accessed September 5, 2016.
111. Rosen T. Caterpillar dermatitis. Dermatol Clin 1990;8(2):245–252.
112. Jurkovich G. Hypothermia in the trauma patient. Adv Trauma 1989;4:111–1140.
113. Hypothermia-related deaths – United States 1999–2002 and 2005. MMWR Morb Mortal Wkly Rep
2006;55(10):282–4.
114. Brown D, Brugger H, Boyd J, et al. Accidental Hypothermia. N Engl J Med 2012;367:1930–1938.
115. Danzl D, Pozos R, Auerbach P, et al. Multicenter hypothermia survery. Ann Emerg Med
1987;16:1042–1055.
116. van der Ploeg G, Gosloings J, et al. Accidental hypothermia: rewarming treatment, complications
and outcomes from one university medical centre. Resuscitation 2010;81(11):1550–1555.
117. Deslarzes T, Rousson V, Yersin B, et al. An evaluation of the Swiss staging model for hypothermia
using case reports from the literature. Scand J Trauma Resusc Emerg Med 2016;24(1):16.
118. Trevino A, Razi B, Beller BM. The characteristic electrocardiogram of accidental hypothermia. Arch
Intern Med 1971;127(3):470–473.
119. Walpoth BH, Walpoth-Aslan BN, Mattle HP, et al. Outcome of survivors of accidental deep
hypothermia and circulatory arrest treated with extracorporeal blood warming. N Engl J Med
1997;337(21):1500–1555.
120. Hauty MG, Esrig BC, Hill JG, et al. Prognostic factors in severe accidental hypothermia: experience
from the Mt. Hood tragedy. J Trauma 1987;27(10):1107–1112.
121. Silfvast T, Pettila V. Outcome from severe accidental hypothermia in Southern Finland–a 10-year
review. Resuscitation 2003;59(3):285–290.
122. Cohen DJ, Cline JR, Lepinski SM, et al. Resuscitation of the hypothermic patient. Am J Emerg Med
1988;6(5):475–478.
123. Ledingham IM, Mone JG. Treatment of accidental hypothermia: a prospective clinical study. Br Med
J 1980;280(6222):1102–1105.
124. Swain JA, White FN, Peters RM. The effect of pH on the hypothermic ventricular fibrillation
threshold. J Thorac Cardiovasc Surg 1984;87(3):445–451.
834
booksmedicos.org
125. White FN. Reassessing acid-base balance in hypothermia–a comparative point of view. West J Med
1983;138(2):255–257.
126. White FN. A comparative physiological approach to hypothermia. J Thorac Cardiovasc Surg
1981;82(6):821–831.
127. Ream AK, Reitz BA, Silverberg G. Temperature correction of PCO2 and pH in estimating acid-base
status: an example of the emperor’s new clothes? Anesthesiology 1982;56(1):41–44.
128. Hansen JE, Sue DY. Should blood gas measurements be corrected for the patient’s temperature?. N
Eng J Med 1984;303:341.
129. Orlowski JP, Erenberg G, Lueders H, Cruse RP. Hypothermia and barbiturate coma for refractory
status epilepticus. Crit Care Med 1984;12(4):367–72.
130. Dobson JA, Burgess JJ. Resuscitation of severe hypothermia by extracorporeal rewarming in a
child. J Trauma 1996;40(3):483–485.
131. Iyer A, Rajkuman V, Sadasivan S, et al. No one is dead until warm and dead. J Thorac Cardiovasc
Surg 2007;134:1042–1043.
132. Schaller MD, Fischer AP, Perret CH. Hyperkalemia. A prognostic factor during acute severe
hypothermia. JAMA 1990;264(14):1842–1845.
133. Wijdicks EF, Varelas PN, Gronseth GS, et al; American Academy of N. Evidence-based guideline
update: determining brain death in adults: Report of the Quality Standards Subcommittee of the
American Academy of Neurology. Neurology 2010;74(23):1911–1918.
134. Greer D, Wang J, Robinson J, et al. Variability of brain death policies in the United States. JAMA
Neurol 2016;73(2):213–218.
135. Moyer JH, Heider C, Morris GC Jr, et al. Hypothermia. III. The effect of hypothermia on renal
damage resulting from ischemia. Ann Surg 1957;146(2):152–166.
136. Debakey ME, Morris G, Moyer JH. Hypothermia. I. Effect on renal hemodynamics and on excretion
of water and electrolytes in dog and man. Ann Surg 1957;145(1):26–40.
137. Curry DL, Curry KP. Hypothermia and insulin secretion. Endocrinology 1970;87(4):750–755.
138. Axelrod DR, Bass DE. Electrolytes and acid-base balance in hypothermia. Am J Physiol
1956;186(1):31–34.
139. Haddix TL, Pohlman TH, Noel RF, et al. Hypothermia inhibits human E-selectin transcription. J Surg
Res 1996;64(2):176–183.
140. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce the incidence of surgical-
wound infection and shorten hospitalization. Study of Wound Infection and Temperature Group. N
Engl J Med 1996; 334(19):1209–1215.
141. Pozos R, Wittmers L. The Nature and Treatment of Hypothermia. Minneapolis: University of
Minnesota Press; 1983.
142. Iampietro PF, Vaughan JA, Goldman RF, et al. Heat production from shivering. J Appl Physiol
1960;15:632–634.
143. Goldberg MJ, Roe CF. Temperature changes during anesthesia and operations. Arch Surg
1966;93(2):365–369.
144. Roe CF. Temperature regulation and energy metabolism in surgical patients. Prog Surg 1973;12:96–
127.
145. Paton B. Accidental hypothermia. Pharmacol Ther 1983;22:331–337.
146. Gentilello LM. Advances in the management of hypothermia. Surg Clin North Am 1995;75(2):243–
256.
147. Gregory JS, Flancbaum L, Townsend MC, et al. Incidence and timing of hypothermia in trauma
patients undergoing operations. J Trauma 1991; 31(6):795–798; discussion 798–800.
148. Luna G, Maier R, Pavlin E, et al. Incidence and effect of hypothermia in seriously injured patients. J
Trauma 1987;27(9):1014–1018.
149. Jurkovich G, Greiser W, Luterman A, et al. Hypothermia in trauma victims: An ominous predictor
of survival. J Trauma 1987;27:1019–1024.
150. Inaba K, Berg R, Barmparas G, et al. Prospective evaluation of ambient operating room
temperature on the core temperature of injured patients undergoing emergent surgery. J Trauma
Acute Care Surg 2012;73(6):1478–1483.
835
booksmedicos.org
151. Psarras P, Ivatury R, Rohman M, et al, eds. Hypothermia in trauma: Incidence and prognostic
significance. Presentation before the Eastern Association for the Surgery of Trauma, Longboat Key,
FL: 1988.
152. Rutherford EJ, Fusco MA, Nunn CR, et al. Hypothermia in critically ill trauma patients. Injury
1998;29(8):605–608.
153. Little R, Stoner H. Body temperature after accidental injury. Br J Surg 1981;68:221–224.
154. Hardy J, Randini I. Some physiologic aspects of surgical trauma. Am Surg 1952;136:345.
155. Perlman R, Callum J, Laflamme C, et al. A recommended early goal-directed management
guideline for the prevention of hypothermia-related transfusion, morbidity, and mortality in
severely injured trauma patients. Crit Care 2016;20(1):107.
156. Blalock A, Mason M. A comparison of the effects of heat and those of cold in the prevention and
treatment of shock. Arch Surg 1945;42:1054–1059.
157. Wu X, Drabek T, Tisherman SA, et al. Emergency preservation and resuscitation with profound
hypothermia, oxygen, and glucose allows reliable neurological recovery after 3 h of cardiac arrest
from rapid exsanguination in dogs. J Cereb Blood Flow Metab 2008;28(2):302–311.
158. Sori A, El-Assuooty A, Rush B, et al. The effect of temperature on survival in hemorrhagic shock.
Am Surg 1987;53:706–710.
159. Alam HB, Bowyer MW, Koustova E, et al. Learning and memory is preserved after induced
asanguineous hyperkalemic hypothermic arrest in a swine model of traumatic exsanguination.
Surgery 2002;132(2):278–288.
160. Cornejo CJ, Kierney PC, Vedder NB, et al. Mild hypothermia during reperfusion reduces injury
following ischemia of the rabbit ear. Shock 1998;9(2):116–120.
161. Jurkovich G, Pitt R, Curreri P, et al. Hypothermia prevents increased capillary permeability
following ischemia-reperfusion injury. J Surg Res 1988;44:514–521.
162. Wright JG, Kerr JC, Valeri CR, et al. Regional hypothermia protects against ischemia-reperfusion
injury in isolated canine gracilis muscle. J Trauma 1988;28(7):1026–1031.
163. Finkelstein RA, Alam HB. Induced hypothermia for trauma: current research and practice. J
164. Tisherman SA. Salvage techniques in traumatic cardiac arrest: thoracotomy, extracorporeal life
support, and therapeutic hypothermia. Curr Opin Crit Care 2013;19(6):594–598.
165. Nozari A, Safar P, Wu X, et al. Suspended animation can allow survival without brain damage after
traumatic exsanguination cardiac arrest of 60 minutes in dogs. J Trauma 2004;57(6):1266–1275.
166. Fay T. Observations on generalized refrigeration in cases of severe cerebral trauma. Ass Res Nerv
Ment Dis Proc 1943;(24):611–619.
167. Clifton GL, Miller ER, Choi SC, et al. Lack of effect of induction of hypothermia after acute brain
injury. N Engl J Med 2001;344(8):556–563.
168. Gentilello LM, Jurkovich GJ, Stark MS, et al. Is hypothermia in the victim of major trauma
protective or harmful? A randomized, prospective study. Ann Surg 1997;226(4):439–447; discussion
447–449.
169. Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac
arrest with induced hypothermia. N Engl J Med 2002;346(8):557–563.
170. Nielsen N, Wetterslev J, Cronberg T, et al. Targeted temperature management at 33 degrees C
versus 36 degrees C after cardiac arrest. N Engl J Med 2013;369(23):2197–2206.
171. Mikkelsen ME, Christie JD, Abella BS, et al. Use of therapeutic hypothermia after in-hospital
cardiac arrest. Crit Care Med 2013;41(6):1385–1395.
172. Cohen MJ, Kutcher M, Redick B, et al. Clinical and mechanistic drivers of acute traumatic
coagulopathy. J Trauma Acute Care Surg 2013;75(1 suppl 1):S40–S47.
173. Bachmann F, McKenna R, Cole ER, et al. The hemostatic mechanism after open-heart surgery. I.
Studies on plasma coagulation factors and fibrinolysis in 512 patients after extracorporeal
circulation. J Thorac Cardiovasc Surg 1975;70(1):76–85.
174. Harker LA, Malpass TW, Branson HE, et al. Mechanism of abnormal bleeding in patients
undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with
selective alpha-granule release. Blood 1980;56(5):824–834.
836
booksmedicos.org
175. Kattlove HE, Alexander B. The effect of cold on platelets. I. Cold-induced platelet aggregation.
Blood 1971;38(1):39–48.
176. Patt A, McCroskey BL, Moore EE. Hypothermia-induced coagulopathies in trauma. Surg Clin North
Am 1988;68(4):775–785.
177. Valeri CR, Feingold H, Cassidy G, et al. Hypothermia-induced reversible platelet dysfunction. Ann
Surg 1987;205(2):175–181.
178. Wolberg AS, Meng ZH, Monroe DM 3rd, et al. A systematic evaluation of the effect of temperature
on coagulation enzyme activity and platelet function. J Trauma 2004;56(6):1221–1228.
179. Reed RL 2nd, Bracey AW Jr, Hudson JD, et al. Hypothermia and blood coagulation: dissociation
between enzyme activity and clotting factor levels. Circ Shock 1990;32(2):141–152.
180. Gubler KD, Gentilello LM, Hassantash SA, et al. The impact of hypothermia on dilutional
coagulopathy. J Trauma 1994;36(6):847–851.
181. Gentilello L, Jurkovich G, Moujaes S. Hypothermia and injury: thermodynamic principles of
prevention and treatment. In: Levine B, ed. Perspectives in Surgery. St. Louis, MO: Quality Medical
Publishers; 1991.
182. Sheaff CM, Fildes JJ, Keogh P, et al. Safety of 65 degrees C intravenous fluid for the treatment of
hypothermia. Am J Surg 1996;172(1):52–55.
183. Herron DM, Grabowy R, Connolly R, et al. The limits of bloodwarming: maximally heating blood
with an inline microwave bloodwarmer. J Trauma 1997;43(2):219–226; discussion 226–228.
184. Darocha T, Jarosz A, Zietkiewicz M, et al. ECMO in Treating patients in critical, life-threatening
medical condition brought on by severe hypothermia-criterion standard. Ann Emerg Med
2016;67(4):558–559.
185. Gentilello LM, Cobean RA, Offner PJ, et al. Continuous arteriovenous rewarming: rapid reversal of
hypothermia in critically ill patients. J Trauma 1992;32(3):316–325; discussion 325–327.
186. Laniewicz M, Lyn-Kew K, Silbergleit R. Rapid endovascular warming for profound hypothermia.
Ann Emerg Med 2008;51(2):160–163.
187. Patton JF, Doolittle WH. Core rewarming by peritoneal dialysis following induced hypothermia in
the dog. J Appl Physiol 1972;33(6):800–804.
188. Moss J. Accidental severe hypothermia. Surg Gynecol Obstet 1986;162:501–513.
189. Gentilello LM, Moujaes S. Treatment of hypothermia in trauma victims: thermodynamic
considerations. J Intensive Care Med 1995;10(1):5–14.
190. Monika BM, Martin D, Balthasar E, et al. The Bernese Hypothermia Algorithm: a consensus paper
on in-hospital decision-making and treatment of patients in hypothermic cardiac arrest at an alpine
level 1 trauma centre. Injury 2011;42(5):539–543.
191. Jacob JR, Weisman MH, Rosenblatt SI, et al. Chronic pernio. A historical perspective of cold-
induced vascular disease. Arch Intern Med 1986; 146(8):1589–1592.
192. Benchikhi H, Roujeau JC, Levent M, et al. Chilblains and Raynaud phenomenon are usually not a
sign of hereditary protein C and S deficiencies. Acta Derm Venereol 1998;78(5):351–352.
193. Auerbach P. Disorders due to physical and environmental agents. In: Mills J, Ho MT, Salber PR, et
al., eds. Current Emergency Diagnosis and Treatment. Los Altos, California: Lange Medical
Publications; 1985.
194. Francis TJ, Golden FS. Non-freezing cold injury: the pathogenesis. J R Nav Med Serv 1985;71(1):3–
8.
195. Mills WJ Jr. Frostbite. A discussion of the problem and a review of the Alaskan experience. 1973.
Alaska Med 1993;35(1):29–40.
196. Urschel J. Frostbite: predisposing factors and predictors of poor outcome. J Trauma
1990;30(3):340–343.
197. Dana H, Rex I, Samitz M. The hunting reaction. Arch Dermatol 1969; 99:441.
198. Britt LD, Dascombe WH, Rodriguez A. New horizons in management of hypothermia and frostbite
injury. Surg Clin N Am 1991;71(2):345–370.
199. Murphy JV, Banwell PE, Roberts AH, et al. Frostbite: pathogenesis and treatment. J Trauma
2000;48(1):171–178.
200. Ozyazgan I, Tercan M, Melli M, et al. Eicosanoids and inflammatory cells in frostbitten tissue:
837
booksmedicos.org
prostacyclin, thromboxane, polymorphonuclear leukocytes, and mast cells. Plast Reconstr Surg
1998;101(7):1881–1886.
201. Bourne M, Piepkorn M, Clayton F, et al. Analysis of microvascular changes in frostbite injury. J
Surg Res 1986;40:26–35.
202. Mileski WJ, Raymond JF, Winn RK, et al. Inhibition of leukocyte adherence and aggregation for
treatment of severe cold injury in rabbits. J Appl Physiol (1985) 1993;74(3):1432–1436.
203. Bruen KJ, Ballard JR, Morris SE, et al. Reduction of the incidence of amputation in frostbite injury
with thrombolytic therapy. Arch Surg 2007;142(6):546–551; discussion 551–553.
204. Heil K, Thomas R, Robertson G, et al. Freezing and non-freezing cold weather injuries: a systematic
review. Br Med Bull 2016;117(1):79–93.
205. Ibrahim AE, Goverman J, Sarhane KA, et al. The emerging role of tissue plasminogen activator in
the management of severe frostbite. J Burn Care Res 2015;36(2):e62–e66.
206. Groechenig E. Treatment of frostbite with iloprost. Lancet 1994; 344(8930):1152–1153.
207. Mills WJ Jr, Whaley R. Frostbite: experience with rapid rewarming and ultrasonic therapy: Part I,
II, III 1960. Alaska Med 1993;35(1):1–27.
208. Petrone P, Kuncir EJ, Asensio JA. Surgical management and strategies in the treatment of
hypothermia and cold injury. Emerg Med Clin North Am 2003;21(4):1165–1178.
209. Heggers J, Robson M, Weingarten M, et al. Experimental and clinical observations on frostbite.
Ann Emerg Med 1987;16(9):1056–1062.
210. Miller MB, Koltai PJ. Treatment of experimental frostbite with pentoxifylline and aloe vera cream.
Arch Otolaryngol Head Neck Surg 1995; 121(6):678–680.
211. Rakower SR, Shahgoli S, Wong SL. Doppler ultrasound and digital plethysmography to determine
the need for sympathetic blockade after frostbite. J Trauma 1978;18(10):713–718.
212. Bouwman DL, Morrison S, Lucas CE, et al. Early sympathetic blockade for frostbite–is it of value? J
Trauma 1980;20(9):744–749.
213. Purdue GF, Hunt JL. Cold injury: a collective review. J Burn Care Rehabil 1986;7(4):331–342.
214. Higdon B, Youngman L, Regehr M, et al. Deep Frostbite treated with hyperbaric oxygen and
thrombolytic therapies. Wounds 2015;27(8):215–223.
215. Twomey JA, Peltier GL, Zera RT. An open-label study to evaluate the safety and efficacy of tissue
plasminogen activator in treatment of severe frostbite. J Trauma 2005;59(6):1350–1354; discussion
1354–1355.
216. Edlich RF, Chang DE, Birk KA, et al. Cold injuries. Compr Ther 1989;15(9):13–21.
217. Nygaard RM, Whitley AB, Fey RM, et al. The Hennepin score: quantification of frostbite
management efficacy. J Burn Care Res 2015.
218. Mills WJ Jr. Summary of treatment of the cold injured patient: frostbite. 1983. Alaska Med
1993;35(1):61–66.
219. Mehta RC, Wilson MA. Frostbite injury: prediction of tissue viability with triple-phase bone
scanning. Radiology 1989;170:511–514.
220. Barker JR, Haws MJ, Brown RE, et al. Magnetic resonance imaging of severe frostbite injuries. Ann
Plast Surg 1997;38(3):275–279.
221. Raman SR, Jamil Z, Cosgrove J. Magnetic resonance angiography unmasks frostbite injury. Emerg
Med J 2011;28(5):450.
222. Cauchy E, Marsigny B, Allamel G, et al. The value of technetium 99 scintigraphy in the prognosis of
amputation in severe frostbite injuries of the extremities: a retrospective study of 92 severe
frostbite injuries. J Hand Surg Am 2000;25(5):969–978.
223. Cauchy E, Chetaille E, Lefevre M, et al. The role of bone scanning in severe frostbite of the
extremities: a retrospective study of 88 cases. Eur J Nucl Med 2000;27(5):497–502.
224. Rustin MH, Newton JA, Smith NP, et al. The treatment of chilblains with nifedipine: the results of a
pilot study, a double-blind placebo-controlled randomized study and a long-term open trial. Br J
Dermatol 1989;120(2):267–275.
225. Heil KM, Oakley EH, Wood AM. British Military freezing cold injuries: a 13-year review. J R Army
Med Corps 2016:pii: jramc-2015-000445.
838
booksmedicos.org
SECTION B: TRANSPLANTATION
839
booksmedicos.org
Chapter 34
Clinical Transplant Immunology

Amit K. Mathur and Satish N. Nadig
Key Points
1 Understanding clinical transplant immunology is predicated on understanding mechanisms of innate

and adaptive immunity, as well as T- and B-cell signal pathways.
2 T cells are responsible for regulatory and effector mechanisms in the immune response. T-cell
effector activity is coordinated by regulatory cells driven by three signals of antigen presentation.
3 Clinical immunosuppression involves induction and maintenance therapies.
4 Induction therapies are used to prevent early acute rejection of allografts, and are generally aimed at
reducing T-cell signaling. Commonly used drugs are lymphocyte depletion agents, IL-2 receptor
antibodies, agents to block costimulatory signals.
5 Maintenance immunosuppression consists of calcineurin inhibitors, mTOR inhibitors, antimetabolite
agents, and steroids. All agents have a clinically significant side effect profile.
6 Acute rejection has a clinical phenotype and may involve cellular infiltration of the allograft as well
as antibody-mediated mechanisms. Chronic rejection, or chronic transplant dysfunction, is driven by
immune and nonimmune mechanisms and results in progressive graft fibrosis that is heretofore
irreversible.
7 Major side effects of chronic immunosuppression include calcineurin inhibitor–related
nephrotoxicity, major and minor infections, and cancer.
8 Clinical tolerance is the holy grail of transplantation, and novel targets in regulatory immunocytes
have emerged as a promising focus of future research.
INTRODUCTION
Modern clinical transplantation has rapidly evolved over the last 50 years. The fortitude of surgeons in
the early development of surgical techniques and basic science have enabled thousands of patients to
realize the gift of a solid organ transplant. The long-term benefit to adults and children who are on the
verge of death from kidney, liver, intestinal, pancreatic, pulmonary, or cardiac failure is directly linked
to our cumulative understanding of clinical transplant immunology. The discovery of the immune
response to alloantigens and the identification of molecular targets for modern immunosuppressive
agents have solidified clinical transplantation as the treatment of choice for patients with organ failure.
Management of the transplant recipient is predicated on understanding the mechanisms and clinical
manifestations of the graft immune response, and applying principles of clinical transplant immunology
to abate deleterious effects on graft function. Graft injury begins as a result of several complex
interactions between inflammatory mediators related to the obligatory ischemia–reperfusion injury tied
to surgical recovery, organ preservation, and implantation in the recipient. This inflammatory injury
overlaps with graft-host immune interactions, and ultimately promotes graft immunogenicity. This
process affects graft function by proliferation of antigen presentation and up-regulation of cell signaling
to recruit effector cells that lead to organ injury. These reactions also play a role in the development of
chronic rejection of the organ, which may lead to the need for repeat transplant or shortened recipient
life expectancy.
The application of transplant immunology principles in the creation of immunosuppression protocols
requires an in-depth understanding of the molecular mechanisms that lead to acute and chronic
rejection. Transplant rejection is the clinical phenotype of organ injury brought on by the recipient
immune system’s recognition of allogeneity. The rejection phenotype is the culmination of several
signals initiated by antigen presentation and effector mechanisms that operate through humoral- and
cell-mediated immune responses. Our growing understanding of transplant immunobiology has been
840
booksmedicos.org
directly responsible for the development of clinical therapeutics used in immunosuppression induction,
as well as maintenance therapy to prevent rejection, and in salvage situations to treat rejection once it
has occurred.
The aim of this chapter is to review the scientific principles behind the use of modern
immunosuppressive agents, the interplay between cell types involved in the alloimmune response, and
an in-depth discussion of modern therapeutics applied to the clinical management of the transplant
patient. Additionally, the complications of immunosuppressive therapy and evolving therapies will be
discussed.
SCIENTIFIC BASIS OF MODERN CLINICAL IMMUNOSUPPRESSION

The Immune Response to a Solid Organ Transplant
1 The interaction of a host’s immune system with foreign antigen is central to understanding the
pathways that modulate organ-directed effector responses. Operational tolerance is defined as the
immunologic acceptance of an organ allograft while maintaining global immune system integrity; down-
regulation of host effector mechanisms must be maintained while minimizing the suppression of
recipient defence mechanisms. T- and B-cell activation and regulatory pathways are primary targets for
conventional immunosuppressive regimens. Immunosuppressive regimens have been developed to
impact isolated pathways in T-cell activation by recipient antigen-presenting cells (APCs). As the field of
transplantation has matured, these pharmacotherapies have become more specific and less toxic to the
host immune system.
The development of mature T cells begins with nascent thymocytes. Thymocytes contain T-cell
receptors (TCR) arranged and rearranged in a random individual-specific manner. These TCR-containing
thymocytes are challenged by “self” antigen and undergo programmed cell death if they express “high
affinity” and activate. In contrast, these immature cells are programmed not to proliferate if they
express “too low” an affinity. Thymocytes with an intermediate affinity are fostered to survive and
differentiate into specific CD4- and CD8-expressing cells which interact with self-restricted major
histocompatibility complexes (MHCs) on APCs, such as dendritic cells, in the peripheral blood.
The foundation of the adaptive immune response lies in the presentation of antigen to T cells which
takes place via macrophages, B cells, and dendritic cells. Dendritic cells present antigen via their MHC
class I or II molecules to CD8+ T cells and CD4+ T cells respectively. The most common scenario occurs
when a T cell interacts with an APC–MHC complex presenting “self” antigen. In normal
(nonautoimmune) circumstances, this is usually a very weak bond and the T cell removes itself from the
interaction and begins to recirculate. In the context of infection or transplantation, the APC–MHC
complex presents a foreign peptide which the T cells recognize as “nonself” and begin the cascade of
activation as well as clonal expansion.
2 T cells are activated by a process that requires three sequential signals. The “three signal” process
of T-cell activation begins with signal 1 as the TCR interacts with the MHC–foreign peptide complex
presented by an APC. T cells become maximally activated only after a threshold number of TCRs have
been occupied.1 Once this occurs, multiple costimulatory supporting molecules on the periphery of both
the APC and T cells “ride” lipid rafts to the synapse of the TCR–MHC interaction.2,3 Once these
costimulation molecules have reached the immunologic synapse they begin to interact with each other,
comprising signal 2. The engagement of TCR by MHC–peptide complexes in combination with the
interaction of costimulatory, accessory, and adhesion molecules results in a cascade of signaling
pathways including activation of NFκB and translocation of the nuclear factor of activation and
transcription (NFAT) to the nucleus of the T cell which translates and transcribes proteins such as
interleukin-2 (IL-2).4 IL-2, formerly known as T-cell growth factor, then contributes to the clonal
expansion of other T-cell populations allowing for cellular expansion to fight against the inciting foreign
antigen. IL-2 also engages with CD25 on the T cell itself thereby activating a doublet complex known as
the mammalian target of rapamycin, or mTOR. Signaling through mTOR constitutes “signal 3” of
activation which affects cell cycling and cytokine production, cellular proliferation, and T-cell
differentiation into an effector cell against the grafted organ. This pathway initiates the slower, more
sophisticated, adaptive immune response (Fig. 34-1).5
Immediately following implantation and reperfusion of an organ allograft, markers of inflammation
are up-regulated which act as homing signals to effector T cells. These inflammatory mediators also
allow for a more efficient uptake of antigen by dendritic cells. Organ-derived dendritic cells are released
841
booksmedicos.org
to the host’s secondary lymphoid tissue. Termed “passenger leukocytes,” these dendritic cells are primed
to present antigen to naïve host T cells.6,7 These activated CD4+ T cells specialize into subsets of helper
T cells each identified by a distinct signature of cytokines. Interferon-γ (IFNγ) secreting TH1 cells are
central to various cell-mediated rejection responses including acute and chronic or delayed-type
hypersensitivity responses. TH2 cells support B-cell production of antibody and secrete cytokines with a
suppressive capacity such as IL-4 and IL-10.7 TH17 cells secrete IL-17, which is a potent instigator of
tissue injury in the setting of transplantation and autoimmune diseases.8
Figure 34-1. The signal hypothesis of T-cell activation and molecular targets of modern clinical immunosuppression. T-cell
activation requires three signals to initiate an effector response: antigen presentation of nonself MHC, costimulatory signal, and
regulation of cytokine signaling at the cell surface. These three signals are thus targets for therapeutic drugs used in modern
clinical immunosuppression in both induction and maintenance phases, as well as in the treatment of rejection. The figure
demonstrates the site of action of these agents.
Memory T-cell subsets react in a more rapid manner to the graft and incite an accelerated rejection
response. Seminal studies investigating memory responses to allografts proved that antigen-experienced
memory T-cell subsets can cause graft destruction in the absence of secondary lymphoid tissue.9
Clinically, these “memory” T cells are generated throughout the lifespan of a potential recipient due to
various infections that the patient may have experienced. Memory T-cell subsets that have been
generated by these infections may then react against an organ at the time of transplant if the antigenic
response from the organ mimics that of the previous infectious episodes. This concept of “heterologous
immunity” may account for early rejection responses in patients who have not been classically
sensitized by foreign human antigen by transfusion, pregnancy, or previous transplant.10 Studies have
also suggested that certain induction therapies may eradicate naïve host T cells yet spare memory
subsets which may also contribute to potential early rejection responses and express resistance to
tolerance induction.11–13
Immunosuppression Induction in Solid Organ Transplantation

Human immunity depends on innate and adaptive responses to foreign antigen. The innate response is
rapid and nonspecific when foreign antigen is encountered; the adaptive response develops over time
and harbors the ability to recall pathogens upon each successive insult. Therefore, adaptive immunity
becomes more efficient with each antigenic interaction. The innate immune response usually sets the
scene for the adaptive response but it is the antigen specificity of the adaptive response that allows for
activation and proliferation of effector cells to rid the system of the pathogenic insult. Current therapies
in clinical immunosuppression target this global activation and proliferation of T cells.
842
booksmedicos.org
3 Induction immunosuppression is used intraoperatively and/or perioperatively as a prophylactic
treatment to attenuate acute rejection responses in the first few months after transplant when the risk is
highest.14 Various induction strategies have been developed in order to spare the use of toxic calcineurin
inhibitors (CNIs) and steroids.
CELL SURFACE RECEPTOR BLOCKADE

4 Each of the three signals in T-cell activation is uniquely important and each depends on the other for
cellular proliferation and effector cell differentiation (Fig. 34-1).15,16 If one signal acts in isolation
without the others, anergic or apoptotic signal ensues.17,18 With this knowledge, various
pharmacotherapies have been developed to block signal 2, or costimulation, in order to inhibit the
clonal proliferation of the effector T cell. Several pathways are involved in the make-up of the second
signal in lymphocyte activation. Costimulation pathways have been targeted by various types of
biologics including monoclonal antibodies as well as recombinant fusion proteins.
A specific APC-T–cell interaction is crucial. The engagement of APC-derived CD80/86 (B7 molecules)
with CD28 on T cells (members of the Ig superfamily) is integral to positive costimulation.5
Pharmacotherapies targeting other costimulatory pathways are in various phases of development and
include monoclonal antibodies to CD40 as well as CD2. Although costimulation blockade has been
successfully utilized for the induction of tolerance in rodent models, this has not been realized in
humans. Costimulation blockade has proven to be beneficial when used as maintenance
immunosuppression.19
The initiation of signal 3 begins with the engagement of IL-2 on CD25 located on the surface of the T
cell. IL-2 receptor blockade has become standard of therapy in the perioperative period (day 0 and day
4) to allow for early allograft acceptance and reduced usage of nephrotoxic CNIs. Early clinical trials
proved that induction therapy with IL-2 receptor blockade significantly reduced acute rejection rates in
renal transplant recipients when compared to placebo groups and in combination with standard CNIs
and steroids.20
B7/CD28 CTLA4 Blockade

The expression of CD80 (B7.1) and CD86 (B7.2) on the surface of APCs provides T cells with either
activation signals, if engaged to CD28, or inhibitory signals, if ligating cytotoxic T-lymphocyte antigen
4 (CTLA4). CD80 and CD86 interact preferentially with CTLA4 (CD152) when compared to CD28.18,21
CTLA4 is also up-regulated following the activation process and its ligation results in inhibition of
activation thereby controlling clonal expansion.22,23 Additionally, CTLA4 is constitutively expressed on
regulatory T cells.24 Blockade of each B7 molecule as monotherapy has not led to significant allograft
survival in nonhuman primate models. In contrast, blockade of both B7 molecules together did lead to
prolonged graft survival but was not able to induce tolerance as rejection occurred once therapy was
stopped.25–27 An immunoglobulin fusion protein of CTLA4 (abatacept), has been shown to inhibit graft
rejection in xenogeneic and allogeneic systems.28,29 These promising early results have prompted the
development of CTLA4-Ig variants.
LEA29Y (belatacept) is a second-generation molecule, derived as a result of mutating two amino acids
of CTLA4-Ig. Belatacept possesses a twofold greater ligation capacity for both CD80 and CD86. The
increase in avidity allows for a more complete blockade of the B7 molecules and a 10-fold greater
suppression in in vitro assays.30 Belatacept has shown improved renal function, reduction in chronic
allograft nephropathy, decreased calcineurin-related toxicity, and no thromboembolic complications in
phase II trials.31 Phase III trials have evaluated the efficacy and renal protection of belatacept in
standard (BENEFIT) and expanded criteria donors (BENEFIT-Ext). There was an increased incidence of
posttransplant lymphoproliferative disease in Epstein–Barr virus (EBV)-seronegative patients and acute
rejection at 1 year in the belatacept treatment groups compared to CNIs. Additional results revealed an
improved glomerular filtration rate (GFR) and lipid profile over a 5-year period.32–35
IL-2 Receptor Blockade

Basiliximab is a chimeric mouse/human IgG1 monoclonal antibody to the alpha chain of CD25 (IL-2
receptor) which has proven to reduce acute rejection rates in adult and pediatric renal and pancreas
transplant recipients. In clinical trials with 6-month follow-up, basiliximab had a significant impact on
acute rejection rates with no increase in infectious complications.36 Often used in kidney transplant
843
booksmedicos.org
patients as induction therapy, and in liver transplantation in order to spare the nephrotoxic effects of
tacrolimus, long-term follow-up remains to be provided.37–39 In a randomized, prospective, placebo-
controlled trial of patients investigating immunoprophylaxis in liver transplantation, investigators
identified a lower acute rejection rate in HCV-negative patients at 6-month follow-up in patients treated
with basiliximab in combination with standard CNI therapy.40
LEUKOCYTE DEPLETION
In order to achieve tolerance to an organ transplant, it may be necessary to maximize the potential of
engraftment by depleting the alloreactive effector T cells (and B cells in some therapeutic regimens)
which mediate a rejection response. Many investigators have identified the value of monoclonal or
polyclonal antibodies designed to bind to peripheral alloreactive lymphocytes. The short-term depletion
of leukocytes using antithymocyte globulin, anti-CD3, anti-CD2, anti-CD4, and anti-CD8 has proven
successful in terms of long-term graft survival in animal models; these results are further enhanced with
thymectomy prior to transplantation in order to prevent posttransplantation peripheral effector cell
repopulation.41,42 In nonhuman primate models, anti-CD3 conjugated to diphtheria immunotoxin
administered alone prior to transplantation or in conjunction with sirolimus (rapamycin) or
deoxyspergualin, inhibitor monocytes and macrophages, produced tolerance via T-cell depletion.43–45
Clinical trials in kidney transplant recipients using anti-CD52 antibody (alemtuzemab)–mediated
leukocyte depletion alone and in combination with deoxyspergualin were not able to induce
tolerance.46,47 In subsequent trials, alemtuzumab therapy allowed for the use of low-dose
immunosuppression in steroid-free regimens in order to control effector responses; alemtuzumab is now
a commonly used and inexpensive induction agent.48–52 Memory T cells are the most resistant to
depletion with alemtuzumab therapy.13,53
Polyclonal leukocyte-depleting antibodies, such as thymoglobulin (rabbit antithymocyte globulin
[rATG]), are useful as induction agents, and are mainstays of induction therapy in renal transplant
recipients.54 Upon binding various T-cell epitopes, rATG lyses leukocytes using complement-dependent
pathways and opsonization leading to mononuclear cell phagocytosis of T cells.55 rATG also binds to
surface receptors on dendritic cells, which impair antigen presentation.55 Polyclonal antithymocyte
globulin is wrought with serious side effects including a predisposition to posttransplant
lymphoproliferative disorder and the cytokine release syndrome.56,57
Depleting the recipient of leukocytes creates a window of opportunity for an allograft to “settle in”
without attack by effector immunocytes. The recipient’s transient immunodeficiency is dictated by the
strength and duration of depletion. T-cell depletion strategies have paved the way for future studies
involving administration of donor antigen along with leukocyte depletion in an attempt to achieve
chimeric states.58
CLINICAL THERAPEUTICS FOR MAINTENANCE

IMMUNOSUPPRESSION IN SOLID ORGAN TRANSPLANTATION
Calcineurin Inhibitors
5 One of the greatest medical discoveries of 20th century was the identification of the CNIs with their
effects on T-cell signaling, and their alterations in cell-mediated immunity. This class of agents has
potent biologic activity and minimal myelosuppressive effects, which were a significant limitation in
early clinical transplantation. Cyclosporine A was the first of these drugs identified, initially found in a
soil sample from the fungus Tolypocladium inflatum. Cyclosporine is a cyclical fungal peptide composed
of 11 amino acids, with significant immunosuppressive effects.59,60 Subsequently, the clinical efficacy of
cyclosporine A was demonstrated in human kidney transplantation, opening the gates to a new era for
clinical organ transplantation. Cyclosporine remained the mainstay of clinical immunosuppression for
several years, and was used across organ types by thousands of patients. In 1984, FK506 (tacrolimus)
was identified as another CNI with a similar mechanism of action. FK506 is a macrolide
immunosuppressant that was approved by the U.S. Food and Drug Administration for use in liver
transplantation.61–63 Tacrolimus has become the mainstay of maintenance immunosuppression in solid
organ transplant programs due to a gentler side effect profile and potency of immunosuppression, and is
used in virtually all solid organ types.
844
booksmedicos.org
CNIs, as a class, disrupt regulatory T-cell signaling and lead to a down-regulation of IL-2 production,
which eventually decreases the activity of cytotoxic T cells. Antigen presentation at the TCR leads to an
increase in cytoplasmic calcium levels through a protein kinase and G-protein reaction within regulatory
T cells. This calcium binds to calmodulin, a regulatory subunit of the phosphatase calcineurin, prevalent
in immunocompetent lymphocytes and nerve cells. Calcineurin is responsible for cleaving the phosphate
bound to NFAT (nuclear factor of activated T-cells) which in its activated form traverses the T-cell
nuclear membrane and promotes transcription of IL-2. Inhibition of calcineurin occurs through the
activation of immunophilins, such as cyclophilin and FK-binding protein, which are endogenous
cytosolic peptides. The cyclosporine–cyclophilin complex and its counterpart, the FK506–FKBP12
complex, prevent dephosphorylation of NFAT, which in turn leads to reduced IL-2 production and
diminished T-cell signal transduction to effector lymphocytes.
Side Effects
CNIs have a variety of side effects which present challenges in the clinical management of transplant
recipients. One of the issues relates to drug interactions for patients on tacrolimus or cyclosporine.
Common interactions that may boost levels of CNIs occur in patients requiring antifungal therapy,
particularly in the azole class, as well as other drugs metabolized by hepatic/intestinal cytochrome P450
3A4 enzyme. As implied by the name, calcineurin is also present in nerve tissue as well as lymphocytes.
Drug activity in nerve tissue leads to several clinical effects including tremors, seizures, and posterior
reversible encephalopathy syndrome.64 Additional side effects include hyperkalemia,
hypercholesterolemia, and gastrointestinal dysfunction including diarrhea. Cyclosporine has also been
associated with gingival hyperplasia that is seen less frequently with tacrolimus. The most significant
long-term effects include chronic nephrotoxicity that may precipitate end-stage renal disease, as well as
new-onset diabetes mellitus after transplantation. Consultation with a transplant pharmacist is integral
to the successful management of the posttransplant patient to prevent toxicity and achieve therapeutic
immunosuppression goals.
mTOR Inhibitors
The first discovered mTOR inhibitor was sirolimus. Sirolimus, or rapamycin, is a bacterial macrolide
derived from Streptomyces hygroscopicus, found initially in a soil sample from Easter Island (Rapa Nui).
Like CNIs, its mechanism of action leads to decreased IL-2 proliferation. Sirolimus binds to FK-binding
protein 12, as does tacrolimus. The site of action of the sirolimus–FKBP12 complex is known as the
mammalian target of rapamycin, or mTOR. Despite having structural similarity to tacrolimus, sirolimus
has limited activity on calcineurin when bound to FKBP12. The complex disrupts signal transduction of
the IL-2 receptor and decreases nuclear transcription of molecules active in lymphocyte homing.65
Sirolimus also has significant antiproliferative properties, and inhibits cell cycle activity in lymphocytes
and fibroblasts.66–68
Sirolimus has been adopted in a variety of clinical protocols. Sirolimus is currently used primarily in
place of CNIs, most commonly in patients who are weeks to months out from the transplant operation.69
Sirolimus has less nephrotoxicity than CNIs, but has been associated with a higher risk of acute rejection
in some studies. In liver transplantation, conversion from tacrolimus to sirolimus in patients with
reduced kidney function was associated with more acute rejection episodes but did not have a tangible
benefit in terms of kidney function in a randomized control trial.70 Some have advocated for lower-dose
CNIs as maintenance therapy in patients with impaired renal function compared to sirolimus
monotherapy,71 and studies have demonstrated the potential of low-dose CNIs in conjunction with
sirolimus for maintenance immunosuppression. Importantly, there is an FDA black box warning against
using sirolimus in conjunction with higher-dose CNIs due to higher risk of mortality and graft loss in
liver transplantation, as well as an increased risk of hepatic artery thrombosis within the first month
after transplant.
Everolimus is another mTOR inhibitor that has recently been approved for use in kidney and liver
transplantation. Everolimus is a hydroxylated derivative of sirolimus, and its preserved structure allows
for a similar mechanism of action via FKBP12 binding and mTORC1 inhibition. Its immediate appeal
was its lower risk of nephrotoxicity. In a recent multicenter prospective clinical trial, patients with
reduced-dose tacrolimus and everolimus had improved GFR at 2 years posttransplant compared to
patients on standard tacrolimus-based regimens, without any higher risk of biopsy-proved acute
rejection or major side effects.72,73 This improvement in GFR has also been identified retrospectively in
patients converted to everolimus in maintenance immunosuppression.74
845
booksmedicos.org
Side Effects of mTOR Inhibitors
Sirolimus has been associated with impaired wound healing after transplant, including anastomotic
dehiscence in lung transplantation, surgical site infections, and fascial union problems.75–80 Surgeons
confronted with transplant patients who are on mTOR inhibitors should consult with transplant
professionals prior to operative intervention if possible, in order to guide alterations in
immunosuppressive therapy to minimize complications. Several other complications have been noted in
patients on mTOR inhibitors. Pulmonary toxicity manifested as pneumonitis has been identified, and
caution should be taken in administering the drug to patients with pre-existing lung disease. Metabolic
complications including hyperlipidemia and new-onset diabetes mellitus after transplant have also been
identified as significant side effects.81 In low- to moderate-risk renal transplant recipients, conversion
from tacrolimus to mTOR inhibitors was associated with a higher risk of acute rejection, higher rates of
proteinuria, hypercholesterolemia, and anemia.81
Antimetabolite Drugs
Antimetabolite drugs in solid organ transplantation comprise a class of agents aimed at suppressing
lymphocyte proliferation by reducing the rate of de novo purine synthesis, which prevents effective
nucleotide synthesis and DNA transcription. Typically, these drugs are used in combination with CNIs
and steroids. One of the first antimetabolite drugs applied in clinical transplantation was azathioprine.
Azathioprine has been applied in a multitude of disease states including inflammatory bowel disease and
autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. While it is
effective in reducing T-cell and B-cell propagation, azathioprine is also a potent suppressive agent of
bone marrow, increases the risk of anemia, and is also associated with pancreatitis.
A newer antimetabolite, mycophenolic acid (MPA), has emerged as a mainstay in solid organ
transplantation. MPA was identified in a Penicillium fungal species, and is hepatically metabolized. MPA
has less myelosuppressive activity than azathioprine, but side effects are common.
Side Effects of Antimetabolite Drugs

Myelosuppression and leukopenia are common side effects of this class of agents. Mycophenolate is also
associated with a significant risk of gastrointestinal dysfunction including diarrhea, nausea, and
vomiting. Azathioprine has been recognized as a group 1 carcinogen by the National Toxicology
Program in the United States, related to length of use and dosage.82–85 Mycophenolate should be
avoided in pregnancy or in transplant recipients trying to conceive due to the risk of miscarriage and
congenital malformations.86–90
Steroids
Steroids have represented the mainstay of immunosuppressive therapy since the beginning of clinical
transplantation. Glucocorticoids are steroids that arise from the zona fasciculata in the adrenal gland.
These molecules have a plethora of effects in humans, and their receptors are omnipresent across human
cell types. In lymphocytes, glucocorticoids act on cytosolic receptors that in turn lead to a variety of
intracellular signals that are responsible for gene transcription, and decrease the expression of several
cytokines, including IL-2. Glucocorticoids also reduce the number and function of both T cells and B
cells.
Side Effects of Steroid Therapy

Steroid therapy is used in a variety of clinical treatments including maintenance immunosuppression and
in high doses as a rescue therapy in patients presenting with acute rejection. There are several side
effects to chronic corticosteroid use, which have prompted transplant clinicians and researchers to
develop protocols that reduce the need for chronic steroid use. Common side effects include glucose
intolerance, weight gain, skin and tissue frailty, osteopenia and osteoporosis, muscle breakdown,
neuropsychiatric dysfunction, glaucoma and cataracts, secondary hypercortisolemia, and other effects.
Many transplant programs are shifting toward steroid avoidance in maintenance immunosuppression in
low-risk patients.91–93
TREATING REJECTION IN SOLID ORGAN TRANSPLANTATION

6 Immunologic rejection can occur minutes to years after an organ transplant. The early phases of
846
booksmedicos.org
rejection, termed hyperacute rejection, can occur on the operating room table to 24 hours after surgery
and is mediated by the humoral immune system. Acute rejection is a cell-mediated phenomenon which
often manifests days to months after transplant. Chronic rejection occurs in the months to years after
transplant and continues to be one of the leading causes of graft loss in the long term. Acute and chronic
antibody-mediated rejection (AMR) is a separate phenomenon that may occur days to years after
transplant and remains an important barrier to successful engraftment of organs.
Hyperacute Rejection
Hyperacute rejection is a rare clinical entity in modern clinical transplantation. Hyperacute rejection is
generally attributed to ABO blood group incompatibility or the presence of preformed anti-HLA
antibodies. In the allograft, the capillary endothelium expresses blood group antigens which may join
with circulating antibodies to A and B glycoproteins. For example, a blood group B transplant candidate
would have circulating anti-A IgG antibodies in blood. If a blood group A kidney allograft were
transplanted into that recipient without any other treatment, these antibodies would react with the
donor endothelium and activate complement and humoral immunity effector mechanisms, which would
lead to endothelial injury, thrombosis, as well as intraparenchymal hemorrhage. This response usually
happens within minutes after reperfusion of the allograft, and requires removal of the allograft in order
to prevent a systemic inflammatory response which may lead to multiorgan failure. Prevention of this
type of rejection is central to the practice of clinical transplantation, and mandates confirmation of
donor and recipient compatibility via ABO blood group verification and cross-matching prior to
implantation of the allograft.
Acute Rejection
Induction protocols in combination with immunosuppressive therapy successfully prevent the relatively
quick onset of acute rejection episodes. In the case of renal transplantation, induction therapies in
combination with potent maintenance therapies have fostered a significant improvement of 1-year
outcomes.94 Less than 10% of organs experience clinically significant acute cellular rejection (ACR)
episodes leading to graft loss at 1 year.95 As discussed above, ACR is an adaptive response characterized
by T-cell interactions with donor antigens either presented directly by the donor APC or indirectly by
the recipient professional presenting cells.96 Once clonal expansion occurs “effector” T cells then
infiltrate the graft and mediate various methods of organ injury.
The gold standard in pathologic categorization of renal transplant rejection is the Banff classification
model. The Banff classification originated at a consensus conference in 1991 aimed at ranking the levels
of rejection seen on kidney transplant biopsies based on degree of structural damage, such as tubulitis,
arteritis, and cellular infiltrate.97 In renal transplantation, the diagnosis of ACR occurs with tissue
confirmation after ruling other causes for declining graft function. Treatment of ACR is usually dictated
by the Banff classification. For example, borderline rejection characterized by Banff class IA or IB is
often treated with pulse corticosteroids and increases in maintenance immunosuppression whereas,
more severe ACR is more often treated with multiple doses of thymoglobulin. Today, ACR is often the
result of inadequate immunosuppression due to noncompliance/adherence or early immunosuppression
withdrawal/underdosing. Repeated episodes of acute rejection are associated with chronic dysfunction
and early graft failure.
Chronic Rejection
The clinical sequelae of chronic rejection (more recently termed chronic transplant dysfunction or CTD)
are varied and organ specific. The unifying factor of CTD among all organs transplanted is the
histopathologic effect of arterial intimal thickening in the vessels supplying the organ, termed
transplant arteriosclerosis or transplant vasculopathy. Both immune and nonimmune stimuli may up-
regulate pathways leading to progressive graft fibrosis. Immune-dependent mechanisms, including HLA
mismatching, inadequate immunosuppression, and episodes of acute rejection, promote the
development of CTD and eventual graft failure. Additionally, immune-independent mechanisms, such as
prolonged ischemia time and usage of brain dead donor organs, as well as recipient factors such as
native hypertension may also play a role in the onset of CTD. Various studies suggest that the
development of vascular fibrosis progressing to parenchymal fibrosis is multifactorial and includes
effector responses mediated by complement, CD4+ T cells, CD8+ T cells, and alloreactive
antibodies.98–102
847
booksmedicos.org
Figure 34-2. Time course, mechanism, and morphology of transplant rejection. Allograft rejection responses have many different
phenotypes, which also lead to different therapies. This figure provides a summary of the types of clinically significant rejection
episodes, the root cause behind them, and histopathologic features identified on biopsy.
Clinically, the manifestations of CTD depend on the type of organ allograft. Recipients of renal
allografts with CTD often manifest with proteinuria, decreases in GFR, increases in plasma creatinine,
and arterial hypertension. Patients who have undergone liver transplantation may present with
abnormal liver function tests or an increase in serum bilirubin secondary to the so-called vanishing bile
duct syndrome. Bronchiolitis obliterans, detected by computed tomography and altered pulmonary
function tests indicate the onset of CTD in lung transplant recipients. Patients receiving cardiac
allografts may present with a range of symptoms from arrhythmias to fatal myocardial infarction.103
The timing, mechanism, and morphology of hyperacute, acute, and chronic rejections are summarized
in Figure 34-2.
Antibody-Mediated Rejection
Antibody-mediated rejection or AMR can occur in both the acute and chronic phases of transplantation.
Increasingly, AMR has been shown to occur in multiple organs including liver and heart.104 AMR starts
with production of donor-specific antibody (DSA) directed to the endothelial lining of organ allografts.
DSA–endothelial cell interactions lead to complement activation as well as innate responses resulting in
allograft injury.105,106 In the chronic setting, persistent DSA leads to microthrombotic events and late
graft failure. Diagnostically, along with serum titers of circulating DSA, tissue biopsy reveals deposition
of complement split products including C4d and inflammation of capillaries and renal tubules. AMR has
also been diagnosed using newer endothelial, cell-specific biomarkers of capillaritis.107 Liver allografts
have shown susceptibility to AMR and DSA in recent studies.108
The treatment of acute AMR is based on removal of inciting antibodies (Fig. 34-3). Although there are
no high-quality evidence-based treatments for acute AMR, strategies include plasmapheresis,
immunoadsorption, use of B-cell toxic antibodies such as rituximab, newer proteasome inhibitors such as
bortezomib, and even splenectomy.109 In patients with drug-resistant AMR, monoclonal antibodies to
complement C5 (eculizumab) have been used off-label with some encouraging results although the
extreme expense of the drug has hindered its investigation in randomized control trials.109
848
booksmedicos.org
Figure 34-3. Current strategies to treat various phases of antibody-mediated rejection. Antibody-mediated rejection involves
antigen presentation, T-cell signaling, and effector responses that result in stimulation of B cells, antibody formation and release,
and antibody deposition and initiation of the innate immune response via complement activation. This figure demonstrates the site
of action of drugs and treatments common to antibody-mediated rejection treatment protocols, which are ultimately aimed at
reducing antibody. (Adapted from Djamali, Kaufman DB, Ellis TM, et al. Diagnosis and management of antibody-mediated
rejection: current status and novel approaches. Am J Transplant 2014; 14:25514;plantand management.)
COMPLICATIONS OF IMMUNOSUPPRESSIVE THERAPY

7 The need for continued immunosuppression after transplant is a necessary evil in clinical
transplantation. In order to maintain long-term graft function, the immune system is suppressed as
discussed using a variety of agents. Long-term exposure to these agents does carry a risk of serious
complications that must be discussed with any patient considering a transplant for the treatment of end
organ failure.
Renal Failure with Calcineurin Inhibitors

The nephrotoxic effects of CNIs have long been recognized in clinical transplantation, and several
protocols have been designed to reduce the risk of acute and chronic renal failure in the renal and
nonrenal solid organ transplantation. Registry analyses suggest that 7% to 21% of nonrenal transplant
recipients are at risk for renal failure, and patients treated with CNIs are at significantly increased risk
of requiring dialysis treatment in the months and years after transplant.110
In the acute setting immediately after transplant, CNIs may cause renal dysfunction by affecting renal
blood flow via several mechanisms including vasoactive/nitric oxide-dependent pathways, as well as
activation of the renin/angiotensin system. These mechanisms result in increased renal vascular
resistance and lower GFR. In the early posttransplant setting, these nephrotoxic effects are typically
reversed with reduction in CNI dosage, and seem to be independent of plasma concentration.
CNI-related renal dysfunction may also result in chronic organ injury. Histologically, kidneys
demonstrate interstitial fibrosis and tubular atrophy. Cyclosporine has been implicated in up-regulation
of TGF-beta, a profibrotic cytokine.111 Reduction in CNI dosage does not improve renal function in the
long term in patients with global fibrosis, and patients may require renal replacement therapy. In liver
transplantation, the need for long-term dialysis represents a significant increase in posttransplant
mortality risk and attenuates the survival benefit of the initial transplant.112–115 In order to preempt
CNI-associated effects on kidney function, patients with pre-existing renal insufficiency and other end
organ failure are often considered for combined nonrenal and renal transplantation if they meet certain
criteria.
Infections after Transplant

Posttransplant infections are directly related to the level of immunosuppression in the host. In the early
period after transplant, when levels of immunosuppression are high and proximal to the use of T-cell
depleting induction agents, the risk of opportunistic infections is high and management is focused on
antimicrobial prophylaxis. Further from transplant, less immunosuppression is typically required, and
prophylaxis is not necessary. However, the prevalence and incidence of infectious diseases in solid
organ transplant recipients mandate close monitoring of clinical signs and symptoms, and appropriate
diagnostic testing when a clinical suspicion arises of a bacterial, viral, parasitic, or fungal infection.
Infections after transplant may consist of donor-derived infections transmitted with the organ, recipient-
derived infections due to colonization or other pretransplant exposure, nosocomial infections acquired in
the healthcare setting, and community-acquired infections.116 Figure 34-4 demonstrates the peak
incidence of common opportunistic infections as a function of time after transplant. When faced with a
transplant patient with a high clinical suspicion of an infection, transplant providers and infectious
disease specialists use this information, clinical history, affected organs and systems, and a battery of
cause-oriented diagnostic tests to establish the diagnosis and treatment strategy (Fig. 34-5).
Donor-Derived Infections
Deceased organ donors may be exposed to community-acquired infections prior to death, infectious risk
related to lifestyle exposures (i.e., intravenous drug abuse), as well as nosocomial infections acquired
during hospital care. Several infectious transmissions have occurred as a result of donor transmission,
849
booksmedicos.org
including human immunodeficiency virus (HIV), West-Nile virus, rabies, Chagas disease, and
lymphocytic choriomeningitis virus. Careful attention must be paid to the circumstances surrounding the
donor’s death as well as reported signs and symptoms such as fever and altered mental status. Prior to
organ recovery, organ donors are routinely serologically screened for several infectious pathogens,
including HIV, hepatitis, cytomegalovirus (CMV), EBV, and syphilis. Routine blood, urine, and sputum
cultures may be used in premortem care. Serologic testing consists of antibody testing, which is not
100% sensitive, but the recent inclusion of nucleic acid testing in many centers may help mitigate risk in
organ acceptance and aid patient counseling.117 In the case of CMV, hepatitis, and EBV serologic testing,
serologic matching between donors and recipients drives the perception of posttransplant infectious risk
and guides antimicrobial prophylaxis decisions and selection of immunosuppression.
Figure 34-4. Timeline of common infections after transplantation. Immunosuppression predisposes transplant recipients to
infection by deterring host defenses. In this context, bacterial, viral, and fungal infections may arise which have distinct peaks of
onset. Treatment of these infections usually involves withdrawal or reduction of immunosuppression in most cases, particularly
when infections are life-threatening or are causing significant morbidity. (Adapted from Fishman JA. Infection in solid-organ
transplant recipents. N Eng J Med 2007;357:2601–2614.)
Recipient-Derived Infections
The incidence of posttransplant infections that arises from pretransplant exposure to the recipient is
increasingly recognized. Transplanting patients with active infections should be undertaken with
extreme caution due to the risk of dissemination of disease with early immunosuppression.
Nosocomial pathogens may colonize the recipient prior to transplant, when healthcare utilization may
be high due to organ failure, or may infect patients at any point after transplant. Pathogens may acquire
antibiotic resistance which may make treatment difficult, such as in cases with vancomycin-resistant
Enterococcus, methicillin-resistant Staphylococcus, azole-resistant Candida, as well as in Clostridium
difficile colitis, several gram-negative enteric pathogens, and fungi.116 Recipient exposure via travel or
residence in geographically endemic areas can also be a risk for infection (fungal infections such as
histoplasmosis, aspergillosis, coccidiomycosis, atypical bacterial infections such as Mycobacterium
tuberculosis, parasitic infections caused by Strongyloides or Trypanosoma cruzi), as well as reactivation of
dormant viruses (hepatitis, CMV, or varicella-zoster virus). Exposures to relatively benign pathogens
may result in major infections after transplant. Respiratory viruses may further weaken natural tissue
defenses in the bronchopulmonary tree and lead to superinfection with other pathogens. Fungal
infections derived from the soil such as Nocardia or Aspergillus may arise in this fashion, and require
changes in immunosuppression to prevent exacerbation of infection.
850
booksmedicos.org
Figure 34-5. Common infections after transplantation, prophylaxis, and treatment strategies. After transplant, while predisposed to
multiple infections related to immunosuppression, certain infections are particularly common and virulent. Clinical decisions
regarding prophylaxis against these pathogens and how this affects immunosuppression are key decision points in managing the
posttransplant patient.
While the spectrum of potential infectious pathogens is broad, infectious epidemiology in the
immunocompromised population guides targeted prophylaxis strategies. Common posttransplant
infections are listed in Figure 34-5. Immunosuppression management in the infected transplant recipient
is often challenging, and dependent on the relative immunogenicity of the organ transplanted, the
virulence of the pathogen, and the presence or potential of disseminated disease. Minimization of
immunosuppression is a mainstay during infectious episodes, but must be balanced with the risk of
intervening acute rejection.
Cancer
Chronic immunosuppressive therapy weakens host defenses against neoplastic processes. There is well-
established evidence that solid organ transplant recipients of every type have an increased risk of
malignancy, both related to immunosuppression and oncogenic viral infections.118 The most common
cancers incurred by solid organ transplant recipients are skin cancers, followed by posttransplant
lymphoproliferative disease.118,119 In this context, posttransplant patients are strongly recommended to
have yearly skin examinations by a dermatologist. Screening for malignancy in chronically
immunosuppressed patients follows general screening guidelines. Treatment of cancers is driven by site
and extent of disease, but in all cases includes reduction in the amount of immunosuppression.
APPROACHES TO TOLERANCE
8 The perpetual goal of clinical transplant immunology is the induction of tolerance. Several advances
have been made in identifying potential cellular and molecular targets and pathways on a basic science
level, and case reports of maintaining transplant recipients with normal graft function without any or
very little immunosuppression are well known. While clinical tolerance remains out of reach in the
current era, several potential mechanisms are the focus of research and drug development.
Immunodeletion
Experimental strategies to deplete graft-specific effector T cells have been employed both centrally, in
the thymus, as well as in the periphery. These methods take advantage of developing T cells by
exposing them to donor-specific antigens at an early stage such that they are deleted to the graft during
transplantation. This has been achieved with the use of intrathymic administration of donor-specific
antigen such as bone marrow in large animal models of kidney and skin transplantation in conjunction
with total lymphoid irradiation.120–122 Infusion of intrathymic alloislets in combination with peripheral
lymphocyte depletion has also been shown to reverse diabetes in experimental animal models.123 More
recently, studies have demonstrated this concept in models of autoimmunity.124 These observations
suggest that centrally inoculated donor antigen or allopeptides combined with peripheral leukocyte
851
booksmedicos.org
depletion may lead to the successful induction of tolerance.125–127
Immunoregulation
Postthymic immunomodulatory strategies to induce graft acceptance are often referred to as “peripheral
tolerance.” Various approaches exist to induce peripheral tolerance. Since the discovery of CD4+ T cells
expressing the biomarkers CD25+ CD127low and the master gene regulator Foxp3+, the field of
immunoregulation has expanded to include CD8+ regulatory cells, regulatory dendritic cells, and B-
regulatory cells.100,128–130
Regulatory T cells (Tregs) have shown the most promise and exert suppressive capabilities over
effector-type T cells in various ways.131–133 Naturally occurring Tregs make up 1% to 2% of the T-cell
repertoire and clonally expand when needed; when removed from immunocompetent individuals the
lack of these cells leads to spontaneous autoimmunity in both mouse and man.128,134 Their suppressive
ability ranges from direct toxic effects on effector cells using granzyme/perforin pathways, to secretion
of suppressive cytokines such as IL-10 and TGF-β, to modulation of donor APCs.135 Human Treg cells
may be isolated, expanded ex vivo, and then reintroduced as therapy in vivo to inhibit chronic rejection
responses using human cells and tissue.100 These findings have allowed Tregs to be introduced into
various clinical trials.136 Studies have also suggested that existing immunotherapies, such as sirolimus,
may also allow for the expansion of these suppressive T-cell subsets.137,138 Along with naturally
occurring Tregs, inducible Tregs may arise in the presence of donor antigen and may be generated by
naïve T cells even in the absence of their naturally occurring counterpart.139–141 Tregs have proven to be
essential for graft-specific self-tolerance and the expansion of pure populations of these cells will almost
certainly be the key to efficient clinical translation.
Immunologic Anergy and Exhaustion

Mechanisms of T- and B-cell anergy are important to the development of graft-specific tolerance.
Anergic responses occur within lymphocytes when incomplete activation takes place and all three
signals of activation are not fully engaged. Anergic responses have also been associated with regulatory
activity. Blockade of accessory molecules and costimulation may also lead to anergic-type lymphocyte
responses.121 T-cell exhaustion occurs when donor antigen load exceeds the activation capacity of
recipient T cells thereby overwhelming their activation and clonal expansion capabilities. This concept
has been invoked to explain the tolerant effects of liver and multiorgan transplants given the high donor
antigen load and chronic stimulation.142
Chimerism
The introduction of donor-type immunocytes within a recipient prior to allograft transplantation has
been the subject of many investigations over recent years. Combinations of donor and recipient cell
types in a single host have been thought to confer a state of operational tolerance to organ allografts.
Historically, stable mixed chimerism of donor and recipient cells was a concept limited to the field of
bone marrow transplantation. Long-term allograft acceptance without the need for chronic
immunosuppression in bone marrow transplant recipients who subsequently received renal allografts
from the bone marrow donor encouraged the use of experimental macrochimeric models in the
investigation of tolerance.143–146 Although bone marrow transplantation is not feasible or appropriate
for patients on transplant waiting lists, in vivo models of tolerance utilizing the principles of
macrochimerism have demonstrated that it is essential in the tolerogenic potential of mixed chimerism.
Macrochimerism, has been shown to result in tolerant states but requires the use of cytoreductive
therapy to ensure hematopoietic stem cell engraftment.147,148 Conditions necessary to achieve stable
chimerism include the use of lymphoablative therapy alone or in conjunction with bone marrow
infusion. Under these conditions, tolerance to allografts has been reported in rodent and nonhuman
primate models.149,150 The requirement for lymphoid irradiation has limited the translation of these
models to the clinic, and has resulted in a search for effective nonmyeloablative strategies. In an
attempt to circumvent the use of irradiation conditioning, many groups have attempted the
experimental use of costimulation blockade or T-cell depletion in conjunction with high-dose bone
marrow infusions to delete donor reactive cells in the thymus. Results from these nonmyeloablative
regimens have proven to be encouraging in mouse models and some large animal models.151–155
Immunomodulating Stem Cells

Recent reports have focused on the suppressive capacity of mesenchymal stem cells (MSCs). MSCs have
852
booksmedicos.org
shown great promise in both small and large animal models of transplantation.156 Mechanistically, MSCs
have been shown to down-regulate costimulation molecules on APC thereby inducing anergic responses
in T cells, keeping APC in an immature, and thus tolerogenic state.157 Additionally, MSCs have shown
the ability to engraft and incorporate into healing tissues. MSCs also inhibit T- and B-cell expansion by
dampening the metabolic activity of T cells with the production of indolamine 2,3-dioxygenase which
deprives lymphocytes of nutritional tryptophan, inducing cell death.156,158 Furthermore, MSCs have also
been shown to synergize with standard therapies of costimulation blockade to induce Treg and
tolerogenic phenotypes making them a target for future clinical translation.159
References
1. Valitutti S, Lanzavecchia A. Serial triggering of TCRs: a basis for the sensitivity and specificity of
antigen recognition. Immunol Today 1997;18(6):299–304.
2. Horejsi V. Lipid rafts and their roles in T-cell activation. Microbes Infect 2005;7(2):310–316.
3. Manes S, Viola A. Lipid rafts in lymphocyte activation and migration. Mol Membr Biol
2006;23(1):59–69.
4. Kovacs B, Parry RV, Ma Z, et al. Ligation of CD28 by its natural ligand CD86 in the absence of TCR
stimulation induces lipid raft polarization in human CD4 T cells. J Immunol 2005;175(12):7848–
7854.
5. Larsen CP, Knechtle SJ, Adams A, et al. A new look at blockade of T-cell costimulation: a
therapeutic strategy for long-term maintenance immunosuppression. Am J Transplant 2006;6(5 Pt
1):876–883.
6. Larsen CP, Morris PJ, Austyn JM. Migration of dendritic leukocytes from cardiac allografts into
host spleens. A novel pathway for initiation of rejection. J Exp Med 1990;171(1):307–314.
7. Janeway CA, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease
6th Edition. 6th ed. Janeway, CA: Garland Science Publishing; 2005.
8. Chen Y, Wood KJ. Interleukin-23 and TH17 cells in transplantation immunity: does 23+17 equal
rejection? Transplantation 2007;84(9):1071–1074.
9. Chalasani G, Dai Z, Konieczny BT, et al. Recall and propagation of allospecific memory T cells
independent of secondary lymphoid organs. Proc Natl Acad Sci U S A 2002;99(9):6175–6180.
10. Adams AB, Pearson TC, Larsen CP. Heterologous immunity: an overlooked barrier to tolerance.
Immunol Rev 2003;196:147–160.
11. Yang J, Brook MO, Carvalho-Gaspar M, et al. Allograft rejection mediated by memory T cells is
resistant to regulation. Proc Natl Acad Sci U S A 2007;104(50):19954–19959.
12. Brook MO, Wood KJ, Jones ND. The impact of memory T cells on rejection and the induction of
tolerance. Transplantation 2006;82(1):1–9.
13. Pearl JP, Parris J, Hale DA, et al. Immunocompetent T-cells with a memory-like phenotype are the
dominant cell type following antibody-mediated T-cell depletion. Am J Transplant 2005;5(3):465–
474.
14. Kirk AD. Induction immunosuppression. Transplantation 2006;82(5):593–602.
15. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970;169(950):1042–1049.
16. Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci
1975;53(1):27–42.
17. Schwartz RH. A cell culture model for T lymphocyte clonal anergy. Science 1990;248(4961):1349–
1356.
18. Snanoudj R, de Preneuf H, Creput C, et al. Costimulation blockade and its possible future use in
clinical transplantation. Transpl Int 2006;19(9):693–704.
19. Pilat N, Schwarz C, Wekerle T. Modulating T-cell costimulation as new immunosuppressive concept
in organ transplantation. Curr Opin Organ Transplant 2012;17(4):368–375.
20. Nashan B, Moore R, Amlot P, et al. Randomised trial of basiliximab versus placebo for control of
acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet
1997;350(9086):1193–1198.
21. Thompson CB. Distinct roles for the costimulatory ligands B7-1 and B7-2 in T helper cell
differentiation? Cell 1995;81(7):979–982.
853
booksmedicos.org
22. Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol
1997;158(5):1989–1993.
23. Thompson CB, Allison JP. The emerging role of CTLA-4 as an immune attenuator. Immunity
1997;7(4):445–450.
24. Stamper CC, Zhang Y, Tobin JF, et al. Crystal structure of the B7-1/CTLA-4 complex that inhibits
human immune responses. Nature 2001;410(6828):608–611.
25. Ossevoort MA, Ringers J, Kuhn EM, et al. Prevention of renal allograft rejection in primates by
blocking the B7/CD28 pathway. Transplantation 1999;68(7):1010–1018.
26. Kirk AD, Tadaki DK, Celniker A, et al. Induction therapy with monoclonal antibodies specific for
CD80 and CD86 delays the onset of acute renal allograft rejection in non-human primates.
Transplantation 2001;72(3):377–384.
27. Birsan T, Hausen B, Higgins JP, et al. Treatment with humanized monoclonal antibodies against
CD80 and CD86 combined with sirolimus prolongs renal allograft survival in cynomolgus monkeys.
28. Lenschow DJ, Zeng Y, Thistlethwaite JR, et al. Long-term survival of xenogeneic pancreatic islet
grafts induced by CTLA4lg. Science 1992;257(5071):789–792.
29. Larsen CP, Elwood ET, Alexander DZ, et al. Long-term acceptance of skin and cardiac allografts
after blocking CD40 and CD28 pathways. Nature 1996;381(6581):434–438.
30. Larsen CP, Pearson TC, Adams AB, et al. Rational development of LEA29Y (belatacept), a high-
affinity variant of CTLA4-lg with potent immunosuppressive properties. Am J Transplant
2005;5(3):443–453.
31. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal
transplantation. N Eng J Med 2005;353(8):770–781.
32. Satyananda V, Shapiro R. Belatacept in kidney transplantation. Curr Opin Organ Transplant
2014;19(6):573–577.
33. Durrbach A, Pestana JM, Pearson T, et al. A phase III study of belatacept versus cyclosporine in
kidney transplants from extended criteria donors (BENEFIT-EXT study). Am J Transplant
2010;10(3):547–557.
34. Vincenti F, Charpentier B, Vanrenterghem Y, et al. A phase III study of belatacept-based
immunosuppression regimens versus cyclosporine in renal transplant recipients (BENEFIT study).
Am J Transplant 2010;10(3):535–546.
35. Rostaing L, Vincenti F, Grinyo J, et al. Long-term belatacept exposure maintains efficacy and safety
at 5 years: results from the long-term extension of the BENEFIT study. Am J Transplant
2013;13(11):2875–2883.
36. Adu D, Cockwell P, Ives NJ, et al. Interleukin-2 receptor monoclonal antibodies in renal
transplantation: meta-analysis of randomised trials. BMJ 2003;326(7393):789.
37. Penninga L, Wettergren A, Wilson CH, et al. Antibody induction versus corticosteroid induction for
liver transplant recipients. Cochrane Database Syst Rev 2014;5:CD010252.
38. Schmeding M, Sauer IM, Kiessling A, et al. Influence of basiliximab induction therapy on long term
outcome after liver transplantation, a prospectively randomised trial. Ann Transplant
2007;12(3):15–21.
39. Turner AP, Knechtle SJ. Induction immunosuppression in liver transplantation: a review. Transpl Int
2013;26(7):673–683.
40. Neuhaus P, Clavien PA, Kittur D, et al. Improved treatment response with basiliximab
immunoprophylaxis after liver transplantation: results from a double-blind randomized placebo-
controlled trial. Liver Transpl 2002;8(2):132–142.
41. Waldmann H. Manipulation of T-cell responses with monoclonal antibodies. Annu Rev Immunol
1989;7:407–444.
42. Monaco AP, Wood ML, Russel PS. Studies on heterologous anti-lymphocyte serum in mice: III.
Immunologic tolerance and chimerism produced across the H-2 locus with adult thymectomy and
anti-lymphocyte serum. Ann N Y Acad Sci 1966;129:190.
43. Golshayan D, Buhler L, Lechler RI, et al. From current immunosuppressive strategies to clinical
tolerance of allografts. Transpl Int 2007;20(1):12–24.
44. Knechtle SJ, Vargo D, Fechner J, et al. FN18-CRM9 immunotoxin promotes tolerance in primate
854
booksmedicos.org
renal allografts. Transplantation 1997;63(1):1–6.
45. Armstrong N, Buckley P, Oberley T, et al. Analysis of primate renal allografts after T-cell depletion
with anti-CD3-CRM9. Transplantation 1998;66(1):5–13.
46. Kirk AD, Mannon RB, Kleiner DE, et al. Results from a human renal allograft tolerance trial
evaluating T-cell depletion with alemtuzumab combined with deoxyspergualin. Transplantation
2005;80(8):1051–1059.
47. Kirk AD, Hale DA, Mannon RB, et al. Results from a human renal allograft tolerance trial
evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H).
48. Tzakis AG, Tryphonopoulos P, Kato T, et al. Preliminary experience with alemtuzumab (Campath-
1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Transplantation
2004;77(8):1209–1214.
49. Vathsala A, Ona ET, Tan SY, et al. Randomized trial of alemtuzumab for prevention of graft
rejection and preservation of renal function after kidney transplantation. Transplantation
2005;80(6):765–774.
50. Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH 1H) induction therapy in
cadaveric kidney transplantation–efficacy and safety at five years. Am J Transplant 2005;5(6):1347–
1353.
51. Trzonkowski P, Zilvetti M, Friend P, et al. Recipient memory-like lymphocytes remain
unresponsive to graft antigens after CAMPATH-1H induction with reduced maintenance
immunosuppression. Transplantation 2006;82(10):1342–1351.
52. Morris PJ, Russell NK. Alemtuzumab (Campath-1H): a systematic review in organ transplantation.
53. Barth RN, Janus CA, Lillesand CA, et al. Outcomes at 3 years of a prospective pilot study of
Campath-1H and sirolimus immunosuppression for renal transplantation. Transpl Int
2006;19(11):885–892.
54. Brennan DC, Daller JA, Lake KD, et al. Rabbit antithymocyte globulin versus basiliximab in renal
transplantation. N Eng J Med 2006;355(19):1967–1977.
55. Naujokat C, Berges C, Fuchs D, et al. Antithymocyte globulins suppress dendritic cell function by
multiple mechanisms. Transplantation 2007;83(4):485–497.
56. Caillard S, Dharnidharka V, Agodoa L, et al. Posttransplant lymphoproliferative disorders after
renal transplantation in the United States in era of modern immunosuppression. Transplantation
2005;80(9):1233–1243.
57. Hardinger KL. Rabbit antithymocyte globulin induction therapy in adult renal transplantation.
Pharmacotherapy 2006;26(12):1771–1783.
58. Kean LS, Gangappa S, Pearson TC, et al. Transplant tolerance in non-human primates: progress,
current challenges and unmet needs. Am J Transplant 2006;6(5 Pt 1):884–893.
59. Stahelin HF. The history of cyclosporin A (Sandimmune) revisited: another point of view.
Experientia 1996;52(1):5–13.
60. Cheng M. Hartmann Stahelin (1925-2011) and the contested history of cyclosporin A. Clin
Transplant 2013;27(3):326–329.
61. Fung JJ, Starzl TE. FK506 in solid organ transplantation. Ther Drug Monit 1995;17(6):592–595.
62. Warty V, Diven W, Cadoff E, et al. FK506: a novel immunosuppressive agent. Characteristics of
binding and uptake by human lymphocytes. Transplantation 1988;46(3):453–455.
63. Zeevi A, Duquesnoy R, Eiras G, et al. In vitro immunosuppressive effects of FK506 in combination
with other drugs. Transplant Proc 1988;20(1 suppl 1):220–222.
64. Kuo PC, Schroeder RA, eds. Clinical Management of the Transplant Patient. New York, NY: Oxford
University Press; 2001.
65. Thomson AW, Turnquist HR, Raimondi G. Immunoregulatory functions of mTOR inhibition. Nat Rev
Immunol 2009;9(5):324–337.
66. Akselband Y, Harding MW, Nelson PA. Rapamycin inhibits spontaneous and fibroblast growth
factor beta-stimulated proliferation of endothelial cells and fibroblasts. Transplant Proc
1991;23(6):2833–2836.
67. Biecker E, De Gottardi A, Neef M, et al. Long-term treatment of bile duct-ligated rats with
855
booksmedicos.org
rapamycin (sirolimus) significantly attenuates liver fibrosis: analysis of the underlying mechanisms.
J Pharmacol Exp Ther 2005;313(3):952–961.
68. McKenna GJ, Trotter JF, Klintmalm E, et al. Limiting hepatitis C virus progression in liver
transplant recipients using sirolimus-based immunosuppression. Am J Transplant 2011;11(11):2379–
2387.
69. Schena FP, Pascoe MD, Alberu J, et al. Conversion from calcineurin inhibitors to sirolimus
maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the
CONVERT trial. Transplantation 2009;87(2):233–242.
70. Abdelmalek MF, Humar A, Stickel F, et al. Sirolimus conversion regimen versus continued
calcineurin inhibitors in liver allograft recipients: a randomized trial. Am J Transplant
2012;12(3):694–705.
71. DuBay D, Smith RJ, Qiu KG, et al. Sirolimus in liver transplant recipients with renal dysfunction
offers no advantage over low-dose calcineurin inhibitor regimens. Liver Transpl 2008;14(5):651–
659.
72. Saliba F, De Simone P, Nevens F, et al. Renal function at two years in liver transplant patients
receiving everolimus: results of a randomized, multicenter study. Am J Transplant 2013;13(7):1734–
1745.
73. De Simone P, Nevens F, De Carlis L, et al. Everolimus with reduced tacrolimus improves renal
function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant
2012;12(11):3008–3020.
74. Saliba F, Dharancy S, Lorho R, et al. Conversion to everolimus in maintenance liver transplant
patients: a multicenter, retrospective analysis. Liver Transpl 2011;17(8):905–913.
75. Knight RJ, Villa M, Laskey R, et al. Risk factors for impaired wound healing in sirolimus-treated
renal transplant recipients. Clin Transplant 2007;21(4):460–465.
76. Schaffer M, Schier R, Napirei M, et al. Sirolimus impairs wound healing. Langenbecks Arch Surg
2007;392(3):297–303.
77. Grim SA, Slover CM, Sankary H, et al. Risk factors for wound healing complications in sirolimus-
treated renal transplant recipients. Transplant Proc 2006;38(10):3520–3523.
78. Kuppahally S, Al-Khaldi A, Weisshaar D, et al. Wound healing complications with de novo sirolimus
versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant
2006;6(5 Pt 1):986–992.
79. Flechner SM, Zhou L, Derweesh I, et al. The impact of sirolimus, mycophenolate mofetil,
cyclosporine, azathioprine, and steroids on wound healing in 513 kidney-transplant recipients.
80. Chua AP, Budev M, Mehta AC. Late airway anastomotic dehiscence associated with sirolimus and
migratory staples in a lung transplant recipient. Transplantation 2010;89(10):1293–1294.
81. Murakami N, Riella LV, Funakoshi T. Risk of metabolic complications in kidney transplantation
after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am J Transplant
2014;14(10):2317–2327.
82. Kwong YL. Azathioprine: association with therapy-related myelodysplastic syndrome and acute
myeloid leukemia. J Rheumatol 2010;37(3):485–490.
83. Perrett CM, Harwood CA, McGregor JM, et al. Carcinogenic mechanisms related to
immunosuppressive therapy. Cancer Treat Res 2009;146:123–132.
84. Nguyen T, Vacek PM, O’Neill P, et al. Mutagenicity and potential carcinogenicity of thiopurine
treatment in patients with inflammatory bowel disease. Cancer Res 2009;69(17):7004–7012.
85. Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and
contributions to therapy-related cancer. Nat Rev Cancer 2008;8(1):24–36.
86. Gerosa M, Meroni PL, Cimaz R. Safety considerations when prescribing immunosuppression
medication to pregnant women. Expert Opin Drug Saf 2014;13:1–9.
87. Vos R, Ruttens D, Verleden SE, et al. Pregnancy after heart and lung transplantation. Best Pract Res
Clin Obstet Gynaecol 2014;28(8):1146–1162.
88. Rostas S, Kim M, Gabardi S. Risk evaluation and mitigation strategies: a focus on the mycophenolic
acid preparations. Prog Transplant 2014;24(1):33–36.
89. Hou S. Pregnancy in renal transplant recipients. Adv Chronic Kidney Dis 2013;20(3):253–259.
856
booksmedicos.org
90. Kim M, Rostas S, Gabardi S. Mycophenolate fetal toxicity and risk evaluation and mitigation
strategies. Am J Transplant 2013;13(6):1383–1389.
91. Pascual J, Zamora J, Galeano C, et al. Steroid avoidance or withdrawal for kidney transplant
recipients. Cochrane Database Syst Rev 2009;(1):CD005632.
92. Montagnino G, Sandrini S, Iorio B, et al. A randomized exploratory trial of steroid avoidance in
renal transplant patients treated with everolimus and low-dose cyclosporine. Nephrol Dial Transplant
2008;23(2):707–714.
93. Heilman RL, Mazur MJ, Reddy KS, et al. Steroid avoidance immunosuppression in low-risk kidney
transplant recipients. Transplant Proc 2005;37(4):1785–1788.
94. Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation
in the United States, 1988 to 1996. N Eng J Med 2000;342(9):605–612.
95. Heeger PS, Dinavahi R. Transplant immunology for non-immunologist. Mt Sinai J Med
2012;79(3):376–387.
96. Vesley D, Norlien KG, Nelson B, et al. Significant factors in the disinfection and sterilization of
flexible endoscopes. Am J Infect Control 1992;20(6):291–300.
97. Solez K, Racusen LC. The Banff classification revisited. Kidney Int 2013;83(2):201–206.
98. Moseley EL, Atkinson C, Sharples LD, et al. Deposition of C4d and C3d in cardiac transplants: a
factor in the development of coronary artery vasculopathy. J Heart Lung Transplant 2010;29(4):417–
423.
99. Warnecke G, Bushell A, Nadig SN, et al. Regulation of transplant arteriosclerosis by CD25+CD4+
T cells generated to alloantigen in vivo. Transplantation 2007;83(11):1459–1465.
100. Nadig SN, Wieckiewicz J, Wu DC, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-
expanded human regulatory T cells. Nat Med 2010;16(7):809–813.
101. Pober JS, Jane-wit D, Qin L, et al. Interacting mechanisms in the pathogenesis of cardiac allograft
vasculopathy. Arterioscler Thromb Vasc Biol 2014;34(8):1609–1614.
102. Lee RS, Yamada K, Houser SL, et al. Indirect recognition of allopeptides promotes the development
of cardiac allograft vasculopathy. Proc Natl Acad Sci U S A 2001;98(6):3276–3281.
103. Hillebrands JL, Rozing J. Chronic transplant dysfunction and transplant arteriosclerosis: new
insights into underlying mechanisms. Expert Rev Mol Med 2003;5(2):1–23.
104. Campbell P. Clinical relevance of human leukocyte antigen antibodies in liver, heart, lung and
intestine transplantation. Curr Opin Organ Transplant 2013;18(4):463–469.
105. Hidalgo LG, Sellares J, Sis B, et al. Interpreting NK cell transcripts versus T cell transcripts in renal
transplant biopsies. Am J Transplant 2012;12(5):1180–1191.
106. Sis B, Halloran PF. Endothelial transcripts uncover a previously unknown phenotype: C4d-negative
antibody-mediated rejection. Curr Opin Organ Transplant 2010;15(1):42–48.
107. Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of c4d-negative antibody-
mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014;14(2):272–283.
108. O’Leary JG, Michelle Shiller S, Bellamy C, et al. Acute liver allograft antibody-mediated rejection:
an inter-institutional study of significant histopathological features. Liver Transplant
2014;20(10):1244–1255.
109. Djamali A, Kaufman DB, Ellis TM, et al. Diagnosis and management of antibody-mediated rejection:
current status and novel approaches. Am J Transplant 2014;14(2):255–271.
110. Ojo AO, Held PJ, Port FK, et al. Chronic renal failure after transplantation of a nonrenal organ. N
Eng J Med 2003;349(10):931–940.
111. Goldfarb DA. Expression of TGF-beta and fibrogenic genes in transplant recipients with tacrolimus
and cyclosporine nephrotoxicity. J Urol 2003;169(6):2436–2437.
112. Sharma P, Goodrich NP, Schaubel DE, et al. Patient-specific prediction of ESRD after liver
transplantation. J Am Soc Nephrol 2013;24(12):2045–2052.
113. Sharma P, Schaubel DE, Guidinger MK, et al. Impact of MELD-based allocation on end-stage renal
disease after liver transplantation. Am J Transplant 2011;11(11):2372–2378.
114. Sharma P, Welch K, Eikstadt R, et al. Renal outcomes after liver transplantation in the model for
end-stage liver disease era. Liver Transpl 2009;15(9):1142–1148.
115. Sharma P, Goodrich NP, Zhang M, et al. Short-term pretransplant renal replacement therapy and
857
booksmedicos.org
renal nonrecovery after liver transplantation alone. Clin J Am Soc Nephrol 2013;8(7):1135–1142.
116. Fishman JA. Infection in solid-organ transplant recipients. N Eng J Med 2007;357(25):2601–2614.
117. Theodoropoulos N, Jaramillo A, Ladner DP, et al. Deceased organ donor screening for HIV,
hepatitis B, and hepatitis C viruses: a survey of organ procurement organization practices. Am J
Transplant 2013;13(8):2186–2190.
118. Engels EA, Pfeiffer RM, Fraumeni JF Jr, et al. Spectrum of cancer risk among US solid organ
transplant recipients. JAMA 2011;306(17):1891–1901.
119. Krynitz B, Edgren G, Lindelof B, et al. Risk of skin cancer and other malignancies in kidney, liver,
heart and lung transplant recipients 1970 to 2008–a Swedish population-based study. Int J Cancer
2013;132(6):1429–1438.
120. Manilay JO, Pearson DA, Sergio JJ, et al. Intrathymic deletion of alloreactive T cells in mixed bone
marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation
1998;66(1):96–102.
121. Getts DR, Shankar S, Chastain EM, et al. Current landscape for T-cell targeting in autoimmunity
and transplantation. Immunotherapy 2011;3(7):853–870.
122. Horton PJ, Hawthorne WJ, Walters S, et al. Tolerance induction in a large-animal model using total
lymphoid irradiation and intrathymic bone marrow. Transplantation 2008;86(12):1830–1836.
123. Posselt AM, Barker CF, Tomaszewski JE, et al. Induction of donor-specific unresponsiveness by
intrathymic islet transplantation. Science 1990;249(4974):1293–1295.
124. Hosseini H, Oh DY, Chan ST, et al. Non-myeloablative transplantation of bone marrow expressing
self-antigen establishes peripheral tolerance and completely prevents autoimmunity in mice. Gene
Ther 2012;19(11):1075–1084.
125. Jones ND, Fluck NC, Mellor AL, et al. The induction of transplantation tolerance by intrathymic
(i.t.) delivery of alloantigen: a critical relationship between i.t. deletion, thymic export of new T
cells and the timing of transplantation. Int Immunol 1998;10(11):1637–1646.
126. Oluwole SF, Chowdhury NC, Ingram M, et al. Mechanism of acquired thymic tolerance induced by
a single major histocompatibility complex class I peptide with the dominant epitope: differential
analysis of regulatory cytokines in the lymphoid and intragraft compartments. Transplantation
1999;68(3):418–429.
127. Turvey SE, Hara M, Morris PJ, et al. Mechanisms of tolerance induction after intrathymic islet
injection: determination of the fate of alloreactive thymocytes. Transplantation 1999;68(1):30–39.
128. Sakaguchi S, Sakaguchi N, Asano M, et al. Immunologic self-tolerance maintained by activated T
cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-
tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151–1164.
129. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative
control of immune responses. Annu Rev Immunol 2004;22:531–562.
130. Wood KJ, Bushell A, Hester J. Regulatory immune cells in transplantation. Nat Rev Immunol
2012;12(6):417–430.
131. Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in
patients with FOXP3 mutations. J Clin Invest 2006;116(6):1713–1722.
132. Ng WF, Duggan PJ, Ponchel F, et al. Human CD4(+)CD25(+) cells: a naturally occurring
population of regulatory T cells. Blood 2001;98(9):2736–2744.
133. Baecher-Allan C, Brown JA, Freeman GJ, et al. CD4+CD25high regulatory cells in human
peripheral blood. J Immunol 2001;167(3):1245–1253.
134. Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun
2005;25(suppl):56–62.
135. Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol
2003;3(3):199–210.
136. Juvet SC, Whatcott AG, Bushell AR, et al. Harnessing regulatory T cells for clinical use in
transplantation: the end of the beginning. Am J Transplant 2014;14(4):750–763.
137. Hester J, Schiopu A, Nadig SN, et al. Low-dose rapamycin treatment increases the ability of human
regulatory T cells to inhibit transplant arteriosclerosis in vivo. Am J Transplant 2012;12(8):2008–
2016.
138. Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3
858
booksmedicos.org
+regulatory T cells. Blood 2005;105(12):4743–4748.
139. Hara M, Kingsley CI, Niimi M, et al. IL-10 is required for regulatory T cells to mediate tolerance to
alloantigens in vivo. J Immunol 2001;166(6):3789–3796.
140. Kretschmer K, Apostolou I, Hawiger D, et al. Inducing and expanding regulatory T cell populations
by foreign antigen. Nat Immunol 2005;6(12):1219–1227.
141. Karim M, Kingsley CI, Bushell AR, et al. Alloantigen-induced CD25+CD4+ regulatory T cells can
develop in vivo from CD25-CD4+ precursors in a thymus-independent process. J Immunol
2004;172(2):923–928.
142. Bishop GA, Sun J, Sheil AG, et al. High-dose/activation-associated tolerance: a mechanism for
allograft tolerance. Transplantation 1997;64(10):1377–1382.
143. Sayegh MH, Fine NA, Smith JL, et al. Immunologic tolerance to renal allografts after bone marrow
transplants from the same donors. Ann Intern Med 1991;114(11):954–955.
144. Jacobsen N, Taaning E, Ladefoged J, et al. Tolerance to an HLA-B,DR disparate kidney allograft
after bone-marrow transplantation from same donor. Lancet 1994;343(8900):800.
145. Sorof JM, Koerper MA, Portale AA, et al. Renal transplantation without chronic immunosuppression
after T cell-depleted, HLA-mismatched bone marrow transplantation. Transplantation
1995;59(11):1633–1635.
146. Wood K, Sachs DH. Chimerism and transplantation tolerance: cause and effect. Immunol Today
1996;17(12):584–587; discussion 8.
147. Monaco AP. Prospects and strategies for clinical tolerance. Transplant Proc 2004;36(1):227–231.
148. Monaco AP. The beginning of clinical tolerance in solid organ allografts. Exp Clin Transplant
2004;2(1):153–161.
149. Slavin S, Strober S, Fuks Z, et al. Induction of specific tissue transplantation tolerance using
fractionated total lymphoid irradiation in adult mice: long-term survival of allogeneic bone marrow
and skin grafts. J Exp Med 1977;146(1):34–48.
150. Myburgh JA, Smit JA, Stark JH, et al. Total lymphoid irradiation in kidney and liver
transplantation in the baboon: prolonged graft survival and alterations in T cell subsets with low
cumulative dose regimens. J Immunol 1984;132(2):1019–1025.
151. Wekerle T, Sykes M. Induction of tolerance. Surgery 2004;135(4):359–364.
152. Wekerle T, Kurtz J, Ito H, et al. Allogeneic bone marrow transplantation with co-stimulatory
blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat Med
2000;6(4):464–469.
153. Guo Z, Wang J, Dong Y, et al. Long-term survival of intestinal allografts induced by costimulation
blockade, busulfan and donor bone marrow infusion. Am J Transplant 2003;3(9):1091–1098.
154. Huang CA, Fuchimoto Y, Scheier-Dolberg R, et al. Stable mixed chimerism and tolerance using a
nonmyeloablative preparative regimen in a large-animal model. J Clin Invest 2000;105(2):173–181.
155. Adams AB, Durham MM, Kean L, et al. Costimulation blockade, busulfan, and bone marrow
promote titratable macrochimerism, induce transplantation tolerance, and correct genetic
hemoglobinopathies with minimal myelosuppression. J Immunol 2001;167(2):1103–1111.
156. Ebrahimi A, Rahim F. Recent immunomodulatory strategies in transplantation. Immunol Invest
2014;43(8):829–837.
157. Oh W, Kim DS, Yang YS, et al. Immunological properties of umbilical cord blood-derived
mesenchymal stromal cells. Cell Immunol 2008;251(2):116–123.
158. Chinnadurai R, Copland IB, Patel SR, et al. IDO-independent suppression of T cell effector function
by IFN-gamma-licensed human mesenchymal stromal cells. J Immunol 2014;192(4):1491–1501.
159. Takahashi T, Tibell A, Ljung K, et al. Multipotent mesenchymal stromal cells synergize with
costimulation blockade in the inhibition of immune responses and the induction of Foxp3+
regulatory T cells. Stem Cells Transl Med 2014;3(12):1484–1494.
859
booksmedicos.org
Chapter 35
Organ Procurement and Preservation

Michael J. Englesbe
Key Points
1 Organ donation: Efforts to expand organ donation are critical to save lives. Organ donation must be
done within a regulated system that is deeply rooted in ethical standards of care.
2 Organ selection: A careful balance must be maintained between using every viable donor organ and
assuring each patient a chance of a successful posttransplant outcome.
3 Organ procurement techniques: The organ procurement operation requires coordination of a
multidisciplinary team including surgeons, anesthesiologists, nurses, and organ perfusion technicians.
Careful procurement and perfusion techniques are mandatory for successful transplant recipient
outcomes.
4 Applied sciences of organ preservation: Organ procurement and storage results in significant alterations
in the homeostasis of the organ. The degree of organ preservation injury contributes to the degree to
which normal organ function is delayed or prevented following transplantation. Novel organ
preservation techniques aim to mitigate organ preservation injury.
Organ transplantation has become a standard of care for end-organ failure. For the majority of
recipients, organ transplantation is the only life-saving therapy available. With improvements in
outcomes and expansion of indications for both donation and transplantation, the demand for
transplantation continues to expand. As of August 2014, there were 123,256 patients waiting for an
organ transplant in the United States and 6,315 patients died while waiting for a life-saving organ in the
previous year.1–3 In certain regions of the United States, wait times for kidney transplantation exceeds
10 years.
The successful procurement and preservation of these life-saving organs is critical.
ORGAN DONATION
Living Donation
Considering high wait-list mortality and long wait times, early transplant for patients with end-organ
failure has significant benefits. For example, patients who receive a kidney transplant prior to initiating
dialysis (a preemptive transplant) have a lower rate of allograft failure and mortality and a higher
quality of life compared to patients who receive a transplant after beginning dialysis.4,5 Living donation
facilitates early transplantation and these recipients have better outcomes. The 5-year graft survival of
patients receiving a living donor transplant is 79.8% versus 66.6% for recipients of deceased donor
transplants.2 In the United States, 25.6% of liver and kidney transplants are done with living donor
organs, though there is a trend toward less living organ donation, likely related to mounting concerns
about donor safety (Fig. 35-1).2 In certain cultures, deceased donation is not well accepted and living
donation is the primary source of life-saving organs.
In kidney transplantation, living donation is preferable for most recipients. Efforts should be made to
encourage potential recipients to secure a living donor organ. Significant advances have facilitated
living donation. These include the use of social media to link potential donors with recipients and paired
exchange transplant programs. In a paired exchange, a potential recipient secures a willing donor. If this
pair is incompatible (blood type or recipient–donor antibody sensitization), then organs are exchanged
with another donor–recipient pair (Fig. 35-2). Criteria for living donation are strict. Living donors must
be excellent surgical candidates with minimal comorbidities (medical and psychiatric) and must decide
upon donation autonomously.
860
booksmedicos.org
Deceased Donation
In 2013 in the United States, the majority (79.3%) of organs used for transplantation came from
deceased donors.1 In general, organ donors are brain-dead, previously in good health, and free of life-
threatening communicable disease. Permission for organ donation is obtained from the patient’s next of
kin prior to organ donation.
Considering the strong demand for life-saving organs, regulations are necessary to assure fair and
equitable distribution across populations and to assure that every suitable organ is procured from every
organ donor. Organ donation must be managed by a not-for-profit entity (organ procurement
organization or OPO) that is not directly involved in the care of the patient. The OPO as well as the
transplant surgical team must be separated from the declaration of death process. Patients who are not
brain dead may donate following cessation of cardiac function; this is known as donation after cardiac
death or DCD donation.
Declaration of Death
1 In the United States, a patient is considered dead when they have irreversible cessation of brain
function (brain dead) or irreversible cessation of circulatory and respiratory functions. The definition of
brain death is established locally by hospitals using rules that conform to the Harvard Criteria.6
Established criteria for brain death are detailed in Table 35-1. The caring physician must rule out
potentially reversible causes of coma including hypothermia, shock, sedation, or pharmacologic
paralysis. Once the clinical diagnosis of brain death is made, a confirmatory test must be completed
before organ donation. Most frequently, nuclear scintigraphy is used to confirm brain death. This test
can be done at the bedside, avoiding the transport of the potentially unstable brain-dead patient through
the hospital.
Figure 35-1. The number of living and deceased organ donors in the United States.2
In response to the shortage of donor organs, advances have been made to enable the utilization of
organs following cardiac death.7 These patients have a devastating neurologic injury but do not fulfill
criteria for brain death. Family members who intend to withdrawal support (inotropes and mechanical
ventilation) may wish to consider DCD donation. Following informed consent, ventilator and circulatory
support are withdrawn. The patient is declared dead by the caring physician upon cessation of
circulation. It is critical that members of the transplant teams are not involved in the process of
declaration of death. Each hospital establishes policies and protocols for procurement of DCD donors. In
general, the patient is given systemic anticoagulation prior to withdrawal. After the patient is declared
dead, 5 additional minutes are usually allowed to elapse prior to organ procurement surgery. If the
patient does not reach criteria for death within 60 to 90 minutes, kidney recovery is not pursued. For
liver and lung procurement, the maximal acceptable agonal time (time from withdraw to death) is
approximately 30 minutes. The transplant surgeon rapidly recovers the organs using a similar technique
as brain-dead donor procurement. DCD organs have acceptable but inferior outcomes.7
861
booksmedicos.org
Figure 35-2. Schematic for paired exchange kidney transplantation.
Consent for Donation

Effective efforts to augment organ donation have focused on increasing organ donor registration,
usually associated with automobile licensing. A signed and witnessed organ donor card is sufficient
indication of the decedent’s wishes to allow organ donation. Despite this declaration, the family’s
consent is routinely obtained even when a valid organ donor card is present. Many hospitals have
specific team members who seek consent for donation. It is critical that this request is done with great
care. Explanation of the organ donation process by an empathetic party not directly involved in the care
of the deceased patient yields the highest consent rates.
ORGAN SELECTION
2 Organ quality is closely linked to recipient outcomes. A careful balance must be maintained between
using every viable donor organ and assuring each patient a chance of a successful posttransplant
outcome. The surgeon should assess general health issues of the donor as well as organ-specific function.
Donor age is also relevant, as older organs have inferior long-term outcomes and thus are better suited
for older recipients.2
Donor History of Cancer: Potential organ donors should be cured of cancer. Transmission of cancer to
the organ recipient results in rapid death related to cancer progression in the setting of severe illness
and systemic immunosuppression. Criteria and guidelines for suitability for donation among cancer
survivors are well detailed in the literature.8,9 Donors with a history of melanoma, leukemia,
lymphoma, or small-cell carcinoma are excluded from donation. For most major cancers associated with
systemic progression, organ donors should be disease free for 5 years. Some donor cancers have been
shown to have minimal risk of transmission to the recipient. These include nonmelanoma skin cancers
without nodal involvement, small renal cell and prostate cancers, and many intracranial malignancies
that have not recently had intracranial surgical intervention.
Table 35-1 Criteria for Brain Death6
Donor History of Infectious Disease: All donors are screened for communicable disease. The predonation
work-up is detailed in Table 35-2. Many donors have been critically ill for many days prior to donation
and hospital acquired infections are common. Donors with a recent history of systemic bacteremia are
acceptable while donors with fungemia are not. The transplant center needs to follow donor cultures
862
booksmedicos.org
and make sure that the recipient is appropriately treated.
Donor transmission of HIV, hepatitis B, or hepatitis C can lead to disastrous outcomes in the recipient.
Donor history of an ongoing viral infection must be carefully assessed. All donors are tested for an
antibody response to HIV. Nucleic acid testing (NAT) for HIV is also done in most cases. NAT testing
reduces the “window period” for false-negative test results.10 Recipients with a previous history of these
viruses can receive organs that are infected with them. For example, HIV-positive patients on the
waitlist can receive HIV-positive donor organs. Similarly, hepatitis C-positive donor organs without
significant liver disease have excellent outcomes in hepatitis C-positive liver transplant recipients.11
With advances in the viral therapies, many hepatitis C-positive patients will no longer have systemic
viremia, though they remain antibody positive for hepatitis C. These individuals should not receive
hepatitis C-positive organs. Similarly, the HCV viral genotype of the recipient should be considered
when deciding to accept a HCV-positive donor organ. Organs from donors with the previous history of
hepatitis B infection can transmit the infection to recipients. These organs should be used in recipients
who have been immunized against hepatitis B. In liver and kidney transplantation, donors who test
positive for hepatitis B core antibody but negative surface antigen can be used in most recipients with
excellent results.12 The recipient does require long-term antiviral therapy.
Other important infectious pathogens can be transmitted during organ transplantation.9 Many of these
are endemic to specific communities. A cause of death that is suspicious for a communicable disease
(such as rabies, encephalitis, etc.) is a red flag against organ donation. The transplant surgeon should
discuss infectious disease issues with a transplant infectious disease expert prior to accepting any
questionable organs.
Table 35-2 Standard Organ Donor Work-up
Organ-Specific Issues
In addition to a global assessment of the donor, each organ has specific considerations.
Kidney – Primary considerations include donor age, history of hypertension, diabetes, cardiovascular
disease, or renal dysfunction. Patients with acute renal failure are suitable donors, though such grafts
are more frequently associated with delayed graft function (DGF). Renal biopsy to assess for
glomerular fibrosis can aid in graft selection.13 High circulatory resistance while on organ
preservation pump is associated with inferior outcomes. Kidneys with significant arterial plague or
multiple arteries can be technically more complex to transplant, but rarely do these issues preclude
use of the allograft. Efforts should be made to keep the cold ischemia time less than 24 hours.
Liver – Primary considerations include donor age and history of liver disease. Donor elevations in
transaminases or bilirubin should be considered; preterminal liver injury is associated with primary
nonfunction of the allograft. Allograft size is an important consideration, especially in smaller
recipients. A preprocurement liver biopsy is frequently available on patients with risk factors for liver
disease. Greater than 30% macrosteatosis and/or parenchymal fibrosis may preclude transplantation.
More than a grade 2 traumatic liver laceration generally precludes transplantation. Efforts should be
made to keep the cold ischemia time less than 12 hours.
Pancreas – Selection of pancreas allografts must be done with care since recipient complications and
allograft failure are relatively common events. Donor age should be less 40 and donors should be free
863
booksmedicos.org
of major comorbidities and be hemodynamically stable. The pancreas should be soft to palpation (a
firm pancreas suggests previous injury) without significant fat infiltration. Donor iliac vessels used for
the vascular conduit should be free of atherosclerotic disease. Pancreatic branches from the splenic
artery and superior mesenteric artery must be intact (Fig. 35-3). Injury to pancreatic parenchyma
precludes use of the organ. Efforts should be made to keep the cold ischemia time less than 12 hours.
Heart – Primary considerations include donor age and history of cardiovascular disease. Predonation
work-up includes an echocardiogram; significant structural cardiac disease or abnormal cardiac
function precludes donation. Potential donors with risk factors for cardiac disease undergo cardiac
catheterization to rule out significant coronary artery disease. The relationship between the donor and
recipient body size should be considered. Prior to procurement, the procuring surgeon should examine
the beating heart for size and function before the recipient surgeon begins the heart transplant
operation. Efforts should be made to keep the cold ischemia time less than 4 hours.
Lungs – Primary considerations include donor age, history of smoking, history of pulmonary disease,
and events surrounding death (i.e., aspiration or accident with chest injury). Predonation work-up
includes chest X-rays, arterial blood gases, CT scan, and a bronchoscopy with airway cultures. Lung
contusions or pneumonia may preclude transplantation. Donors are ventilated on 100% oxygen to
assure high blood oxygen levels. The relationship between the donor and recipient body size are
considered. At the time of procurement, the donor surgeon performs a repeat bronchoscopy and a
median sternotomy to physically inspect the lungs for damage, infection, or underlying lung disease.
Efforts should be made to keep the cold ischemia time less than 6 hours.
Figure 35-3. Donor superior mesenteric artery and splenic artery with arterial conduit created from the donor iliac artery.
THE ORGAN PROCUREMENT OPERATION

3 The organ procurement operation requires coordination of a multidisciplinary team including
surgeons, anesthesiologists, nurses, and organ perfusion technicians. By convention, transplant centers
send their own teams to procure the heart, liver, lungs, and pancreas. The kidneys are procured by one
of the other abdominal teams and are shipped to the appropriate transplant center. In most cases,
procurement teams travel to the hospital where the donor is admitted; both air and ground
transportation is usually required. In some regions, the donors are transported to a centralized
procurement facility. This has been shown to reduce costs, travel time, and cold ischemia times.14 The
recipient liver, lung, and heart operations usually begin before organs return to the transplant center;
thus continuous communication and coordination are needed between transplant centers and the
procurement teams.
Upon arrival to the donor operating room, the transplant surgeon must check the appropriate
documentation. This includes identification of the donor, consent for donation, and the donor medical
chart. The surgery teams should discuss hemodynamic and anticoagulation management with the
anesthesia team.
The surgeons should tuck the arms to facilitate four surgeons being able to work on the donor
simultaneously. After induction of general anesthesia, an incision is made from the sternal notch to the
symphysis pubis and the abdomen and sternum are opened (Fig. 35-4). Even if the thoracic organs are
not being procured, a median sternotomy facilitates exposure for the abdominal operation. The key
organ-specific steps are detailed below.
864
booksmedicos.org
Liver Procurement: The right colon and small bowel are mobilized to expose the entirety of the
retroperitoneum, including the intrahepatic vena cava and the aorta. The superior mesenteric artery is
encircled at the root of the mesentery close to the aorta. The gallbladder is opened and all of the bile is
removed. The left lateral segment of the liver is mobilized and the pars flaccida is inspected for a
replaced or accessory left hepatic artery. If an artery is noted, the surgeon must carefully dissect all of
the branches from the proximal left gastric artery, staying close to the lesser curvature of the stomach.
Failure to properly manage these small branches will result in a postreperfusion hematoma around this
artery, potentially causing arterial thrombosis. The porta hepatis is palpated to assess the location of the
arteries. If present, a replaced right hepatic artery is noted right and posterior to the common bile duct.
The aorta is dissected at its bifurcation to facilitate proximal and distal control (Fig. 35-5). The
surgeon should assure that there are no renal arteries from the distal aorta or iliac arteries. If there are,
the cannulation should occur distal to these arteries to make sure they are flushed. The supraceliac aorta
is exposed by retracting the caudate lobe and the left lateral segment of the liver to the right, grasping
the crux of the diaphragm, and dividing it with electrocautery. Circumferential control of the
supraceliac aorta is not needed, though sufficient exposure for occlusive clamping is a necessity.
When all teams are ready, the donor is given systemic heparin and the aorta is cannulated (Fig. 35-6).
The supraceliac aorta is clamped and the abdominal organs are flushed with cold preservation solution.
The inferior vena cava is incised in the chest to drain the perfusate and blood. The liver is surrounded
with ice and flushed with approximately 5 L of preservation solution.
Figure 35-4. Exposure for the organ procurement operation.
865
booksmedicos.org
Figure 35-5. Exposure of the distal abdominal aorta in preparation for aortic cannulation.
Once the flush is complete, the diaphragm is divided leaving a cuff around the suprahepatic inferior
vena cava. The infrahepatic inferior vena cava is divided approximately 1 cm above the renal veins. The
bile duct and portal vein are divided in the porta (if the pancreas is being used) or the entire head of the
pancreas is excised, assuring maximal length of the portal vein. The superior mesenteric artery and the
aorta are divided. The surgeon must be sure to not divide the aorta below the orifice of the superior
mesenteric artery; the renal arteries are close to the superior mesenteric artery origin and easy to
injure. The liver is removed and the portal vein and bile duct are flushed on the back table. Tissue
surrounding the liver is removed on the back table to prepare the organ for transplantation.
Arterial anatomy has many variations and, failure to identify variation may jeopardize the transplant
operation (Fig. 35-7). On occasion, dissection of the replaced right hepatic artery can jeopardize the
pancreas allograft, but usually both teams can agree to an acceptable dissection plane. There are several
options for reconstruction of a replaced right hepatic artery. The replaced vessel can be sewn end to end
to the gastroduodenal artery. If the replaced right hepatic artery is large, anastomosis to the splenic
artery may result in a better reconstruction. A cuff of superior mesenteric artery along with the replaced
right hepatic artery can be sewn to the celiac.
Figure 35-6. Aorta cannula securely fixed to the distal abdominal aorta.
866
booksmedicos.org
Figure 35-7. Variations in hepatic arterial anatomy. Lack of identification of this anatomy may jeopardize the transplant operation.
Figure 35-8. Upon dividing the ureter in the pelvis, a robust amount of periureteral tissue is left around the ureter.
Kidney Procurement: Kidney procurement is the final step in the procurement operation. Kidney
procurement is significantly easier if the liver has been removed. If the liver has not been removed and
will not be used for transplantation, the portal triad and the right diaphragm should be divided. This
results in the liver falling into the right chest, greatly facilitating the kidney procurement.
The supraceliac and the infrarenal aorta should be exposed as described in the liver procurement
section. Arterial cannulation should occur distal to all renal arteries, even if they arise from the iliac
arteries. The kidneys are mobilized bilaterally out of the retroperitoneum to facilitate packing with ice
at the time of cold perfusion. Heparin administration and clamping is coordinated with the other
procurement teams. The abdominal viscera are flushed as described in the liver section.
867
booksmedicos.org
Figure 35-9. Method of procuring the kidneys. Retraction of both kidneys and ureters superiorly while clamping the distal aorta
and inferior vena cava together. Division of tissue on the spine, posterior to the great vessels.
The ureters are divided bilaterally in the pelvis and mobilized toward the kidney. The periureteral
tissue should be left intact in order to maintain the blood supply to the ureter (Fig. 35-8). The inferior
vena cava and the aorta are divided at the bifurcation and the two vessels are clamped together with a
single large clamp (Fig. 35-9). The ureters, kidneys, and vessels are retracted superiorly and the tissue
posterior to the kidneys is incised. The left renal vein is divided just off of the inferior vena cava,
leaving the entire inferior vena cava with the right kidney. The aorta is divided in the midline,
providing an aortic cuff to all renal arteries (Fig. 35-10). The kidneys are flushed on the back table and
carefully examined for vascular disease and parenchymal lesions. The kidneys are placed in cold storage
or on a perfusion pump.
Figure 35-10. Division of the aorta in the midline leaving an aortic cuff around each renal artery.
Figure 35-11. Retraction of the pancreas allograft out of the retroperitoneum during the procurement operation.
Pancreas Procurement: All of the steps necessary for the liver procurement up to the point of perfusion
868
booksmedicos.org
are completed. The pancreas must be mobilized out of the retroperitoneum with care. This can be done
in the cold following flushing, but mobilization prior to flushing allows a careful examination of the
organ as well as assuring that the vasculature is ligated.
The short gastric vessels are divided to widely expose the pancreas. The gland is assessed for fatty
infiltration or firmness, both of which may preclude transplantation. The retroperitoneal tissue inferior
to the pancreas and behind the spleen is incised. The spleen is retracted both anteriorly and medially
(Fig. 35-11). The tissue behind the spleen and pancreas is divided until the aorta is reached. The
duodenum is divided distal to the pylorus (Fig. 35-12). A vessel loop is placed around the splenic artery.
The retrograde cold perfusion is described in the liver section. After approximately 3 L of cold
profusion, the splenic artery is occluded to avoid over perfusion, which may result in edema of the
pancreas.
Once perfusion is complete, the pancreas is removed in situ or en bloc along with the liver. The
proximal jejunum is divided as it exits the retroperitoneum. It is critical that the root of the mesentery
is securely divided with a vascular stapler. Division of the portal vein, the superior mesenteric artery,
and splenic artery should be done in communication with the liver surgeon (Fig. 35-13). The iliac artery
is procured for creation of the Y graft for the transplant operation (Fig. 35-3). The iliac vein is procured
in case an extension graft is needed for the portal vein.
Heart and Lung Procurement: A bronchoscopy is done to examine anatomy, remove secretions and rule
out pneumonia. A median sternotomy is performed and a retractor placed. The thymus gland is
dissected and the innominate vein is identified in the superior aspect of the chest. The pericardium is
incised and stay sutures are placed. The aorta is mobilized, freeing it from the main pulmonary artery
and the right pulmonary artery. The superior and inferior vena cava are mobilized (Fig. 35-14). The
chest and abdominal teams must agree on where to drain the inferior vena cava. The heart and lung
teams must agree on where to drain the left side of the heart. This is usually accomplished by making
an incision at the junction of the left atrium and the left superior pulmonary vein, or by transecting the
left atrial appendage.
When all teams are ready, systemic heparin is administered. The aortic root is cannulated with a
standard needle-tipped cannula. A purse-string suture is placed on the distal main pulmonary artery. A
hole is made in the center of this suture and an “L”-shaped cannula is placed in the pulmonary artery.
Prostaglandin is administered into the pulmonary artery. The superior vena cava is ligated, the inferior
vena cava is incised, an incision is made to vent the heart, and the aortic cross-clamp is placed distal to
the coronary perfusion cannula (Fig. 35-15). The heart and lung cold perfusion is started and the organs
are surrounded with ice.
Once perfuse is complete, left atrium is divided, leaving an oval cuff of atrial tissue for the pulmonary
veins on each lung (Fig. 35-16). The superior and inferior vena cava are divided in collaboration with
the liver surgeon. The pulmonary artery is divided, taking care not to damage the left main pulmonary
artery. The aorta is divided just distal to the aortic arch and the heart is removed. The lateral and
posterior borders of the pericardium are divided, including the posterior wall of the left atrium. The
innominate vein is divided and the anterior trachea is identified. The trachea is encircled as high in the
chest as possible. The lungs are inflated and the main bronchus and left main bronchus are stapled. The
trachea is divided proximal to the staple line and the inflated lungs are removed (Fig. 35-17A,B). The
lungs are retrogradely flushed on the back table.
Figure 35-12. Division the duodenum just distal to the pylorus.
869
booksmedicos.org
Figure 35-13. Pancreas allograft following procurement, with ample length of portal vein, superior mesenteric artery, and splenic
artery.
APPLIED SCIENCES IN ORGAN PRESERVATION

4 Organ procurement and storage result in significant alterations in the homeostasis of the organ. The
degree of organ preservation injury contributes to the degree to which normal organ function is delayed
or prevented following transplantation. Organ preservation injury is largely mediated by ischemia and
hypothermia. The duration when the organ is in cold storage is termed “cold ischemia time.”
Minimizing this time as well as careful organ preservation is critical for successful outcomes. The core
concepts of organ preservation are detailed in the Table 35-3.
Cold ischemia and warm reperfusion cause much of the organ damage. As a result, novel strategies
for warm perfusion of organs are being used. These techniques involve perfusion with blood or a blood-
like analog with or without oxygenation. These perfusion models are mostly investigational at this time,
but offer promise for better organ preservation in the future.
Figure 35-14. Chest exposure for the heart- and lung procurement operation.
870
booksmedicos.org
Figure 35-15. Steps in the thoracic procurement operation. Clamping in a counter-clockwise manner, beginning with the superior
vena cava and ending with the aorta.
■ Step 1: Ligation of the superior vena cava, assuring that the azygous is either ligated or the clamp is below the azygous vein.
■ Step 2: Division of the inferior vena cava at the pericardial reflection within the chest to drain the right heart adequately. This
line of transection must be discussed with the liver surgeon.
■ Step 3: An incision to vent the left heart by cutting across the base of the left atrial appendage.
■ Step 4: An aortic cross-clamp distal to the coronary perfusion cannula.
Figure 35-16. Preparation of the pulmonary vein cuffs during the lung procurement operation.
871
booksmedicos.org
Figure 35-17. Stapling of the main bronchus and left main bronchus (A and B). The lungs are then divided between these staple
lines.
Several strategies have been developed to mitigate the effects of ischemia on organs obtained
following DCD procurement procedures. These include the infusion of antifibrinolytics into the donor
organ at the time of flush or transplant.15 Early reports suggest these strategies result in fewer postliver
transplant biliary complications. Another approach is to resume normothermic perfusion of the
abdominal viscera following death using an extracorporeal membrane oxygenation (ECMO) circuit. This
strategy has several benefits including enabling withdraw of support in the ICU with the family present,
resuscitation of the organs following the agonal period, and avoidance of urgency in the procurement
operation. A diagram of the ECMO circuit used for DCD procurement is detailed in Figure 35-18.
Machine cold perfusion is now commonly done in clinical transplantation, and in some regions is the
standard of care for renal preservation (Fig. 35-19). Some of the injury during cold ischemia and
reperfusion is related to the accumulation of metabolites; perfusion may mitigate these effects by
washing out deleterious metabolites and by maintaining patency of the microvasculature of the organ.
Machine cold perfusion is now used on nearly 50% of deceased donor kidneys in the United States.16
Early trials of cold perfusion of high-risk livers and lungs have also been successful (Fig. 35-20).3,17,18
Such strategies may expand usable organs, provide therapeutic interventions directly to the organ
during the perfusion process, and rehabilitate damaged organs.
Table 35-3 Key Concepts in Organ Preservation
872
booksmedicos.org
Figure 35-18. Extracorporeal membrane oxygenation circuit used to perfuse the abdominal viscera following withdraw of support
and death in DCD procurement procedures.
Figure 35-19. Renal machine cold-perfusion circuit with renal artery cannula.
Figure 35-20. Machine liver cold-perfusion circuit with hepatic artery and portal vein cannulas.
References
1. United Network for Organ Sharing - Annual Data Assessment 2014. Available from:
http://www.unos.org. Accessed October 9, 2014.
2. The Scientific Registry of Transplant Recipients - Annual Report 2014. Available from:
http://www.srtr.org. Accessed October 9, 2014.
3. Graham JA, Guarrera JV. “Resuscitation” of marginal liver allografts for transplantation with
machine perfusion technology. J Hepatol 2014;61(2):418–431.
873
booksmedicos.org
4. Mange KC, Joffe MM, Feldman HI. Effect of the use or nonuse of long-term dialysis on the
subsequent survival of renal transplants from living donors. N Eng J Med 2001;344(10):726–731.
5. Weng FL, Mange KC. A comparison of persons who present for preemptive and nonpreemptive
kidney transplantation. Am Journal Kidney Dis 2003; 42(5):1050–1057.
6. Harvard criteria: an appraisal. JAMA 1972;221(1):65.
7. Morrissey PE, Monaco AP. Donation after circulatory death: current practices, ongoing challenges,
and potential improvements. Transplantation 2014; 97(3):258–264.
8. Nalesnik MA, Woodle ES, Dimaio JM, et al. Donor-transmitted malignancies in organ
transplantation: assessment of clinical risk. Am J Transplant 2011;11(6):1140–1147.
9. Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation.
Am J Transplant 2011;11(6):1123–1130.
10. Ison MG, Llata E, Conover CS, et al. Transmission of human immunodeficiency virus and hepatitis
C virus from an organ donor to four transplant recipients. Am J Transplant 2011;11(6):1218–1225.
11. Northup PG, Argo CK, Nguyen DT, et al. Liver allografts from hepatitis C positive donors can offer
good outcomes in hepatitis C positive recipients: a US National Transplant Registry analysis.
Transplant Int 2010;23(10):1038–1044.
12. Fabrizio F, Bunnapradist S, Martin P. Transplanting kidneys from donors with prior hepatitis B
infection: one response to the organ shortage. J Nephrol 2002;15(6):605–613.
13. De Vusser K, Lerut E, Kuypers D, et al. The predictive value of kidney allograft baseline biopsies
for long-term graft survival. J Am Soc Nephrol 2013; 24(11):1913–1923.
14. Doyle MB, Vachharajani N, Wellen JR, et al. A novel organ donor facility: a decade of experience
with liver donors. Am J Transplant 2014;14(3):615–620.
15. Hashimoto K, Eghtesad B, Gunasekaran G, et al. Use of tissue plasminogen activator in liver
transplantation from donation after cardiac death donors. Am J Transplant 2010;10(12):2665–2672.
16. Cannon RM, Brock GN, Garrison RN, et al. To pump or not to pump: a comparison of machine
perfusion vs cold storage for deceased donor kidney transplantation. J Am Coll Surg
2013;216(4):625–633; discussion 33–34.
17. Guarrera JV. Assist devices: machine preservation of extended criteria donors. Liver Transplant
2012;18(Suppl 2):S31–S33.
18. Cypel M, Keshavjee S. Strategies for safe donor expansion: donor management, donations after
cardiac death, ex-vivo lung perfusion. Curr Opin Organ Transplant 2013;18(5):513–517.
874
booksmedicos.org
Chapter 36
Renal Transplantation
Chris E. Freise and Peter G. Stock
Key Points
1 The major barriers to successful renal transplantation include ABO compatibility and the human
leukocyte antigen (HLA) system.
2 Before a renal transplant is undertaken, histocompatibility of the donor and recipient is determined.
3 Methods to expand the donor pool of kidneys include the use of donation after cardiac death donors
and high kidney donor profile index kidneys.
4 The etiology of kidney disease resulting in end-stage failure, and the necessity for transplantation is
led by glomerulonephritis, diabetes, and hypertension.
5 The kidney transplant is heterotopically placed in the extraperitoneal iliac fossa.
6 Surgical complications of kidney transplantation include vascular, urologic, lymphocele, and wound
problems.
7 Hyperacute rejection is humorally mediated by preformed anti-HLA antibodies. Hyperacute rejection
occurs within minutes to hours following reperfusion of the kidney.
8 Acute cell-mediated rejection most typically occurs between 1 week and 3 months following
transplantation.
9 Chronic rejection leads to loss of graft function over the course of months to several years.
Renal transplantation has evolved to become the preferred therapeutic modality for patients with end-
stage renal failure. Improved patient survival and quality of life as compared with dialysis has been
established, with cost effectiveness achieved after a minimum of 18 months of allograft function. The
importance of minimizing time on dialysis, compounded by the exponential growth of patients on the
wait list, has led to several strategies to increase the number of deceased and living-donor organs in an
effort to decrease waiting time and mortality on the wait list. These new strategies have been the focus
of clinical research in kidney transplantation and will be discussed in this chapter. Other important
topics that will be reviewed include immunologic considerations specific to kidney transplantation;
preoperative assessment of kidney allograft recipients; the standard surgical approach in kidney
transplantation and advances in laparoscopic technology for the donor; current strategies in
immunosuppression; management of the technical and immunosuppressive complications; new kidney
allocation policies affecting waitlist management; and future trends.
IMMUNOLOGY OF RENAL TRANSPLANTATION

The immunologic response to allografted tissue is well defined and under the influence of both T-cell–
and B-cell–derived reactions. The cells and cytokines responsible for rejection vary with time
posttransplant (hyperacute, acute, and chronic rejection) and have a differential response to currently
available immunosuppressive agents.
1 The major barriers to successful renal transplantation include ABO compatibility and the human
leukocyte antigen (HLA) system. In general, renal transplantation is done between ABO-compatible
donor and recipients using the same guidelines as for blood transfusion. However, because of the
shortage of donors, cadaver kidneys are nearly always used in recipients of identical blood type.
Recently, ABO-incompatible living-donor transplants have been performed on an experimental basis
secondary to excessive wait times for ABO-compatible deceased-donor transplants.1,2
The HLA system is made up of well-defined antigens present on most cell types that are genetically
determined for each patient and are termed the major histocompatibility complex. These genes reside on
875
booksmedicos.org
chromosome 6 and are distributed in a Mendelian fashion to offspring. The HLA system includes several
loci, but the most commonly characterized are the HLA-A, HLA-B, and HLA-D regions. Given that each
human has two alleles for each locus, there are six potential HLA antigens of clinical significance. These
are characterized using tissue-typing techniques and can be used to determine the degree of matching
between a donor and potential recipient, that is, one-antigen match to six-antigen match. Improved
results of graft survival are seen when the degree of matching reaches the six-antigen level and long-
term results may be less favorable with matching to a lesser degree.
Class I antigens include the HLA antigens A, B, and C, whereas class II antigens include the D and DR
loci. Class I antigens act as targets for cytotoxic T lymphocytes, and class II antigens are important for
antigen presentation. Class II antigens are also responsible for triggering lymphocyte proliferation in
the mixed lymphocyte culture system.
2 Before a renal transplant is undertaken, histocompatibility of the donor and recipient are
determined. Standard pretransplant workup consists of several assays that will help to determine future
compatibility with a potential donor. First, donors and recipients undergo tissue typing, which involves
characterization of their respective HLA type. Secondly, recipient serum is tested against a panel of
antigens that contain the known HLA types, to identify anti-HLA antibodies. The sensitivity for
detecting anti-HLA antibodies continues to improve and newer technology uses single antigen beads to
detect antibodies against a specific HLA antigen. The amount of reactivity that a potential recipient has
against a panel of HLA antigens is indicative of the degree of sensitization. Based on the number of anti-
HLA antibodies detected, a calculated percent reactive antibodies (cPRA) can be estimated. A cPRA of
70% would suggest that the potential recipient would have anti-HLA antibodies against 70% of the
potential donor pool. Sensitization to HLA antigens occurs as a result of previous exposure to foreign
HLA antigen either from pregnancy, previous blood transfusion, or a previous organ transplant. A
patient who is highly sensitized is more difficult to transplant because of the greater likelihood of
having antibodies to a potential donor.
The last critical test performed prior to transplantation is commonly known as the final crossmatch.
This final crossmatch can be performed in several ways. Recipient serum samples collected at different
times are mixed with donor lymphocytes in a culture system. This assay will detect preformed cytotoxic
antibodies that would result in a hyperacute rejection if the transplantation were performed (see
Rejection, later). A more sensitive method of detecting these antibodies uses a fluorescent-activated cell
scanner crossmatch and is commonly used when evaluating potential recipients who are highly
sensitized or receiving second transplants. Many transplant centers have adopted “virtual
crossmatching” based on the detection of anti-HLA antibodies present in a given recipient. The most
sensitive technology will be used to detect the presence of anti-HLA antibodies in a given recipient.
Based on these antibodies, each recipient will have a list of unacceptable donor antigens. Compatibility
with each donor will be determined in the absence of the serum-based final crossmatch by eliminating a
potential donor based on the presence of unacceptable antigens. This strategy facilitates an expedited
transplant and minimization of cold ischemia times, as it avoids the additional time and expense
associated with the serum-based final crossmatch. The use of the virtual crossmatching is particularly
beneficial for determining potentially compatible kidneys allocated to highly sensitized recipients, a
scenario occurring with increasing frequency as a result of the new kidney allocation algorithm initiated
in December 2014. Widespread acceptance of the virtual crossmatch will require further confirmation
that all donor antigens are sufficiently identified using the single antigen bead technology. Currently, at
least for highly sensitized recipients, most centers will still perform a serum-based final crossmatch to
verify the virtual crossmatch result.3
THE DONOR POOL: LIVING DONORS, DECEASED DONORS,

DONATION AFTER CARDIAC DEATH
There is marked improvement in graft survival for both living and deceased donors when a transplant
can be completed before the initiation of dialysis.4 The significantly better outcomes achieved with
preemptive transplantation and minimizations of dialysis times have given rise to several strategies to
increase the number of available kidneys.
Living Donors
The first long-term success in renal transplantation over 60 years ago involved a live-donor transplant
876
booksmedicos.org
between twin brothers. The number of living donors has increased significantly in the last few years, in
part as a result of the increased use of the laparoscopic technique for donor nephrectomies. For the first
time, in 2001 the number of living donors exceeded the number of deceased donors, although deceased-
donor transplants still represent the majority of kidney transplants done today.5 This trend toward
increased live donation may also be the result of the excessive waiting times for deceased-donor
transplants, now more than 8 years for blood type O and B recipients in many parts of the United States.
Despite initial concerns about the safety and efficacy of the laparoscopic technique for the donor
procedure, morbidity and mortality rates (0.03%) remain low and comparable with those of the open
technique.6,7
The evaluation of a potential living kidney donor begins with a brief overall assessment of physical
condition because potential donors must be in good health with normal kidney function. Diabetes,
hypertension, and cardiovascular disease generally rule out a potential donor. ABO is also determined
before further workup, because ABO incompatibility has been a relative contraindication to donation. A
crossmatch test is usually performed at this time to ensure donor and recipient immunologic
compatibility. After this initial screen, a careful medical and psychosocial screen takes place to confirm
donor suitability. Following a normal physical examination, further studies should include chest
radiography, electrocardiogram, urinalysis, and blood work. During this phase, any conditions that
could predispose to later renal insufficiency need to be ruled out. For example, donors from families
with a history of type II diabetes are at a significant risk for the development of diabetes and glucose
tolerance testing is justified as part of the screening process. A history of renal stones warrants stone
analysis to assess likelihood for recurrent stones. Any inherited disorders of kidney disease must also be
ruled out, particularly in potential living-related donors when the recipient has polycystic kidney
disease.
The psychosocial history is directed at assessing the motivation of the donor, and to ensure that there
are adequate resources for the donor to proceed with the surgery and recovery. Many centers require a
relationship between the donor and intended recipient, although it is becoming increasingly common to
have general members of the public show interest in being evaluated as a donor, with no particular
recipient identified. These nondirected donors require the same careful scrutiny as any living donor and
the psychosocial evaluation is especially important. The motivation for donation should be clear and not
be connected in any way to financial gain. As a further safety measure living donors are also evaluated
and counseled by an Independent Living Donor Advocate, usually a social worker, who is not directly
involved in the recipient care, and can assess for any psychosocial issues or donor concerns that may
interfere with a smooth donation and recovery process. It is also the duty of the physician evaluating
the potential donor to review the current statistics on morbidity and mortality. The final testing of a
potential donor involves anatomic definition of the two kidneys and is typically done with either a
computed tomography angiogram or MR angiogram, both of which avoid the arterial needle stick and
catheters associated with a conventional angiogram. The results of these studies are used to detect any
anatomic abnormalities that would exclude a donor and to decide which kidney will be removed. In
general, the left kidney is favored for transplant because it has a longer renal vein.
Several strategies are currently being considered to increase the frequency of living donation.
Potential donors with well-controlled hypertension on a single antihypertensive agent are being
considered, although this remains controversial. Controversy also exists regarding the potential
reimbursement for living donors, specifically providing financial compensation regarding lost wages
during the donation. Consideration is also being given to providing health insurance to living donors for
complications related to the donor procedure. The extent of the reimbursement provided to living
donors continues to be debated by medical ethicists and transplant professionals. Finally, a national
exchange system is currently being designed that matches living donors who were incompatible with
their intended recipient (either because of ABO incompatibility or a positive crossmatch test) with other
recipients with incompatible living donors. Such exchange systems have already been successful on a
regional and national level, and extending this to a single national system will permit many more
successful exchanges and further expand the living donor pool. The creation of a single national
exchange system is still a work in progress. The advantage of having greater numbers of donor and
recipient pairs in the “pool” is to increase the likelihood that a highly sensitized recipient will be able to
be matched to a compatible donor. There have also been some preliminary attempts at including
compatible donor and recipient pairs in the pool, with their consent, in an effort to facilitate
transplantation of highly sensitized recipients.8
Deceased Donors
877
booksmedicos.org
3 Procurement of kidneys from brain-dead deceased donors has not increased at the same pace as the
rapid growth of the national wait list (Fig. 36-1). Although most deceased donors are brain dead, there
has been an increased use of kidneys from donors who do not meet the strict definitions of brain death
but have cardiopulmonary support withdrawn because of a severe brain injury or high spinal cord
injury, with little hope of living without the use of ongoing mechanical ventilation and/or the
possibility of existing in a persistent vegetative state. Organs are recovered after withdrawal of support,
once the heart stops beating, hence the terminology of donors by cardiac death or DCD donors. Usually
support is withdrawn in a controlled setting so that the time of warm ischemia and poor organ perfusion
can be minimized. Minimizing the time from cessation of the heart to perfusion of organs with
preservation fluid requires an experienced procurement team, and the successful use of these organs is
dependent on rapid procurement. Although the use of livers from DCD donors appears to be associated
with a higher incidence of biliary tract complications following transplantation, kidneys procured from
DCD donors are proving to be an important source of donor kidneys.9 Several studies from the United
States and Japan have demonstrated comparable graft success between kidneys procured from DCD
donors and brain-dead donors, although the incidence of initial delayed graft function is higher in DCD
kidneys.10 The percentage of DCD donors in the United States has progressively increased over the last
decade and presently represents about 10% of deceased donors.
Placement of deceased-donor kidneys is guided by a series of complex allocation rules established by
the United Network for Organ Sharing (UNOS). Unfortunately, the number of people being added to
waiting lists continues to be significantly greater than the number of people being removed following
transplantation. UNOS has recently implemented a new kidney allocation algorithm, although it is
unlikely that it will have a significant impact on the overall waiting times for deceased kidney
transplants, now approximating 7 to 8 years for certain blood types in several parts of the country.
Nonetheless, there are some significant changes which will impact the allocation process. Donor kidneys
are now assigned a kidney donor profile index (KDPI) score, the lower the score the better predicted
survival of the kidney (better quality kidney). The new allocation system attempts to match the
predicted longevity of the deceased-donor organ quantified by the KDPI with the estimated
posttransplant survival (EPTS) of the recipient. The top 20% of kidneys (KDPI scores less than 20%)
will be transplanted to recipients with longest EPTS (top 20%). In the new allocation scheme, the
highest KDPI kidneys (KDPI >85%) will be allocated to recipients who have consented to receive an
expanded criteria donor. Highly sensitized patients will receive a significant number of allocation
points, so if in the rare event that a compatible kidney becomes available (based on the virtual
crossmatch), that kidney will be allocated to the compatible highly sensitized recipient. Highly
sensitized recipients with cPRA’s of 99% or 100% will get access to the regional and national lists
respectively to increase the chances of finding a compatible kidney. Finally, waiting times will be
backdated to the time of the initiation of dialysis, although patients can still be listed when the
glomerular filtration rates drop below 20 mL/min.11
878
booksmedicos.org
Figure 36-1. The growth in the number of patients awaiting transplant (A) has exceeded the relatively stagnant rate of deceased-
donor kidney transplants leading to progressively increasing waiting times over the last decade. Living donors had a slight increase
early in the last decade, which may be in part due to the introduction of the laparoscopic donation procedure, but rates of living
donation are currently flat (B). (Adapted from: SRTR and OPTN Annual Data Report, 2012, available at:
http://srtr.transplant.hrsa.gov/annual_reports/2012/Default.aspx. Accessed July 15, 2015)
Further Strategies for Increasing the Number of Donor Kidneys

Many of the unique approaches for increasing the number of potential donors have come from Japan,
where cultural beliefs have limited the number of available deceased-donor transplants. Several groups
have reported successful kidney transplantation across ABO blood group barriers, using aggressive
pretransplant immunosuppression, plasmapheresis to decrease anti-ABO titers, and in some cases
splenectomy.1,2 This strategy has been implemented with increasing frequency in the United States as a
result of the marked increases in the waiting times for blood group O and B recipients.12 While this
strategy may be effective for living-donor pairs that are ABO incompatible in the United States, it is
more common to place these ABO-incompatible pairs into one of the kidney exchange programs.
For donor recipient pairs that are incompatible due to a positive crossmatch, an important strategy
currently being implemented in the United States, as well as internationally, involves the use of
desensitization protocols to facilitate transplantation across a known positive anti-HLA crossmatch.
These protocols may involve pretransplant infusion of gamma globulin in the recipient to bind
circulating antibody, plasmapheresis of the recipient to remove circulating antibody, and/or the use of
agents, such as rituximab, to decrease antibody production. These protocols could potentially impact the
increasing number of sensitized patients on waiting lists who have little hope of finding a compatible
donor.13 Lastly, a hybrid approach for the highly sensitized recipient with a crossmatch-incompatible
donor could involve finding a kidney that is “less incompatible” through an exchange program, and then
converting the positive crossmatch to a compatible crossmatch with desensitization techniques. Further
strategies have recently been implemented to expand the number of kidneys procured from deceased
donors. In addition to the use of kidneys from DCD donors described earlier, transplant centers have
considered using kidneys from donors that are less than optimal, previously designated as expanded
criteria donors (ECD). In the previous allocation scheme, these donors were between age 50 and 59, and
had two out of three other clinical feature: history of hypertension, died of a cerebrovascular injury, or
had a terminal creatinine of greater than 1.5 mg/dL. Additionally, any donor over age 60 was
considered an ECD. These kidneys clearly had a shorter survival compared to younger, healthier donors
and therefore potential recipients were required to give consent to receive these kidneys before
transplant. The advantage to certain patient groups who were predicted to do poorly on dialysis (i.e.,
older patients or patients with diabetes) was an increased overall patient survival if they received a
879
booksmedicos.org
timely transplant with an ECD kidney, rather than wait a prolonged time on the list. In the newer
allocation scheme, ECD kidneys are now defined as KDPI >85%. In the new allocation system, kidneys
with KDPI >85% will be allocated to an expanded list (regional versus local) in order to increase organ
utilization and minimize the chance of discard. The increased use of “kidney pumping” may help to
determine the quality of these ECD kidneys by observing flow rates on the pump, and may also
decrease the rates of posttransplant delayed graft function.14
THE TRANSPLANT PROCEDURE

Recipient Preoperative Assessment
4 The etiologies of kidney disease resulting in end-stage failure and the necessity for transplantation are
led by glomerulonephritis, diabetes, and hypertension (Table 36-1).15 Because of the high incidence of
cardiovascular disease associated with many of these conditions, most notably diabetes, a careful
assessment of the cardiovascular status of the potential recipient is critical. For patients at risk, this
assessment should include at a minimum an echocardiogram and an exercise or pharmacologic stress
test as a screen for reversible ischemia requiring cardiac catheterization. Controversy remains with
regard to the accuracy of noninvasive studies in terms of identifying significant disease of the coronary
arteries, particularly in diabetic patients. Nonetheless, for most centers this remains the standard
screening strategy, and updated studies should be obtained within 1 year of the transplant procedure. If
either coronary artery bypass or stenting has taken place in preparation for renal transplantation,
follow-up angiograms and/or stress tests should be repeated within 1 to 2 years of the actual transplant.
If stenting of the coronary arteries is required, patients with drug eluting stents will commonly require
clopidogrel (Plavix) for an extended period of time. Although controversial, many centers will proceed
with transplantation while recipients are on Plavix, within 6 months of the stenting procedure.
Table 36-1 Etiology of Renal Disease as Indications for Renal Transplantation,

Ranked in Order of Prevalence
880
booksmedicos.org
Although the evaluation of potential recipients is focused on the assessment of cardiovascular status,
further studies must exclude malignancies and infections that would contraindicate transplantation and
immunosuppression. Potential kidney recipients who are infected with hepatitis C should be evaluated
by a hepatologist to determine the risks of immunosuppression causing progression to end-stage liver
disease. Potential kidney recipients with evidence of advanced liver disease should be evaluated for a
combined liver and kidney transplant. For patients with less advanced liver disease, consideration could
be given to treatment with newer antiviral drugs before proceeding with kidney transplantation to
provide the opportunity for viral clearance.16 Kidney transplantation was previously contraindicated in
people with HIV infection secondary to concerns of exacerbating an already immunologically
compromised state. Recent advances in antiretroviral therapy and the ability to provide effective
prophylaxis against opportunistic infections has prompted several centers to perform transplantation in
people with end-stage renal disease and HIV infection. Early results suggest that progression of HIV to
AIDS has not been seen following transplantation and immunosuppression, with early allograft success
rates comparable to those in non–HIV-positive recipients.17 Potential patients with a previous history of
tuberculosis or conversion to purified protein derivative positivity should be evaluated for active
disease.
Colonoscopy, mammography, and Pap smear should be performed as dictated by age-specific standard
guidelines. For most malignancies, a disease-free interval of 5 years is recommended before kidney
transplantation. Controversy exists about pretransplant waiting times for certain malignancies, such as
early stage breast cancer or prostate cancer, and some centers will not require any pretransplant
waiting. Similarly, pretransplant wait times are probably not necessary for nonmelanoma skin cancers
and early stage renal cancers. For patients with congenital abnormalities as the cause of renal failure, a
complete workup of the genitourinary systems is necessary, including urodynamics and voiding
cystourethrograms. These studies are particularly important in children with end-stage disease resulting
from posterior urethral valves, to ensure that the bladder will serve as an adequate conduit for the
kidney transplant. For patients with severe reflux disease and chronic pyelonephritis, native
nephroureterectomy may be required to prevent posttransplant infection secondary to chronic reflux
into the native ureters. For patients with inadequate bladder capacity and function, pretransplant
reconstructive procedures such as ileal augmentation or ileal conduits may be required.
For patients with suspected clotting disorders based on a previous history of thromboembolic events
(frequent clotting problems with dialysis access) or diseases associated with an increased frequency of
clotting disorders (i.e., lupus), a hematologic workup is necessary to determine the necessity for
anticoagulation at the time of the transplant. The length of time for anticoagulation is dependent on the
severity of the clotting disorder and a history of a previous thrombotic event. This workup should
include a determination of serum levels of protein C, protein S, anticardiolipin antibody, factor V
Leiden, antithrombin III levels, and the G20210 A prothrombin gene mutation.
Living-Donor Nephrectomy: Open and Laparoscopic

A living kidney donor operation is a unique surgical procedure for two reasons. First, the donor has no
medical reason to be in the operating room, and the process is driven only by his or her willingness to
help another person with the gift of donation. Second, the removed tissue must be in perfect condition
because it will be reimplanted into the recipient. These two features, therefore, necessitate that the
donor operation is done safely and done well. The original donor operation was done through a
generous flank incision, allowing for good exposure and careful dissection of the renal vessels.
Unfortunately, this flank approach generally left a large incision, with its accompanying morbidity,
pain, and sometimes adverse cosmetic result. The development of the laparoscopic procedure to remove
kidneys has revolutionized the field, although its initial introduction was met with trepidation because
of concerns over donor safety. With the explosive growth and dissemination of this procedure, it has
now become the standard for donor nephrectomy.
The procedure is most commonly done through a transperitoneal approach, although some surgeons
prefer to remain retroperitoneal. Once the operative space is expanded with carbon dioxide gas and the
scope is inserted, two to three additional ports are placed to allow for the passage of instruments to
dissect the kidney (Fig. 36-2). Some centers also favor the use of a gastight “hand-port,” which allows
placement of the surgeon’s hand in the operative space to assist in exposure and to have available if
sudden bleeding is encountered. Once the kidney vessels are transected and the vessel stumps are
controlled by laparoscopic staples, the kidney can be removed through a 2- to 3-in incision, which can
be placed in a position that leaves minimal scarring and avoids cutting muscle tissue. Most commonly
881
booksmedicos.org
this is via a Pfannenstiel incision, and recently the use of natural orifice approaches has been described.
Additionally, some centers have adopted the use of a robotic assisted technique, to facilitate the
dissection of important vascular structures. Donors who undergo the laparoscopic procedure typically
have reduced pain medicine requirements, have a slightly shorter hospital stay, and are able to return to
their usual activities sooner.6,7
The safety of this relatively new procedure has been established, in addition to the demonstration that
kidneys recovered through a laparoscopic approach function as well as kidneys removed in an open
operation. There has been an increased interest in live donation, coincident with the introduction of the
laparoscopic procedure, suggesting that this procedure has removed some of the disincentives of the
donation process.
Recipient Operative Procedure

The kidney transplant is heterotopically placed in the extraperitoneal iliac fossa. Although this is a less
technically demanding procedure than either liver or pancreas transplants, attention to detail is
imperative to optimize immediate graft function and avoid technical complications resulting in loss of
the kidney transplant.
5 The operation is initiated by exposure of the iliac fossa through a curvilinear incision and can be
done on either the right or left side. The incision extends from 1 cm above the symphysis pubis to
approximately 2 cm medial to the anterior iliac spine (Fig. 36-3). The fascia is divided along the lateral
border of the rectus sheath, and the contents of the peritoneal cavity are reflected cephalad and
medially, exposing the iliac vessels in the retroperitoneum. Lymphatics overlying the iliac vessels are
ligated and divided to prevent the development of lymphoceles. In males, the spermatic cord is secured
with a vessel loop and can be retracted away from the operative field. In females, the round ligament is
suture ligated and divided. The inferior epigastric artery and vein are typically divided to prevent
potential compression of the transplanted ureter. Placement of a mechanical retractor should avoid
compression of the iliac artery and vein as well as the femoral nerve to prevent neuropraxias.
The living- or deceased-donor kidney is inspected for the presence of multiple vessels, duplication of
the urinary collecting system, and parenchymal abnormalities. The artery and vein are dissected from
surrounding structures to provide the necessary length for transplantation. In the case of multiple
arteries, a decision must be made as to whether to perform ex vivo reconstruction to achieve a single
implantable conduit versus implanting the vessels separately. This decision is in part dependent on the
quality of the recipient vessels and an assessment as to whether the anastomosis of multiple vessels
directly into the recipient would require an unacceptable period of warm ischemia to the kidney. In
general, in an adult the anastomosis of the renal artery and vein are performed in an end-to-side fashion
to the external iliac vessels, although occasionally the presence of atherosclerotic disease requires
transplantation to the common iliac vessels. In children who weigh less than 20 kg, or for third
transplants in adults, an intraperitoneal approach is used and the vascular anastomoses are frequently
performed to the aorta and inferior vena cava. For kidneys from deceased donors, a Carrel patch of
aorta is used to prevent stenosis and to provide a common patch for multiple arteries. Warm ischemia
time should be minimized to prevent delayed graft function. Ensuring adequate intravascular volume
and stable hemodynamics at the time of reperfusion is extremely important to achieve optimal function
of the transplant.
882
booksmedicos.org
Figure 36-2. A: The laparoscopic donor procedure is performed with the donor in a lateral position, typically using three to four
ports, with extraction of the kidney through a 6- to 8-cm incision. B: Preoperative computed tomography angiogram revealing the
arterial and venous anatomy. C: Intraoperative photograph of laparoscopic view of right kidney just prior to transection of the
renal vein. The artery has already been divided.
The reimplantation of the ureter is most frequently performed through an extravesicular technique.
Following positioning of the revascularized kidney in the iliac fossa and assurance of hemostasis, the
ureter is shortened to permit a tension-free anastomosis with adequate blood supply to the distal ureter.
In men, the ureter is placed under the spermatic cord to prevent ureteral obstruction. The bladder is
distended with an antibiotic solution to identify a suitable area for ureteral implantation on the dome of
the bladder, and a cystotomy is made at this site. An anastomosis between the mucosa of the bladder
and transplanted ureter is constructed using an absorbable suture to prevent stone formation. A second
layer of the bladder musculature is closed over the distal portion of the ureter to prevent reflux during
micturition.
Figure 36-3. A: Curvilinear iliac fossa incision used for the kidney transplant recipient procedure. B: Vascular anastomoses
completed between the recipient external iliac artery and vein and donor renal artery and vein. Insets: ureteral anastomosis
performed using the external ureteroneocystostomy technique.
There are alternative techniques to reimplant the ureter, including the Politano–Leadbetter
transvesical ureteroneocystostomy. This technique involves tunneling the ureter through the bladder
wall from the inside of the bladder. This technique is still preferred by some surgeons who believe the
long-term prevention of reflux is superior with the transvesicular approach. However, this technique
883
booksmedicos.org
requires a second cystotomy, and posttransplant hematuria is more common than with the
extravesicular technique. A third technique for ureteral implantation in recipients with normal native
ureters is ureteroureterostomy over a double-J stent. In general, this technique is reserved as a salvage
procedure for reimplantation of transplanted ureters with distal strictures secondary to ischemia. It can
also be used as a primary technique if there are questions regarding the blood supply to the distal ureter
at the time of transplant. This technique is preferred if the donor ureter was damaged or inadvertently
stripped of its blood supply at the time of procurement but is dependent on the availability of normal
native ureters to serve as an adequate conduit. The routine placement of a double-J stent is center
dependent, with some centers reserving placement of the stent for challenging extravesicular
anastomosis to poor quality bladders.
The surgical procedure has changed little over the last 60 years, with the exception of limited reports
of implantation of the kidney with the use of a robotic-assisted laparoscopic approach. The purported
advantage is smaller incisions, which appear to have an advantage in obese patients, avoiding some of
the frequent wound complications. Widespread adaptation of this technique has not occurred.18
COMPLICATIONS
Early Graft Dysfunction
Most kidneys begin to function immediately after implantation, especially in the case of a living donor.
When the initial function results in only a slow drop in serum creatinine, the diagnosis of slow graft
function is made. When dialysis is needed in the first week because of poor function, the diagnosis of
delayed graft function is made. Delayed graft function typically occurs in 15% to 30% of deceased-
donor transplants. The diagnosis of slow graft function or delayed graft function is important to
establish because other problems, such as rejection, vascular occlusion, or ureteral obstruction, can also
result in low urine output and need for dialysis. These other causes must be eliminated before the
diagnosis of slow graft function or delayed graft function can be made.
In the immediate postoperative period, careful attention to fluid status is critical. In cases of
immediate graft function, fluid orders should include replacement for urine output as well as a
maintenance fluid rate. This approach ensures that the patient does not become volume depleted and
compromise perfusion to the new kidney. In cases of delayed graft function, fluid should be restricted
and dialysis instituted when electrolyte imbalance or fluid overload are evident.
A decrease in urine output in the early postoperative period requires immediate diagnostic and
therapeutic intervention. A stepwise algorithm to assist in diagnosing the etiology of oliguria is shown
in Figure 36-1. Once mechanical obstruction of the indwelling Foley catheter has been excluded by
irrigation, the volume status of the patient should be assessed, preferably with a central venous pressure
line or pulmonary artery catheter. Fluid replacement to restore intravascular volume should be initiated
in the volume-depleted patient.
Radiologic evaluation using various imaging techniques is required if urine output remains low in the
face of adequate volume status. Ultrasonography is most helpful to diagnose ureteral obstruction caused
by technical complications at the anastomosis or fluid collections that may be obstructing the ureter by
extrinsic compression. With the addition of duplex and color Doppler imaging, blood flow to the kidney
can be evaluated and technical problems with the vessels can be assessed. Nuclear medicine techniques
are also valuable for assessing renal function. Technetium 99m diethylenetriamine pentaacetic acid
(DTPA) and iodine-131 iodohippurate (Hippuran) are the two major radionuclides used in the
evaluation of renal allograft function. DTPA renal scans evaluate the vascular flow pattern of the kidney
as well as the gross anatomy of the ureter and bladder. Scans are performed over 30 minutes, with
uptake of contrast within 6 seconds indicating adequate flow to the graft. Peak activity in the
parenchyma should be reached within 2 minutes, followed by a gradual decline in radioactivity in the
renal parenchyma and an increase in radioactivity in the urinary collecting system and bladder. Iodine-
131 iodohippurate scans are more sensitive in evaluating renal function. Peak activity is also reached in
2 to 4 minutes, with gradual decline over the next 30 minutes. In rejection, acute tubular necrosis and
drug toxicity poor uptake and poor excretion are the typical findings with a nuclear medicine scan.
If these imaging techniques do not provide an explanation for poor urine output, the diagnosis of
delayed graft function is made. Immunosuppression can then be adjusted to minimize or avoid the
calcineurin inhibitors, which can prolong the recovery from delayed graft function, and also to initiate
antibody therapy to protect the kidney from rejection. The combination of delayed graft function and
884
booksmedicos.org
early rejection is clearly associated with worse outcome in the long term, and an early biopsy of the
kidney that is functioning poorly is helpful to diagnose rejection and guide therapy.
Technical Complications
6 Most surgical complications are experienced in the immediate postoperative period. The two main
types of complications can be classified as vascular and urologic.
Renal artery thrombosis is a rare complication occurring in about 1% of transplants. The risk of this
complication is higher with size mismatch of donor renal artery and recipient internal iliac artery when
an end-to-end anastomosis is performed, in kidneys with multiple renal arteries, in kidneys traumatized
because of rough handling, and in the presence of an unidentified renal artery intimal flap. Sudden loss
of urinary output, not the result of an obstructed Foley catheter or inadequate vascular volume, should
necessitate a workup with duplex Doppler ultrasound. Loss of signal is indicative of no flow to the
kidney. Alternatively, a nuclear medicine renal scan is informative, with lack of isotope uptake by the
kidney indicating no blood flow. Prompt return to the operating room for correction of a technical
problem is imperative, but often the diagnosis is not made quickly enough to salvage the kidney.
Renal artery stenosis occurs in up to 15% of transplanted kidneys. Difficult-to-control hypertension
should suggest the possibility of stenosis. Diagnosis with renal duplex ultrasound followed by
arteriography to better define the anatomy and degree of stenosis should be done before operative
repair or angioplasty. Initial success rates for both methods are similar (75% to 80%), but the restenosis
rate following angioplasty is not well defined. Anastomotic strictures respond less well to angioplasty
and probably should be repaired by operative intervention.
Algorithm 36-1. Stepwise approach to the management of decreased low urine output posttransplant.
Aneurysms that occur in the renal artery are either pseudoaneurysms at the anastomotic site or
mycotic aneurysms secondary to bacterial or fungal infection. A rapidly expanding, tender pulsatile
mass in the region of the kidney suggests a mycotic aneurysm. Arteriography is confirmatory for
diagnosis. Treatment consists of appropriate antibiotics and removal of the transplanted kidney.
Venous complications are less frequent, with thrombosis occurring in 1% to 4% of transplants.
Causative factors include intimal damage during retrieval, kinking at the iliac vein anastomosis, or
pressure secondary to a lymphocele, urinoma, or hematoma. Occasionally, severe rejection can result in
venous occlusion. Heparin infusion for incomplete occlusion and transplant nephrectomy for complete
occlusion are the indicated therapies. Occasionally, graft salvage is possible if the diagnosis is made
885
booksmedicos.org
before progression of clot into the kidney itself. The classic sign of new onset hematuria may be an
early hint of a renal vein problem and should lead to an ultrasound.
Urologic complications include ureteral obstruction, urinary fistula, or bladder leak. These
complications all present with decreased urine output and a rise in serum creatinine. With a urine leak,
pain in the region of the transplant may be severe. Mechanical obstruction of the Foley catheter must
first be eliminated. Ureteral obstruction occurs in 1% to 9% of transplants, and diagnosis can be made
with ultrasonography demonstrating hydronephrosis. A leak is usually diagnosed with a nuclear
medicine renal scan. Further definition of a leak or stricture can be obtained via an antegrade
pyelogram (Fig. 36-4). Early obstruction of the transplant ureter at the site of the bladder anastomosis
may respond to internal stenting. Late strictures usually require reoperation, and urine and blood
polymerase chain reaction for the polyoma virus should be done in that circumstance, because polyoma
viral infection can lead to ureteral stricture. The surgical correction of a ureteral stricture may require
reimplantation of the ureter into the bladder, the creation of a Boari flap, or the use of the recipient’s
native ureter for a ureteroureterostomy (Fig. 36-5).
Figure 36-4. Percutaneous nephrostogram revealing a urine leak from the ureterovesical anastomosis.
886
booksmedicos.org
Figure 36-5. A: Reconstruction of a stenotic donor ureter, showing resection of the stenotic segment and mobilization of the
bladder. B–D: A Boari flap is constructed from a tabularized segment of bladder wall and anastomosed end-to-end to the proximal
donor ureter.
IMMUNOSUPPRESSION, REJECTION, AND IMMUNOSUPPRESSIVE

COMPLICATIONS
Immunosuppression
Major advances in the ability to block immune-mediated destruction of the kidney have taken place in
the past few years, resulting in a significant decrease in the incidence of acute rejection and
improvement in long-term allograft survival rates.15 This advance is the result of numerous agents that
have been added during the past decade to the immunosuppressive armamentarium of prednisone,
azathioprine, and cyclosporine A. These agents include tacrolimus, mycophenolate mofetil, sirolimus,
and everolimus (mTOR inhibitors), anti-interleukin-2 receptor blockers, antithymocyte globulin (a
polyclonal anti–T-cell agent), rituximab (an anti-CD20 monoclonal agent), and most recently
costimulatory blockade with CTLA4-Ig. The addition of various newer drugs targeting different
pathways in the alloimmune cascade has permitted the development of regimens that are less dependent
on the calcineurin inhibitors or prednisone.19
Newer strategies in the immunosuppressive pipeline are targeted to block: costimulatory pathways;
signaling pathways that activate T cells and T-cell proliferation; and trafficking and recruitment of
immune cells. The most promising biologic agents targeted to block the costimulatory pathways include
a second-generation CTLA4Ig (LEA29Y), a humanized anti-CD11-a (anti-LFA1), and a humanized anti-
B7.1/B7.2. Promising agents designed to block T-cell activation and proliferation are the inhibitors of
the Janus protein tyrosine kinase (JAK3) and the leflunomide analog FK778. Finally, drugs to block the
trafficking and recruitment of immune cells are antagonists against the chemokine receptors CCR1,
CXCR3, and CCR5. The chemokine antagonists have been effective in experimental transplantation and
will likely be transitioned to clinical trials in the near future.20
Rejection
7 Hyperacute rejection is extremely rare and is humorally mediated by preformed anti-HLA antibodies.
Hyperacute rejection occurs within minutes to hours following reperfusion of the kidney, whereas
classic cell-mediated rejection typically does not occur until 1 to 2 weeks after the transplant. In
hyperacute rejection, the anti-HLA antigens bind to the vascular endothelium of the kidney transplant,
resulting in activation of the complement cascade and rapid graft thrombosis. The kidney appears blue-
black with poor tissue turgor despite adequate blood flow. The characteristic histologic appearance
includes the triad of polymorphonuclear leukocytes in the glomerular capillary loops, fibrin deposition,
and platelet thrombi. The kidney cannot be salvaged, and a transplant nephrectomy is necessary. The
presence of anti-HLA antibodies should be detected in the pretransplant crossmatch, and with the
sensitivity of current immunologic assays, hyperacute rejection is usually a result of technical or clerical
errors in the crossmatch procedure. A more common and less intense form of humoral rejection
occurring within a few days of transplantation is a result of reactivation of memory B cells following
reexposure to alloantigen. The histologic findings are defined by positive C4d staining on vascular
endothelium, although lymphocytic infiltrates consistent with classic cell-mediated rejection can be
present. Treatment of this aggressive rejection can include plasmapheresis, the anti–B-cell agent
rituximab (anti-CD20 monoclonal antibody), and polyclonal antilymphocyte preparations
(antithymocyte globulin).
8 Classic acute cell-mediated rejection typically occurs between 1 week and 3 months following
transplantation. Most patients with rejection episodes present with decreasing urine volumes and
increases in serum creatinine values. Low-grade fever and allograft tenderness may be present, but
significant physical symptoms frequently are absent. Immediate workup of increasing serum creatinine
should be initiated, beginning with an ultrasound to rule out ureteral obstruction or technical vascular
complications as the cause of the deteriorating function. Similarly, toxicity from calcineurin inhibitors
needs to be determined by checking drug levels. A percutaneous kidney biopsy is performed to confirm
rejection. The severity of the rejection episode is based on the presence of lymphocytes in renal tubules
(tubulitis) and vascular endothelium (vasculitis). Mild rejection is generally treated with pulse
887
booksmedicos.org
corticosteroids and maximizing the maintenance immunosuppression to ensure therapeutic levels of
calcineurin inhibitors. More severe rejection with both tubulitis and vasculitis, as well as steroid-
resistant rejection, is treated with antilymphocyte antibody preparations, most frequently with rabbit
polyclonal antilymphocyte preparations. If the rejection episode occurred while the patients had
therapeutic drug levels, maintenance therapy is frequently altered following the antibody therapy. For
example, if maintenance therapy consisted of cyclosporine A, the calcineurin inhibitor could be switched
to tacrolimus. Other potential strategies include the addition of an mTOR inhibitor to the
immunosuppressive regimen, particularly for cases where there is evidence of calcineurin inhibitor
toxicity on biopsy.
9 Each rejection episode takes a toll on long-term function of the kidney transplant. Even well-
controlled acute rejection episodes initiate a cascade of events leading to interstitial fibrosis and
proliferative changes affecting the vascular endothelium. These histologic and progressive degenerative
changes are classified as chronic rejection or chronic allograft nephropathy. These changes lead to loss
of graft function over the course of months to several years. Current strategies minimizing calcineurin
inhibitor nephrotoxicity are being used to prolong function in kidneys with these chronic changes and
involve the addition of TOR inhibitors to replace the calcineurin inhibitors. It remains unclear whether
the marked decrease in acute rejection episodes, from greater than 50% to less than 20% observed in
the past 5 years, will translate to better long-term function of transplants. Nonetheless, it is evident that
immunosuppression strategies minimizing prednisone and calcineurin inhibitors are providing safer and
more effective immunosuppression for kidney-transplant recipients while decreasing long-term toxicities
associated with immunosuppression.
Immunosuppressive Complications
It would be naive to assume that the intensification of immunosuppressive regimens resulting in
decreased acute and chronic rejection rates can be accomplished without sequelae. Infections and
malignancy remain significant complications associated with long-term immunosuppression and are the
driving force for drug-minimization strategies. Early infections during the perioperative period are
commonly iatrogenic and involve bladder infections or intravenous catheter use. Higher doses of
immunosuppressive drugs used in the early postoperative period predispose patients to these infections
and emphasize the importance of maintaining sterility during Foley catheter placement and insertion of
intravenous catheters. Pneumonia related to mechanical ventilation and poor postoperative inspiratory
effort can occur in the early postoperative period, and early incentive spirometry should be encouraged
to decrease the potential for this infection. Wound infections are relatively uncommon, although
diabetes and obesity are both associated with a much higher incidence of wound complications. Weight
reduction to achieve a body mass index of less than 35 is strongly recommended to facilitate the
operative procedure and minimize the risks of wound complications, particularly in the recipient with
diabetes mellitus.
Cytomegalovirus (CMV), a herpesvirus, remains a problematic infection in the immunosuppressed
patient and can become symptomatic 1 to 2 months following the transplant. CMV-seronegative patients
who receive a kidney from a CMV-seropositive donor are at the highest risk for infection, although
prophylaxis with acyclovir or ganciclovir is generally provided for all recipients for a period of 3 to 6
months following the transplant. Despite prophylaxis, activation of CMV can occur, accompanied by
fever, malaise, pneumonia, gastrointestinal distress, or dysfunction of the kidney transplant. The
effective treatment of blood- or tissue-invasive CMV has been one of the major advances in the
management of kidney transplant patients within the past two decades. What was a life-threatening
disease in the early era of solid organ transplantation can today be effectively managed with oral
antibiotics.
Prophylaxis against Candida albicans with fluconazole and Pneumocystis carinii with trimethoprim–
sulfamethoxazole is also part of most management strategies posttransplant. Other potentially life-
threatening opportunistic organisms that can affect the chronically immunosuppressed transplant
recipient include Aspergillus, Cryptococcus, Listeria, Nocardia, and Mycobacterium.
More potent immunosuppression regimens used in the current era have been associated with the
emergence of polyoma or BK virus, a previously rare infection that may cause graft loss in up to 5% of
infected patients. Reduction in immunosuppression is necessary to prevent progression of viral tubulitis.
There has been some experience with the use of leflunomide, ironically an immunosuppressive agent,
but with an active metabolite, A77 1726, that has substantial antiviral activity in vitro and in animals.
Another potential medication, cidofovir, is a nucleotide analogue that inhibits viral DNA polymerase but
888
booksmedicos.org
unfortunately is also nephrotoxic, and its in vivo efficacy has not been proved. Probably the best
method to prevent graft loss due to polyoma is the use of monitoring of urine and serum levels of BK
virus, with lowering of immunosuppression when early evidence of polyoma is detected.
Patients with a previous history of active tuberculosis or conversion to purified protein derivative
positivity should receive appropriate prophylaxis for 6 months to 1 year following the transplant
procedure.
More potent immunosuppression regimens will also have an impact on the development of neoplasms
following transplantation.21 Skin cancers are the most common malignancy following transplantation,
with more than 90% being squamous or basal cell cancers. The incidence of skin cancers is staggering,
with 50% or more of white recipients ultimately developing lesions. The immunosuppressed patient also
has a higher incidence of nodal spread, and educating the patient about the importance of avoiding
direct sun exposure is essential. Other malignancies that have a particularly high incidence in transplant
recipients include non-Hodgkin lymphomas and carcinomas of the anogenital areas. The etiology of
anogenital carcinoma is related to the presence of human papilloma virus. Although there have been no
prospective trials to date, there is some evidence that TOR inhibitors are advantageous in the setting
malignancies as the preferred immunosuppressive agent based on their antiproliferative qualities.
Conversion to mTOR inhibitors and minimization of calcineurin inhibitors is a strategy that has been
used with increasing frequency in the scenario of malignancies following transplantation.
Figure 36-6. Comparison of graft survival and graft half-life (t1/2) in 1992 and 2002 for different donor types (age >60 years in
1992 group, age >50 years with hypertension, elevated creatinine, or donor death from cerebrovascular accident in 2002 group).
There has been an improvement in survival for all donor types, with the best long-term results with living-donor kidneys. ECD,
expanded criteria donor; LD, living donor; SCD, standard deceased donor.
Posttransplant lymphoproliferative disease is the second most common form of malignancy in

transplant recipients and is associated with Epstein–Barr virus. These lymphoproliferative syndromes
present as a spectrum of pathology, extending from polyclonal lymphoproliferation to monoclonal B-cell
lymphomas. Polyclonal disease has been managed by decreasing or withdrawing immunosuppression,
whereas progression to monoclonal lymphomas has required chemotherapy. CD20-positive lymphomas
have been successfully managed with rituximab, an anti-CD20 antibody, with no significant side effects.
CURRENT RESULTS AND FUTURE TRENDS

Over the past three decades, progressive improvement has been made in patient and graft survival,
independent of donor source. This progression is best shown in Figure 36-6 for the period of time
spanning 1992 to 2002. Overall graft survival, as well as the half-life of the graft, improved
incrementally for live-donor transplants, standard deceased-donor transplants, and even deceased-donor
transplants using suboptimal or expanded criteria donors.15 This change is related to improved organ
preservation, perfected operative technique, and most important, improved immunosuppressive agents.
Current 1-year actuarial graft survival rates for living and deceased-donor transplants are 94.8% and
88.9%, respectively.22 These remarkable 1-year results continue to be overshadowed by the specter of
late graft loss due to chronic rejection. This problem remains unsolved in renal transplantation, and
future improvement in long-term survival will be achieved only when the mechanisms of this process
are understood.
889
booksmedicos.org
The exponential growth in waiting lists compounded by the ongoing critical shortage of organs will
continue to stimulate creative means of increasing both the living- and deceased-donor pools. Expansion
in the number and types of immunosuppressive agents has resulted in marked decreases in the incidence
of acute rejection, which it is hoped will translate to prolongation in the long-term function of kidney
transplants. Newer strategies in immunosuppressive regimens that minimize nephrotoxic cyclosporine
and tacrolimus by adding nonnephrotoxic agents will also benefit the long-term function of transplanted
kidneys. The effect of ischemia-reperfusion injury on both early and late graft function, as well as its
impact on the development of chronic rejection and transplant glomerulopathy, is an area of active
research, and potential therapeutic interventions to minimize this injury are being evaluated. The
induction of tolerance to foreign antigen remains the “holy grail” of transplantation. A paucity of
tolerizing regimens have been applied clinically, although the use of donor bone marrow or stem cells
will likely have a future role in achieving the elusive goal of transplantation tolerance.
References
1. Tanabe K, Tokumoto T, Ishida H, et al. Excellent outcome of ABO-incompatible living kidney
transplantation under pretransplantation immunosuppression with tacrolimus, mycophenolate
mofetil, and steroid. Transplant Proc 2004;36(7):2175–2177.
2. Takahashi K, Saito K, Takahara S, et al. Excellent long-term outcome of ABO-incompatible living
donor kidney transplantation in Japan. Am J Transplant 2004;4(7):1089–1096.
3. Tait BD, Susal C, Gebel HM, et al. Consensus guidelines on the testing and clinical management
issues associated with HLA and non-HLA antibodies in transplantation. Transplantation 2013;95:19–
47.
4. Meier-Kriesche HU, Kaplan B. Waiting time on dialysis as the strongest modifiable risk factor for
renal transplant outcomes: a paired donor kidney analysis. Transplantation 2002;74(10):1377–1381.
5. Rosendale JD. Organ donation in the United States: 1988–2002. Clin Transpl 2003:65–76.
6. Ahearn AJ, Posselt AM, Kang SM, et al. Experience with laparoscopic donor nephrectomy among
more than 1000 cases: low complication rates, despite more challenging cases. Arch Surg
2011;146(7):859–864.
7. Nogueira JM, Jacobs SC, Haririan A, et al. A single center comparison of long-term outcomes of
renal allografts procured laparoscopically versus historic controls procured by the open approach.
Transpl Int 2008;21(9):908–914.
8. Gurkan A, Kacar S, Varilsuha C, et al. Exchange donor transplantation: ethical option for living
renal transplantation. Transplant Proc 2011;43(3):795–797.
9. Cooper JT, Chin LT, Krieger NR, et al. Donation after cardiac death: the university of wisconsin
experience with renal transplantation. Am J Transplant 2004;4(9):1490–1494.
10. Aull MJ, Kapur S. Kidney paired donation and its potential impact on transplantation. Surg Clin
North Am 2013;93:1407–1421.
11. Israni AK, Salkowski N, Gustafson S, et al. New national allocation policy for deceased donor
kidneys in the United States and possible effect on patient outcomes. J Am Soc Nephrol
2014;25:1842–1848.
12. Warren DS, Zachary AA, Sonnenday CJ, et al. Successful renal transplantation across simultaneous
ABO incompatible and positive crossmatch barriers. Am J Transplant 2004;4:561–568.
13. Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to
lower allosensitization and improve transplantation in highly sensitized adult patients with end-
stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol 2004;15:3256–3262.
14. Jochmans I, Moers C, Smits JM, et al. Machine perfusion versus cold storage for the preservation of
kidneys donated after cardiac death: a multicenter, randomized, controlled trial. Ann Surg
2010;252:756–764.
15. Cecka JM. The OPTN/UNOS Renal Transplant Registry 2003. Clin Transpl 2003:1–12.
16. Terrault NA, Stock PG. Management of hepatitis C in kidney transplant patients: on the cusp of
change. Am J Transplant 2014;14(9):1955–1957.
17. Stock PG, Barin B, Murphy B, et al. Outcomes of kidney transplantation in HIV-infected recipients.
N Engl J Med 2010;363:2004–2014.
890
booksmedicos.org
18. Tzvetanov I, Giulianotti PC, Bejarano-Pineda L, et al. Robotic-assisted kidney transplantation. Surg
Clin North Am 2013;93:1309–1323.
19. Vincenti F. Immunosuppression minimization: current and future trends in transplant
immunosuppression. J Am Soc Nephrol 2003;14(7):1940–1948.
20. Vincenti F, Kirk AD. What’s next in the pipeline. Am J Transplant 2008; 8:1972–1981.
21. Morath C, Mueller M, Goldschmidt H, et al. Malignancy in renal transplantation. J Am Soc Nephrol
2004;15:1582–1588.
22. Wynn JJ, Distant DA, Pirsch JD, et al. Kidney and pancreas transplantation. Am J Transplant
2004;4(Suppl 9):72–80.
891
booksmedicos.org
Chapter 37
Hepatic Transplantation
Theodore H. Welling
Key Points
1 The main indication forliver transplantation is end-stage liver disease, defined as the clinical scenario
in which a pathologic process or multiple processes have resulted in a damaged liver that has
minimal function and no potential for recovery.
2 The Organ Procurement and Transplantation Network uses the Model of End-stage Liver Disease
score as a method of prioritizing liver transplant recipients. The Model of End-stage Liver Disease
score is an integer value based on three objective laboratory studies: creatinine, bilirubin, and the
international normalized ratio.
3 The degree of preoperative debilitation and the complexity of the operative procedure make
complications following hepatic transplantation very common.
4 Approximately 2% to 4% of transplanted livers function so poorly in the immediate postoperative
period that death is likely in the absence of retransplantation, a condition referred to as primary
nonfunction of the allograft.
5 For reasons that are not completely understood, liver transplant recipients require less immune
suppression than patients with other types of allografts, such as heart, lung, and kidney recipients.
6 Typical acute rejection in liver transplant recipients is usually cell mediated.
7 Chronic rejection is characterized by relentless immune attack on small bile ducts. Histologically,
small bile ducts are obliterated or completely absent, termed vanishing bile duct syndrome.
8 The patient survival rate following liver transplantation in the United States at 1 year is more than
85% for adults and nearly 90% for children.
Liver transplantation has evolved over the past four decades to be the standard treatment for patients
with a variety of acute and chronic liver diseases. The first successful liver transplant was performed on
a moribund child with a hepatoma by Dr. Thomas Starzl at the University of Colorado in 1967.1 This
child lived more than a year before succumbing to recurrent tumor. Over the next 12 years, liver
transplants continued to be performed at a modest rate. Despite 1-year survival rates of less than 50%,
it was clear that some patients benefited from the procedure.
In 1979 cyclosporine was introduced into clinical organ transplantation by Sir Roy Calne.2 Almost
immediately 1-year patient survival rates jumped to over 70%. As a result, liver transplantation
programs began to appear worldwide. Today more than 10,000 liver transplants are performed annually
in the United States, and survival rates exceed 85% at 1 year and 70% at 5 years, primarily varying on
liver disease indication.3,4
The clinical expanse of liver transplantation is now primarily limited by the availability of suitable
donor organs. Every year more patients are listed for liver transplantation than receive transplants. In
the future it is likely that this problem will worsen because of the large number of individuals with
chronic hepatitis C infection, a significant portion of whom will eventually develop cirrhosis and
hepatocellular carcinoma (HCC), and the expanding numbers of patients with either HCC or
nonalcoholic steatohepatitis (NASH).5 Attention continues to be focused on methods to increase the
available supply of livers for transplantation. Notable efforts to improve the supply of available organs
include the work by the Department of Health and Human Services, which recently took up the cause of
organ donation vigorously. This effort, termed the Organ Donation Breakthrough Collaborative,6
focused on improving the success rate of organ donation efforts at the hospitals that have most potential
organ donors nationwide. The Center for Medicare and Medicaid Services also joined the effort by
declaring specific Conditions of Participation for all hospitals that treat Medicare patients in the United
States.7 This effort focused on encouraging methods of approaching donor families that have been
shown to be optimally effective.
892
booksmedicos.org
Many other methods to increase the number of donor livers are currently being practiced. These
methods include the utilization of older liver donors, steatotic donor livers, the development of
techniques to allow a single liver graft to be split into two grafts, and the utilization of liver grafts from
donors that donate after cardiac death (DCD). Many centers have continued the development of safe
surgical techniques that allow healthy, living volunteers to donate a segment of their liver to a recipient
in need of a liver transplant.8,9
GENERAL INDICATIONS FOR HEPATIC TRANSPLANTATION

1 The most common indication for liver transplantation is end-stage liver disease. The term end-stage
refers to the clinical scenario in which a pathologic process or multiple processes have resulted in a
damaged liver that has minimal function and no potential for recovery. The diagnosis of end-stage liver
disease is made primarily on the basis of clinical findings. Additional information about the etiology of
the liver disease and thus its natural history can often be obtained by supplementary investigations
including serologic studies and histologic examination of a liver biopsy specimen. It is important that
potential liver transplant recipients are evaluated by a hepatologist and surgeon with expertise in end-
stage liver disease, because many other diseases may present similar clinical pictures.
The severity of liver disease in an individual is highly variable, from mild cirrhosis and no symptoms
to severe decompensation resulting in deterioration of mental status and frank renal failure. The rate of
progression of liver disease from a functional state to invalidism and death is variable and may be rapid
or may take several years. The challenge facing liver transplant professionals is to identify patients who
will benefit from transplantation. Hepatic transplantation may result in wonderful and dramatic results,
but at the same time it is always a high-risk procedure. In situations in which patients enjoy full
performance status, and are only minimally symptomatic, transplantation is an inappropriate
therapeutic measure. A liver transplant is a major surgical procedure on a profoundly ill individual with
unavoidable risk that also requires chronic, lifelong immunosuppression. Despite advances in
immunosuppressive medications developed over the past four decades, immunosuppression remains a
treatment that induces a state of vulnerability in the recipient by virtue of the fact that the recipient’s
natural resistance to infection and malignancy is compromised. It is thus critical that patients be
carefully selected who will benefit from the procedure.
Table 37-1 MELD and PELD Score
2 How is it possible to properly select patients and properly time transplantation so that the benefit
of transplantation is assured? In 2002, the Organ Procurement and Transplantation Network began
using the Model of End-stage Liver Disease (MELD)10 score as a method of prioritizing liver transplant
recipients. The MELD score is an integer value based on three objective laboratory studies: creatinine,
bilirubin, and the international normalized ratio (INR) (Table 37-1). This has been adapted to pediatric
patients as the Pediatric End-Stage Liver Disease (PELD) utilizing the variables in MELD along with
albumen instead of creatinine and including age as well as the presence of growth failure (Table 37-1).
Analysis done by the Scientific Registry of Transplant Recipients (SRTR) has shown that patients with
MELD scores of less than 15 have a mortality rate on the waiting list that is less than the mortality rate
of the transplant procedure in the same population.11 This suggests that patients with a MELD score of
less than 15 do not receive an absolute survival benefit from transplantation whereas patients with
higher MELD scores have the potential to receive a survival benefit with liver transplantation. In other
words, there is no evidence that patients who are very ill from liver disease do not benefit from liver
transplantation, but patients who have stable, mild liver disease should not receive a transplant until
their disease has progressed to a more severe state.
Surprisingly, MELD more accurately predicts mortality than clinical factors that were previously
thought to be ominous signs of reduced (6 months or less) survival. Such factors, including the presence
893
booksmedicos.org
of ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or variceal hemorrhage, do not add
to the predictive value of MELD.10 This finding may be related to the difficult nature of accurately
quantifying clinical variables in registry databases or to the fact that MELD is such an accurate way of
measuring functional hepatic capacity that no additional clinical variables are more relevant.
As will be discussed later, the transplant community has agreed upon certain exceptions to the MELD
score for patients with chronic liver disease. It is generally supported that patients with diseases such as
HCC, hepatopulmonary syndrome (HPS), primary oxaluria, and familial amyloidosis benefit from
additional MELD points by regional review boards. Other diseases or complications such as portal vein
thrombosis or portopulmonary hypertension (PPHTN) remain less clear and are handled on a case-by-
case basis.12
Table 37-2 Urgent Listing Criteria for Liver Transplantation
The improved ability to predict mortality for patients with liver failure allowed the development of
national allocation policies that direct livers to those patients that will benefit. Importantly, the
implementation of the MELD system of liver allocation from deceased donors has been associated with a
decrease in the death rate on the waiting list.13 Further refinements of our understanding will
undoubtedly occur as improved long-term follow-up data on waiting list mortality become available and
as quality of life considerations are added to the analysis.
These considerations apply to the chronic forms of liver failure, but not to the important emergency
decisions about transplantation that must be made when a patient presents with fulminant hepatic
failure (FHF), which is defined as the progression from good health to liver failure with hepatic
encephalopathy within 8 weeks. Without transplantation, the mortality rate for FHF is approximately
75%.14 Death often occurs rapidly once patients progress to stage II (confusion), stage III, (stuporous),
or stage IV (unresponsive) hepatic encephalopathy. In these cases, the decision to perform
transplantation is based on clinical grounds. Current liver transplant allocation policy allows for the
rapid transplantation of patients with fulminant hepatic failure. These patients can be listed as “status
1A,” (Table 37-2) which gives them higher priority for available livers than patients with chronic liver
disease who are prioritized based on MELD score.
CONTRAINDICATIONS TO LIVER TRANSPLANTATION

The number of absolute contraindications to hepatic transplantation has steadily decreased during the
past several years as experience with the procedure has increased. Many clinical situations once
considered to be absolute contraindications for transplantation are now either no longer considered to
be contraindications or to be only relative contraindications. A thrombosed portal vein is no longer a
contraindication to transplantation because techniques have been devised to effectively deal with this
condition (see Liver Transplantation: Surgical Procedure).15 The presence of juvenile-onset diabetes
mellitus formerly precluded transplantation. In current practice, this is not usually the case, depending
on the patient’s physiologic status at the time of evaluation. Similarly, advanced age causes concern, but
in most centers the physiologic state of the patient is a more important consideration than the
chronologic age.
The inability to withstand the operative procedure, usually for cardiovascular or pulmonary reasons,
is still generally considered to be a contraindication to liver transplantation. Specific examples include
patients with depressed ejection fraction secondary to ischemic cardiomyopathy, significant pulmonary
894
booksmedicos.org
hypertension, and significant chronic obstructive pulmonary disease. Cardiac disease that is not
amenable to percutaneous therapy poses a particular problem because these patients are frequently
unable to withstand a corrective cardiac procedure because of their severe liver disease. In highly
selected patients it may be possible to perform combined heart and liver transplantation or combined
lung and liver transplantation.
Recent intracranial hemorrhage is almost always a contraindication because during the liver
transplant procedure, coagulopathy is often present along with significant alterations in arterial blood
pressure. The risk of a catastrophic exacerbation of intracranial bleeding during a transplant is therefore
high in this setting. However, the meaning of “recent” is not defined in either the transplant or the
neurosurgical literature. Profound, irreversible neurologic impairment is also considered to be a
contraindication. Active substance abuse remains a contraindication, as is the lack of the necessary
social support network.
HIV infection, long considered a contraindication, is no longer an absolute exclusion due to the
development of highly effective antiretroviral therapies.16,17 Active sepsis or untreated infection and
active extrahepatic malignancy continue to be contraindications.
Although renal insufficiency increases the risk of liver transplantation, it is not a contraindication.
Patients who have hepatorenal syndrome (HRS) frequently experience recovery of renal function
following liver transplantation. However, patients who have longstanding hepatorenal failure and
patients with known renal parenchymal disease requiring renal replacement therapy are often best
served by combined liver/kidney transplantation.
DISEASE-SPECIFIC INDICATIONS AND OUTCOMES

While the MELD score assessment plays a critical role in evaluating and listing patients that might
benefit from liver transplantation, patients that develop liver disease–specific complications, regardless
of MELD, are also appropriate to consider liver transplantation. Some of these complications along with
other liver-specific metabolic diseases are listed in Table 37-3. Hepatitis C is currently the most common
disease for which liver transplantation is currently performed in the United States (33%) (Fig. 37-1).
Alcoholic liver disease, NASH, and cholestatic liver diseases are the next most common ranging from
10% to 14% of cases. However, this trend is believed to be changing with a greater proportion of liver
transplants being performed for NASH (Fig. 37-2).5 Outcomes following liver transplantation are best
for pediatric patients with biliary atresia, while patients with cholestatic liver diseases experience the
best survival among adults (Fig. 37-3). Patients with hepatitis C or HCC experience worse survival
secondary to disease recurrence although recent advances in hepatitis C antiviral therapy may change
this trend.18 Disease-specific indications, outcomes, and considerations will be discussed in the following
sections.
Alcoholic Liver Disease

Excessive alcohol consumption can lead to several hepatic abnormalities, ranging from alcoholic
hepatitis to steatosis, hepatic fibrosis, and cirrhosis. Alcoholic liver disease was once thought to occur
only in individuals who consumed large quantities of alcohol over long periods of time. It has recently
become recognized that even moderate amounts of alcohol consumption can induce liver injury,
suggesting that hereditary and or environmental factors are probably important. Hepatitis C viral
infection, found in 15% to 25% of patients with alcoholic liver disease, appears to exacerbate alcohol-
induced liver injury and vice versa.
Table 37-3 Liver Disease Complications and Liver-Specific Metabolic Diseases
895
booksmedicos.org
When liver transplantation emerged as a standard therapy for end-stage liver disease in the 1980s,
intense debates occurred surrounding the issue of offering liver transplantation. There were two broad
areas of concern. First, many were skeptical that patients with a history of longstanding alcoholism
would be able to successfully comply with the rigorous long-term medical treatment required of
patients who receive lifelong immunosuppression. On a broader level, concern was expressed that
scarce societal resources should not be used to treat patients with “self-induced” diseases. With more
experience in this area, it has been recognized that the incidence of recidivism after transplantation is
low, and both short- and long-term results in this category are as good as for nonalcohol-related
categories. It has also become understood that determining worthiness for receiving a lifesaving organ
by making a judgment about past behavior is neither ethical nor possible.
Today, the same methods of determining suitability for transplantation are used for patients with
alcoholic liver disease as with other diagnoses with one proviso. Alcohol-induced liver injury frequently
regresses following cessation of alcohol consumption as long as cirrhosis is not yet present. Patients
with a history of recent alcohol abuse should therefore be observed for a minimum of 6 months to
ensure that their hepatic dysfunction is not reversible. In addition, all patients with a history of
substance abuse must be evaluated by individuals with expertise in addiction and found to have good
insight into their past self-destructive behavior and a stable social support network for the
posttransplant phase.
Figure 37-1. Percentage of liver transplants for each etiology. (From O’Leary JG, Lepe R, Davis G. Indications for liver
transplantation. Gastroenterology 2008;134:1764–1776.)
Figure 37-2. Changing incidence of liver transplantation for NASH, HCC, and Hepatitis C. (From O’Leary JG, Lepe R, and Davis
GL. Indications for liver transplantation. Gastroenterology 2008;134:1764–1776.)
Viral Hepatitis
896
booksmedicos.org
Most patients who become infected with hepatitis B develop an immunologic response to the virus that
results in complete viral clearance. Patients who do not clear the hepatitis viral antigen may persist as
carriers or may develop chronic hepatitis, which progresses to fibrosis and cirrhosis. In the 1980s,
transplantation for hepatitis B was associated with universal recurrence of viral infection posttransplant
and survival rates were poor. Fortunately, transplantation for this indication was revolutionized by the
development of effective posttransplant prophylaxis using long-term, high-dose, hepatitis B immune
globulin and the nucleoside inhibitors lamivudine or entecavir.19,20 Today, outcomes for transplantation
for hepatitis B–induced liver failure, while varying based on genotype, are equivalent to or better than
those for other conditions.21
Hepatitis C has become the most common etiology among patients receiving liver transplants.5
Antiviral therapy using pegylated interferon and ribavirin for early hepatitis C infection has been
demonstrated to have clinically important responses seen in over half of patients treated. However,
complete clearance of HCV from the serum can only be achieved in a minority of patients which is
largely related to viral genotype and whether significant toxicities to therapy develop.22,23 Fortunately,
multiple new anti-HCV medications have now been FDA approved and show much improved complete
response rates and improved tolerability. These recent developments will serve to change the landscape
for patients with chronic HCV, eliminating the need for transplantation in many cases, and offer new
options to treat HCV recurrence following transplantation.18
Figure 37-3. Disease-specific survival following liver transplantation. (From Roberts MS, Angus DC, Bryce CL, et al. Survival after
liver transplantation in the United States: a disease-specific analysis of the UNOS database. Liver Transpl 2004;10:886–897.)
Following liver transplantation, recurrence of HCV hepatitis in the transplanted liver occurs
universally unless the virus was eradicated pretransplant with therapy.24 Although some patients
experience an indolent course, most patients experience a more rapid progression to liver failure once
cirrhosis has developed posttransplant. These patients can progress to end-stage liver failure within 6
months. Short-term results of transplantation for this disease are comparable to those for the other
noninfectious conditions. However, approximately 25% of patients develop recurrent cirrhosis within 5
years posttransplant, and long-term survival is less likely compared with patients who do not have
hepatitis C infection. Use of livers from donors of increased age are thought to contribute to poorer
results in hepatitis C patients.25 Treatment of recurrent hepatitis C posttransplant is presently being
attempted with some of the new antiviral therapies available and clinical trials underway.18,26 Despite
recurrence, transplantation appears to provide a substantial and worthwhile survival benefit to most
897
booksmedicos.org
patients with hepatitis C.
Hepatocellular Carcinoma and Other Hepatic Malignancy

Cirrhosis is a major risk factor for the development of HCC, and the majority of HCCs develop in
patients who have cirrhosis. Curative resection is unsafe in the setting of advanced cirrhosis, and it does
not eliminate the high likelihood of recurrent malignancy. Because most patients with HCC die of liver
failure, rather than metastatic disease, it was reasoned that transplantation would be potentially
curative. This approach yielded poor survival rates, and during the early 1990s primary hepatic
malignancy was considered a contraindication to liver transplantation by many centers. This
circumstance changed when Mazzaferro et al.27 reported an 85% 4-year survival rate for patients who
had cirrhosis and either stage I or stage II HCC (Table 37-4). Transplantation is now considered
standard therapy for HCC and cirrhosis if there is no evidence of extrahepatic disease, vascular invasion,
and if the tumor burden does not exceed stage II (single tumor ≤5 cm in diameter, or 2 to 3 tumors,
none >3 cm in diameter). While some advocate transplantation of patients with larger tumors,28,29 this
practice is still controversial due to concerns of overall lower disease-free survival. Many centers now
adopt a downstaging strategy with local regional therapies such as radiofrequency ablation (RFA) or
transarterial chemoembolization (TACE) to bring patients down to stage II in order to list for liver
transplantation.30 Transplantation is clearly not beneficial in the presence of known positive nodal or
distant metastases (stage IV disease). To create relative equality for a scarce resource, MELD allocation
points are standardly allocated to HCC patients meeting the Milan criteria so as to minimize waitlist
dropouts due to disease progression and at the same time not over utilize donor livers from the
remainder of the recipient candidate pool. However, in recent reviews of outcomes of liver
transplantation as reported by the SRTR,4 the adjusted 3-year survival rate for HCC patients was 74%
and was statistically lower than non-HCC recipients (81%) during the MELD era while at the same time
one of the lowest waitlist drop-off rates and higher transplant rate among other disease indications for
transplantation,4,31 suggesting that the allocation policy may need further refinements.
Table 37-4 TNM Classification and Staging of Hepatocellular Carcinoma
Other primary tumors of the liver include hepatoblastoma, cholangiocarcinoma, and primary
sarcoma. Hepatoblastoma occurs primarily in children with resection or transplantation being used as
potential curative options.32 Transplantation is utilized for patients who are unresectable because of
bilobar disease or hilar location. Hepatoblastoma can respond partially to chemotherapy, but complete
and sustained tumor regression is uncommon. Patients are often treated with chemotherapy until the
time of transplantation to prevent extrahepatic growth prior to the definitive treatment.
Hepatoblastoma is relatively unique among liver tumors in that long-term survival has been reported
even in children who have had distant metastatic spread.
898
booksmedicos.org
Cholangiocarcinoma has historically been considered a contraindication to transplantation because 5-
year survival rates have been reported at less than 20%. Recently, success similar to other recipients has
been reported for patients who have limited disease (<2.5 cm, no lymph node disease) and have
received neoadjuvant chemotherapy and radiation along with aggressive staging prior to
transplantation.33,34
Although there are anecdotal reports of long-term survival following transplantation for primary
sarcoma of the liver, the majority of experiences indicate that transplantation is not a curative therapy
for this condition. Liver transplantation is generally not appropriate for patients who have secondary
(metastatic) hepatic malignancy, because long-term survival rates are very poor due in part to the
observation that immunosuppression promotes tumor growth. The possible exception to this rule is
patients who have metastatic carcinoid or neuroendocrine tumor that is limited to the liver. These
tumors can progress very slowly and local cure of the primary tumor is frequently possible. While it is
still controversial when compared to other standard therapies, long-term disease-free survival following
liver transplantation is possible in selected circumstances.35
Nonalcoholic Fatty Liver Disease (NAFLD)

NAFLD may be the most common liver disease in the United States. It has a high incidence in obese
patients and those with adult-onset diabetes mellitus. The disease resembles alcoholic liver disease, but
patients do not report a significant history of alcohol use. The degree of hepatic injury varies from
benign elevations of serum hepatic transaminases in association with hepatic steatosis or steatohepatitis
to fibrosis and cirrhosis. A majority of patients previously classified as having cryptogenic cirrhosis
probably have longstanding steatohepatitis. It is estimated that at least two-thirds of the obese
population in the United States has hepatic steatosis and close to one-fifth have steatohepatitis.36
Patients who develop cirrhosis and progress to end-stage liver disease are appropriate candidates for
liver transplantation. Recurrence of steatohepatitis leading to graft dysfunction is possible. Recipient
diabetes or obesity appears to be independent negative prognostic indicators for survival after liver
transplantation.36
Fulminant Hepatic Failure

Acute hepatic failure, defined as the development of altered mental status, coagulopathy and hepatic
dysfunction within 8 weeks of the onset of an acute hepatic disease, is a rare, but lethal disease.14,37
There are over 2,000 cases of acute hepatic failure per year in the United States. The mortality rate
approaches 80% in patients who do not receive liver transplants. The causes of acute hepatic failure
include viral hepatitis, toxins such as aflatoxins from the poisonous mushroom family Amanita phalloides,
acute fatty liver of pregnancy, acute Budd–Chiari syndrome, and drug toxicities. Drug toxicities include
both idiosyncratic reactions and drugs with predictable toxicity when taken in excess. Drugs that have
been reported to induce idiosyncratic liver failure include isoniazid, halothane, valproate, disulfram, and
phenytoin, among many others. The over-the-counter analgesic, acetaminophen, causes dose-dependent
hepatic failure and is now the single most common cause of acute hepatic failure in the United States.
The most generally accepted criteria for transplantation of patients with FHF were described by the
group at the King’s College hospital in London, England (Table 37-5).38 While the King’s College criteria
has been separately validated in other studies, more recent studies have begun to evaluate whether
other scoring systems may have improved abilities to measure severity of illness. MELD has come under
recent investigation in this regard and has been found to be additive to the King’s College criteria in
predicting outcome following FHF.39,40 The current United National Organ Sharing (UNOS) listing
criteria for patients with FHF is in Table 37-2. The outcomes following transplantation have shown
overall higher perioperative mortality, compared to other diseases, with overall similar long-term
survival (Fig. 37-3).3
Biliary Atresia
Biliary atresia is a congenital disorder of infants, occurring in about 1 of 15,000 births, that is
characterized by biliary obstruction resulting from obliteration or discontinuity of the extrahepatic
biliary system resulting in progressive hyperbilirubinemia, cirrhosis, and hepatic failure. Other anatomic
anomalies can also be coassociated with this disorder such as a preduodenal portal vein. The etiology is
not completely defined yet is the most common indication for hepatic transplantation in pediatric
patients. Standard treatment includes creation of a portoenterostomy (Kasai procedure), if this can be
done before 3 months of age. After this point, success rates diminish markedly. Response to the
899
booksmedicos.org
portoenterostomy procedure is highly variable. Patients may develop cirrhosis within the first 6 months
of life or live into their twenties before developing synthetic dysfunction and portal hypertension.
Approximately 75% of children will require transplantation by 6 years of age.
Table 37-5 King’s College Criteria for Liver Transplantation
It is critical that these patients are managed by an experienced pediatric gastroenterologist so that the
correct window for effective transplantation can be identified and so they receive appropriate attention
to their specialized nutritional needs. Specifically, deficiencies of fat-soluble vitamins that depend on
bile for absorption are common and treatable. Transplantation is appropriate when children manifest
growth and nutritional failure, when ascites develops, and when portal hypertension progresses to the
point of variceal hemorrhage. Recurrent cholangitis is also thought to be an indication for liver
transplantation. Transplantation for this population overall has had excellent results with >85% 10-year
survival being achieved in the United States.41 Factors that have been associated with improved survival
include living donor transplants and older recipient age. Patients with significant growth failure
generally have poorer outcomes.
Primary Biliary Cirrhosis

Primary biliary cirrhosis (PBC), thought to be autoimmune in nature, is characterized by gradually
increasing serum bilirubin levels, progressive fatigue, and cirrhosis. Early stages of the disease are
usually asymptomatic, and disease progression may evolve over 20 years. Treatment with
ursodeoxycholic acid appears to slow the progression of the disease, but immunosuppression does not. It
was once thought that PBC does not recur, however, histologic analysis has shown that the incidence of
recurrence is approximately 15% within 5 years of transplantation.42 Eventual progression to graft
failure requiring retransplantation is possible, though rare.
Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) is an autoimmune disease that is characterized by gradually
progressive inflammation of the biliary tree, eventually resulting in cirrhosis. It is associated with
ulcerative colitis, but removal of the colon does not affect progression of the disease. In most cases,
colectomy for associated inflammatory bowel disease is done after successful transplantation because
the failing liver makes the patient a poor candidate for a large abdominal procedure. PSC is also
associated with the development of cholangiocarcinoma. Patients who experience a course that becomes
rapidly progressive should be examined by endoscopic retrograde cholangiopancreatography (ERCP)
with brushings to evaluate for cholangiocarcinoma. In addition to the usual considerations about the
timing of transplantation, it is important to note that these patients are susceptible to bacterial
cholangitis, which can cause systemic sepsis and rapid hepatic decompensation. Episodes of cholangitis
that do not respond to suppressive antibiotic therapy should prompt early consideration for
transplantation. Overall, patients with PBC or PSC experience the best outcomes with transplantation
when compared to adults with other liver diseases, however, disease recurrence remains higher in PSC
patients than in PBC patients.3,43
Inherited Metabolic Disorders

Numerous inherited metabolic disorders are treatable by liver transplantation (Table 37-3). Some
enzymatic deficiencies in this group result in destruction of the liver, so transplantation may resolve the
liver failure as well as supply the missing enzyme. Disorders in this category include Wilson disease,
alpha-1 antitrypsin deficiency, tyrosinemia, and type I glycogen storage disease. In other cases, the liver
900
booksmedicos.org
is not affected by the disease, either structurally or functionally. In these circumstances transplantation
is undertaken solely as enzyme replacement therapy. Diseases that have been cured by hepatic
transplantation in this category include hemophilia A or B, homozygous familial hypercholesterolemia,
Niemann–Pick disease, oxalosis, familial amyloid polyneuropathy, and numerous enzymatic deficiencies
of urea cycle metabolism.44 Determination of eligibility for transplantation depends on determining that
transplantation will cure the disease, or at least halt its progression, and that the consequences of the
disease without transplantation are devastating, making transplantation appropriate.
Budd–Chiari Syndrome
Budd–Chiari syndrome is characterized by obliteration of the hepatic veins. It may be due to congenital
webs of the hepatic veins or suprahepatic cava or may be caused by spontaneous thrombosis of the
hepatic veins. The latter condition is associated with polycythemia vera and other hypercoagulable
states. Diagnosis is made by inferior vena cavagram or magnetic resonance venography. The classic
presentation is a triad of right upper quadrant pain, hepatomegaly, and ascites. Patients may present
with FHF during acute Budd–Chiari and have symptoms of encephalopathy and coagulopathy, or they
may present in a more indolent fashion with ascites as the predominant feature. The natural history of
the indolent form of Budd–Chiari syndrome is the eventual development of cirrhosis.
Patients who present with intact hepatic function should undergo an assessment to determine whether
the liver has evidence of cirrhosis. A transjugular intrahepatic portosystemic shunt (TIPS) is the
preferred therapy for patients who do not have evidence of synthetic failure and have not yet developed
cirrhosis. Transplantation is reserved for cases where portal decompressive shunting is not possible or
for patients who have advanced cirrhosis. Long-term anticoagulation to prevent recurrent hepatic vein
thrombosis in the liver graft is routinely recommended.
Other Considerations
HPS and PPHTN are two other manifestations of cirrhosis whereby transplantation is justified. Similar
to HCC, these two diseases can occur in cirrhosis despite overall preserved hepatic function and appear
to involve dysregulation of vasoactive mediators such as nitric oxide. Therefore, MELD exception scores
are often sought when either HPS or PPHTN are present.12 HPS is diagnosed on the basis of unexplained
hypoxia in the presence of cirrhosis along with a positive “bubble” study for pulmonary shunt on
echocardiography. PPHTN is diagnosed on the basis of pulmonary hypertension in the setting of
cirrhosis without any other explainable etiology such as underlying pulmonary pathology. Recipient
selection and management is critical to achieve reasonable success with liver transplantation. Patients
with HPS experience the best outcomes if preoperative PaO2 is greater than 50 mm Hg.45 Patients with
PPHTN likewise must have mean pulmonary artery pressures less than 35 mm Hg with or without
medical therapy to experience a reasonable chance of recovery following liver transplantation.46,47
In addition to isolated liver disease, liver transplantation is occasionally considered along with other
solid organ transplantation. The two most notable examples are combined kidney and liver
transplantation as well as combined liver and intestine transplantation.4 Intestine transplantation is
usually performed in cases where intestinal failure is present along with progressive cholestatic liver
failure secondary to hyperalimentation.48 Since HRS frequently occurs with advanced cirrhosis and also
frequently resolves with successful liver transplantation, the indications for combined liver and kidney
transplantation are more controversial.49 It is widely accepted that pre-existing end-stage renal disease
along with significant cirrhosis or the existence of HRS requiring eight or greater weeks of renal
replacement therapy warrant consideration of combined liver and kidney transplantation. Ongoing
investigations are required to define patients with HRS who are less likely to recover renal function
following liver transplantation.
LIVER TRANSPLANTATION: SURGICAL PROCEDURE

Anesthetic Management
An anesthesiologist with experience in liver transplantation is invaluable to the transplant team and
liver transplant anesthesiology is rapidly becoming a subspecialty. Proper anesthetic management and
effective communication between the surgery and anesthesiology teams is necessary to optimize patient
care during the surgical procedure. While an extensive outpatient preoperative evaluation is usually
performed, including cardiac risk stratification, many liver candidates report from home when a liver
901
booksmedicos.org
becomes available. If adequate time for fasting has not occurred, consideration of rapid sequence
induction should be given to prevent aspiration. After induction and intubation, general anesthesia is
maintained with a combination of inhalational agents as well as the administration of paralytic agents
and analgesics. For adult patients, cardiac monitoring is often performed either by pulmonary artery
catheterization or intraoperative transesophageal echocardiography. An arterial catheter is placed for
blood pressure monitoring. Adequate vascular access, often including central venous catheters, is
required for the administration of blood products and the potential for rapid resuscitation in the case of
massive blood loss. A device for rapid infusion and the ability to warm blood products or intravenous
fluids is required. Low central venous pressures maintained during the hepatectomy phase of the
procedure may help avoid excess bleeding.
Intraoperative Management of Coagulopathy

Liver transplantation has the potential for massive blood loss for several reasons. Liver transplant
candidates with cirrhosis often have synthetic deficiencies in circulating coagulation factors as well as
severe portal hypertension associated with thrombocytopenia and extensive venous collaterals.
Intraoperative coagulopathy may be worsened during the anhepatic phase of the procedure. Finally,
liver transplantation involves extensive dissection of major vascular structures including the inferior
vena cava, portal vein, and hepatic artery, all with an inherent risk for torrential bleeding.
Intraoperatively, coagulation is monitored by frequent determination of standard parameters
including prothrombin time, partial thromboplastin time, platelet count, and fibrinogen. Abnormalities
of these laboratory values associated with intraoperative bleeding are often corrected with fresh frozen
plasma, platelets, or cryoprecipitate. Normal coagulation is also helped by maintaining normal pH,
calcium levels, and normothermia. While the administration of recombinant factor VII intraoperatively
can rapidly and effectively stop nonsurgical bleeding, its use has a theoretical risk of postoperative
thrombotic complication including hepatic arterial thrombosis. In addition, no definitive data has been
demonstrated to decrease the need for intraoperative blood transfusions.50,51 Therefore, its use is only
recommended in emergent situations.
Following reperfusion of the donor liver, a fibrinolytic state may be encountered. This is related to
the lack of production of fibrinolysis inhibitors during the anhepatic phase and the inability of the liver
to metabolize profibrinolytic compounds. This state may be identified either by thromboelastography,
recurrence of bleeding where hemostasis had been previously obtained (such as the wound edge), or by
extensive and refractory bleeding after revascularization. This state may be treated with the use of
antithrombolytic agents including ε-aminocaproic acid, tranexamic acid, or aprotinin.
Surgical Technique
Transplantation of the liver is among the most technically demanding surgical procedures. During
induction and placement of the appropriate monitoring lines by the anesthesiology team, the donor liver
is prepared on the back table for implantation (Fig. 37-4). Bench preparation includes resection of the
donor diaphragm and adrenal gland off of the bare area of the liver and vena cava. Meticulous ligation
of tributaries from the vena cava (adrenal vein, phrenic vein, and lumbar branches) is performed. The
artery is dissected free from the Carrel patch of the aorta up to the gastroduodenal artery. Dissection
near the right or left hepatic arteries is avoided to prevent unnecessary injury. The portal vein is
circumferentially dissected free. The gallbladder may be removed at this stage or following reperfusion.
Tissues surrounding the common bile duct are left intact to avoid injury of the blood supply.
Following this, the recipient’s abdomen and bilateral groins are prepped and draped in a standard
fashion. The most commonly used incision is a unilateral or bilateral subcostal incision with a midline
extension to the xiphoid process (Fig. 37-4). After dividing the fascia, ascites, which can occasionally be
present in a large volume, is evacuated. The ligamentum teres hepatis is carefully divided between
clamps and ligated because a large recannulized umbilical vein is often present in patients with severe
portal hypertension. After dividing the falciform ligament with cautery, a mechanical retractor is used
to retract the bilateral costal margins anteriorly and superiorly for excellent exposure of the upper
abdomen. The abdominal cavity and liver are then inspected for any abnormalities including
unsuspected malignancy, particularly within the cirrhotic liver which is a risk factor for HCC. Following
this, liver transplantation occurs in three stages: (1) recipient hepatectomy, (2) anhepatic phase, and (3)
postrevascularization.
Recipient Hepatectomy
902
booksmedicos.org
During the recipient hepatectomy phase, the liver is mobilized from its ligamentous attachments and the
porta hepatis is skeletonized. Attention is first directed to dissecting and skeletonizing the structures of
the portal triad. The peritoneum overlying the portal triad is divided with electrocautery near the liver
edge. The right and left hepatic arteries are dissected free, ligated, and divided leaving adequate length
to form a branch patch for the arterial anastomosis. The proper hepatic artery is also dissected free to
the level of the gastroduodenal artery allowing enough length for clamping during the anastomosis.
Because portal venous flow of blood to the liver may be hepatofugal (away from the liver), division of
the artery may leave the patient functionally anhepatic. If a prolonged period of time is expected for
mobilization of the liver, such as when extensive adhesions are present, the artery may be dissected free
but left in continuity to allow whatever synthetic capacity the native liver has to continue. A replaced or
accessory right hepatic artery, which arises as a branch of the superior mesenteric artery and travels in
a posterior position to the common bile duct and lateral to the portal vein, can usually be palpated if
present and can be ligated and divided. When the replaced right hepatic artery is relatively large and
the proper hepatic artery is diminutive in size, the replaced right hepatic artery can be left long and
used for arterial inflow for the donor liver. A replaced or accessory left hepatic artery arises from the
left gastric artery if present and can be identified by inspection of the pars flaccida of the lesser
omentum along the lesser curvature of the stomach (Fig. 37-5).
Figure 37-4. A: The donor liver after excision and before transplantation. B: Bilateral subcostal incision with a subxiphoid
extension.
Figure 37-5. A replaced left hepatic artery usually arises as a branch of the left gastric artery, traversing the pars flaccida of the
lesser omentum from left to right toward the left lobe of the liver.
903
booksmedicos.org
Conceptually, the common bile duct and common hepatic duct should be dissected free with as much
length as possible and without injuring the blood supply to the bile duct. Leaving the recipient bile duct
as long as possible allows the length of the donor bile duct, which may have a tenuous blood supply, to
be shorter and still avoid tension at the time of anastomosis. This is accomplished by first ligating and
dividing the cystic duct. The common bile duct and common hepatic duct are then circumferentially
dissected free leaving the surrounding tissue to preserve the bile duct blood supply. The common
hepatic duct is then ligated as close to the native liver as possible.
Once the bile duct and the hepatic artery are freed from surrounding tissues, the portal vein can be
easily approached from its anterior, medial, and lateral aspects. In general, the portal vein is freed
circumferentially from the edge of the duodenum up to its bifurcation of the right and left portal veins.
Small branches may arise near the pancreas and excessive bleeding may arise if these are inadvertently
injured. Most patients with severe portal hypertension will not develop hypotension, small bowel
edema, or ischemia if the portal vein is clamped and divided because of the presence of portal venous
collaterals. However, patients without portal hypertension such as those undergoing liver
transplantation for fulminant hepatic failure, metabolic deficiency, or those who have had a transjugular
intrahepatic portosystemic shunt (TIPS) for a prolonged period of time, may develop extensive small
bowel edema or hypotension when the portal vein is clamped. Small bowel edema can lead to limited
exposure in the right upper quadrant making implantation of the liver extremely difficult. In these
situations, the portal vein should be left in continuity for as long as possible, particularly when the use
of venovenous bypass is not intended. For those patients with portal vein thrombosis, portal venous
flow can be restored in most cases. Often, the thrombus can be evacuated with the use of forceps or by
placing a Yankauer suction tip within the lumen of the portal vein. If the thrombus is more mature, an
eversion endovenectomy may be necessary.52 If these maneuvers are unsuccessful, the junction of the
splenic vein and superior mesenteric vein may be patent. Dissection of the portal vein behind the
pancreas to this junction can then be performed to allow for future anastomosis. Dissection to the
confluence of the splenic and superior mesenteric veins is sometimes necessary in pediatric recipients
because of the small caliber of the portal vein within the porta hepatis. In rare cases, all of these
maneuvers may be unsuccessful and a venous bypass graft from the superior mesenteric vein may be
necessary. If the superior mesenteric vein is also occluded, the inferior vena cava or left renal vein can
be used for portal inflow, a procedure termed cavoportal or renoportal transposition.53 This procedure
is associated with acceptable outcome despite the fact that portal hypertension may not be alleviated. A
fourth option is arterialization of the portal vein, using a conduit created by anastomosing donor iliac
vessels to the recipient aorta and connecting this to the donor portal vein.54
The ligamentous attachments of the liver, including the left and right triangular and coronary
ligaments are then divided using electrocautery. The bare area of the liver is dissected along a plane just
superficial to the capsule of the liver. Care must be taken to avoid injury to the phrenic or hepatic veins
when freeing the suprahepatic inferior vena cava where it traverses the diaphragm. The hepatocaval
ligament along the right lateral aspect of the vena cava can be divided using a combination of cautery
and ligation as a phrenic venous branch is often present within this ligament. The liver is then dissected
off of the anterior aspect of the inferior vena cava. Small venous branches from the inferior vena cava
to the caudate lobe are ligated and divided. Larger branches, such as an accessory right hepatic vein, are
clamped, divided, and oversewn. Division of the portal vein facilitates exposure for this dissection but is
not required. The liver may be gradually retracted and dissected from either the right or left aspects
until the right, middle, and left hepatic veins are reached. If a bicaval venous anastomosis technique
will be used, the vena cava can be circumferentially mobilized near the diaphragm above the hepatic
veins as well as in an infrahepatic position. However, if a piggyback or cavocavostomy (side-to-side
caval anastomosis) technique is intended; the dissection of the posterior aspect of the vena cava should
be avoided to prevent encountering unnecessary bleeding from collateral or lumbar venous branches in
this area.
Anhepatic Phase and Implantation of the Donor Liver

At this point, the liver has been completely mobilized except for its attachments of the hepatic veins to
the inferior vena cava and in some cases, the portal vein. The decision should now be made whether to
use venovenous bypass. Most patients will tolerate clamping of both the portal vein and the inferior
vena cava without difficulty.55 At this point, communication with the anesthesiologist is essential and
the vena cava should be test clamped before division to make sure that adequate cardiac filling and
blood pressure can be maintained. If the patient becomes hypotensive during test clamping, the clamp
904
booksmedicos.org
should be removed and additional volume or pressor support can be administered. Occasionally patients
will require venovenous bypass, but its use is no longer routine at most centers.
If necessary, venovenous bypass can be accomplished from both the portal vein and inferior vena
cava simultaneously, or a single cannula in either the portal vein or the inferior vena cava may be used
(Fig. 37-6). There are several accepted methods of placing cannulas for venovenal bypass. Cannulas may
be placed percutaneously in the internal jugular vein and femoral vein prior to beginning the procedure.
These cannulas are advanced into the superior and inferior vena cava, respectively. Alternatively, one or
both of the bypass cannulas may be placed by cutdown on the axillary and/or the greater saphenous
vein. Inferior vena caval and mesenteric blood is delivered to the superior vena cava by a centrifugal
pump. The cannulas, tubing, and centrifugal pump head are heparin bonded to reduce the chance of
thrombus formation and subsequent embolism without the use of anticoagulation. Flow rates of 1 to 2
L/min are usual.
Once venovenous bypass has been established or the decision to forego bypass has been made, the
recipient hepatectomy is completed. If still intact, the portal vein is divided as high in the hilum as
possible. Three methods are commonly used for orthotopic liver transplantation: (1) the bicaval
technique, (2) the piggyback technique, (3) cavocavostomy (side-to-side caval technique).
1. For the bicaval technique, the recipient liver is excised en bloc with the retrohepatic inferior vena
cava after caval clamps have been placed in a suprahepatic and infrahepatic position. The hepatic
veins are divided within the substance of the liver to allow the creation of a large suprahepatic cuff
compromising the left, middle, and right hepatic veins (Fig. 37-7). This technique has the
disadvantages of: (a) totally obstructing inferior vena cava flow resulting in renal ischemia and
decreased cardiac filling with associated hypotension possibly leading to the requirement of
venovenous bypass, (b) requires two vena caval anastomoses prolonging the warm ischemic time, (c)
requires dissection posterior to the vena cava possibly leading to bleeding. However, complete
dissection of the caudate lobe off of the vena cava is not necessary making the recipient hepatectomy
phase somewhat easier and faster.
Figure 37-6. Setup for venovenous bypass during hepatic transplantation. Cannulas are placed into the portal vein to decompress
the splanchnic bed and inferior vena cava (through the greater saphenous vein) to decompress the lower extremities and kidneys
905
booksmedicos.org
during the anhepatic phase of the transplantation. A centrifugal pump is used to deliver bypassed blood to the central circulation
by means of a cannula passed into the axillary vein.
Figure 37-7. A: The diseased recipient liver is removed by incising the liver below the level of the hepatic veins. B: The hepatic
veins are then opened to form a large suprahepatic cuff for anastomosis. The suprahepatic vena caval anastomosis: posterior suture
line (C); anterior suture line (D).
2. For the piggyback technique, a clamp is placed transversely, partially occluding the vena cava at the
level of the hepatic veins. The vena cava is left in continuity and the hepatic veins are divided within
the substance of the liver allowing the creation of a common patch of the right, middle, and left
hepatic veins for a wide anastomosis. While the intention is to only partially occlude the vena cava
allowing venous return to the heart, often a clamp placed for the piggyback technique either occludes
or nearly occludes the inferior vena cava. This technique does have the advantage of only requiring a
single vena caval anastomosis helping to limit warm ischemic time. However, torsion may occur if
the right upper quadrant is relatively large, such as when a large volume of ascites is present, and the
donor right hepatic lobe is relatively small. This may lead to right hepatic vein or inferior vena caval
stenosis.
3. For the cavocavostomy technique, clamps can be placed on the right hepatic vein as well as the
junction of the left and middle hepatic veins. The liver is excised and these venous branches are
oversewn and the clamps are removed. Alternatively, the hepatic veins can be divided using an Endo
GIA stapler (Fig. 37-8). Advantages of the cavocavostomy anastomosis include: (a) minimalization of
the time that the vena cava is clamped, (b) the vena caval clamp is placed longitudinally only
906
booksmedicos.org
occluding the anterior third of the vena cava leading to minimal or no changes in the recipient’s
hemodynamics, (c) a cavoplasty is performed limiting the likelihood of caval stenosis, (d) a long
anastomosis is performed, often over 6 cm in length, minimizing the risk for hepatic vein outflow
complications, (e) exposure during suturing of the anastomosis is considerably improved compared to
the piggyback or bicaval technique.
Figure 37-8. Cavocavostomy. A: The recipient right and junction of the middle and left hepatic veins are stapled and the inferior
vena cava is left in continuity. B: The supra- and infrahepatic vena cavae are stapled and a venotomy is made longitudinally on the
posterior aspect of the donor liver. C: A side-to-side caval anastomosis is performed with a running suture.
After removal of the recipient liver, the right upper quadrant is carefully inspected and hemostasis is
obtained. Complete hemostasis in the bare area is essential at this time because this region is easily
visualized when the liver is absent but may be relatively inaccessible once the donor liver is implanted,
especially if the donor liver is relatively large or the recipient is obese. Argon beam coagulation can
also be used to aid in hemostasis at this point.
The donor liver is then brought onto the operative field. The vascular anastomoses are performed
using a running monofilament polypropylene suture. If a bicaval technique is planned, two caval
anastomoses are required. The suprahepatic vena caval anastomosis is first performed by suturing the
posterior walls from within the lumen using an imbricating technique (Fig. 37-7). The anterior wall is
then completed. The infrahepatic anastomosis is then completed in a similar fashion. Redundancy in the
donor vena cava is avoided to prevent the potential for kinking. The completion of the anastomosis may
be left until the time of hepatic revascularization to provide a vent for air, acidotic or hyperkalemic
blood, and for residual preservation solution. Venting of blood prior to reperfusion is most important if
preservative solutions containing a high concentration of potassium, such as University of Wisconsin
solution, were used. Venting of blood is less critical if preservative solutions that do not contain high
concentrations of potassium are used, but care must still be taken to avoid the rapid bolus of air or cold
blood to the heart. For the piggyback technique, the donor infrahepatic vena cava is either oversewn or
stapled. The donor infrahepatic vena cava is then sewn in an end-to-side fashion to the recipient hepatic
vein cuff (Fig. 37-9). As described above, an imbricating suture technique is often helpful to prevent
gaps in the anastomosis and to compensate for size discrepancies. Venting at the time of reperfusion can
either be performed through the suprahepatic anastomosis or at the donor infrahepatic vena cava. For
the side-to-side caval technique, a clamp is placed longitudinally on the anterior third of the recipient
vena cava. A longitudinal venotomy is made on the anterior surface of the recipient vena cava. The
donor supra- and infrahepatic vena cavae are either oversewn or stapled closed. A longitudinal posterior
venotomy was then made matching the length of the recipient venotomy. The liver then placed in the
right upper quadrant in the left lateral segment is elevated. The two vena cavae are then sutured in a
side-to-side fashion with the lateral wall sutured from within the lumen and the medial wall sutured
from outside the lumen (Fig. 37-8). Venting can be performed from either the suprahepatic donor vena
907
booksmedicos.org
cava or the medial wall of the anastomosis. During the caval anastomosis, the donor liver may be
perfused with cold fluid via a cannula placed within the donor portal vein to wash out the preservation
solution and to help maintain the cold temperature of the liver. This step is not required but may be
considered if the liver was preserved with a solution containing a high concentration of potassium or if
a prolonged warm ischemic time is anticipated.
Once the caval anastomosis or anastomoses are completed, either the portal anastomosis, arterial
anastomosis, or both can be performed prior to reperfusion. In theory, reperfusion with arterial blood
would limit the extent of warm ischemia to the biliary tree which, unlike the remainder of the liver,
receives its blood supply exclusively from the arterial blood and not along with portal venous blood.
However, neither sequence has been clearly shown to be an advantage over the other, so the choice is
made based on the surgeon’s preference and the patient’s anatomy. Most commonly, the portal venous
anastomosis is completed and the liver is reperfused. If portal bypass has been used, the portal limb of
the venovenous bypass circuit is removed. The portal anastomosis is usually performed in an end-to-end
fashion using a running technique. To avoid narrowing and allow for expansion under venous flow, an
air knot is used when the suture is tied.
Figure 37-9. A: Recipient liver is dissected off native inferior vena cava by dividing veins draining directly into the inferior vena
cava up to the level of the hepatic veins. B: Clamp placed on recipient hepatic veins in preparation of excision of the recipient’s
native liver and performance of a piggyback anastomosis.
At the time of revascularization, flow is restored to the liver through the portal vein and/or the
hepatic artery. The first several hundred cc of blood may be vented through the infrahepatic vena cava
and the knot can be tied completing the caval anastomosis. Alternatively, the caval clamp can be briefly
opened and the anastomosis inspected for bleeding and, repaired if present. If blood is not vented
through the infrahepatic cava, portal blood should be restored gradually to minimize cardiac irritability,
bradycardia, and hypotension, all of which routinely result from cold blood circulating through the
donor liver and going directly into the right atrium. Close coordination between the surgeon and
anesthesiologist is necessary during this phase as hypotension and bradycardia are routinely
encountered and cardiac arrest may rarely occur. If venovenous bypass has been used during the
anhepatic phase, it can now be discontinued.
Once hemostasis is obtained and the patient has stabilized, attention can now be turned toward the
arterial anastomosis if it has not already been performed. Conceptually, the arterial anastomosis can be
performed in one of two ways. The anastomosis can be performed with the artery being very long,
which allows the artery to lie with a smooth and gentle curve or loop (Fig. 37-10). For this technique,
all branches on the donor artery are ligated and the donor aortic Carrel patch, celiac artery, or branch
patch of the celiac and splenic artery are anastomosed in an end-to-end fashion to a branch patch of the
recipient right and left hepatic arteries (Fig. 37-11). Alternatively, the artery can be cut to just the right
length and sewn in an end-to-end fashion. This is often performed by forming branch patches between
the donor gastroduodenal and recipient proper hepatic arteries and performing the anastomosis in an
end-to-end fashion. However, when the retractor is released, the liver may shift position and kinking of
the artery may occur. Therefore, judging the proper length of the arteries may be difficult and this
technique may be more technically demanding than the method which leaves the artery very long. If
908
booksmedicos.org
the artery is somewhat long but not long enough to allow a gentle or smooth curve or loop, kinking and
obstruction to blood flow may occur. For both techniques, the anastomosis can be performed using a
fine, nonabsorbable, monofilament, running suture. If the recipient arterial inflow is inadequate, an
aortic conduit may be constructed. This is often performed using a graft consisting of the donor
common and external (or internal) iliac artery. A partially occluding aortic clamp can either be placed in
a supraceliac or infrarenal position and the common iliac artery is sutured in an end-to-side fashion to
the recipient aorta. The donor Carrel patch can then be sutured in an end-to-end fashion to the external
iliac artery of the conduit.
Figure 37-10. Hepatic artery anastomosis where the artery is left long to allow for a gentle loop or curve to form.
Figure 37-11. A: The donor hepatic artery is procured with a Carrel patch of aorta. B: The recipient hepatic artery bifurcation is
used to fashion a branch patch for a larger anastomosis. C: The anastomosis is carried out using continuous monofilament suture
material. D: The completed anastomosis.
Postrevascularization Phase
909
booksmedicos.org
Following revascularization, the liver should assume a normal color and consistency within several
minutes. If the liver remains pale or is overly soft, problems with portal inflow should be considered.
Alternatively, if the liver becomes edematous and overly firm, outflow obstruction should be excluded.
Bile production should be seen while in the operating room and is among the first evidence for liver
function. In contrast, watery or milky fluid from the bile duct raises concern for primary nonfunction.
Inspection for surgical bleeding should be performed and entails examination of the vascular
anastomoses as well as a search for branches of the major vessels that may not have been ligated. If
bleeding continues after all surgical bleeding has been resolved, attention should be directed toward
correction of coagulopathy as described above.
While biliary reconstruction does not carry the same risk for intraoperative complications when
compared to the recipient hepatectomy and reperfusion, it is associated with considerable postoperative
morbidity and mortality and requires the same diligence and attention as other step of the operation.
Because of the relatively high complication rate associated with biliary reconstruction, it has been
referred to as the Achilles heel of liver transplantation. There are several options for biliary
reconstruction. In the past, the Calne conduit, or the use of the donor gallbladder, was used but has
been abandoned due to the high rate of biliary complications associated with it. The simplest and most
common technique is currently an end-to-end choledochocholedochostomy from the donor to the
recipient bile duct (Fig. 37-12). If a size discrepancy exists, the narrower duct can be spatulated.
Running or interrupted sutures can be used. Absorbable monofilament suture is most commonly used to
avoid a nidus for future stone formation within the bile duct. While T. tubes were commonly used in the
past to stent the anastomosis, evidence now shows that more leaks or strictures develop as a result of
the T tube than are prevented. Internal biliary stents may be used and may help prevent leaks or
strictures.56 Alternative biliary reconstruction methods may be necessary for those with a bile duct of
inadequate quality or size or in those whose primary disease is biliary pathology such as PSC or biliary
atresia. The most common option employed in these situations includes a standard Roux-en-Y
choledochojejunostomy. If a prior choledochojejunostomy had been performed in the past, the limb of
small bowel used may often be salvaged and used for biliary drainage of the new liver. Placement of
drains is optional but may help identify and treat biliary leaks. Abdominal wall and skin closure is then
performed in the standard fashion.
Technique for Reduced Size and Split Liver Transplantation

In the 1980s, the waiting list mortality for small, pediatric liver candidates was relatively high because
the number of suitably sized small liver donors was inadequate. As a result, techniques to reduce the
size of an adult liver, based on Couinaud segmental anatomy (Fig. 37-13), were developed so that the
left lobe, left lateral segment, or even a single segment could be used for a recipient more than 10 times
smaller by weight than the donor.57,58 During the early experience, the donor hepatectomy was
performed in a standard fashion and the liver was brought back to the recipient hospital. The needed
segments of the liver were cut down on the back table with the organ on ice, the vessels were left intact
to the future transplant graft, and the remainder of the liver was discarded. Techniques have now
developed so that both sides of the liver can be transplanted into two recipients, either a child and an
adult or two adults.59,60 In addition, the liver may be split in situ at the donor hospital, allowing
coagulation of the cut edge of the liver so that bleeding is minimized following reperfusion. Perfusion
to both sides of the liver can be inspected prior to flushing ensuring that blood flow to all segments of
each future graft has been preserved. Because of technical and practical issues, both the cut down
technique and in situ splitting of the liver are still employed. Split liver transplantation has been
associated with a decreased survival rate and the potential for increased risk of complications, including
primary nonfunction, hepatic artery thrombosis, and biliary complications. Because of this, while
widespread adoption of allocation policies to encourage greater utilization of split liver grafts in the
adult population has been suggested, split liver transplantation only accounts for a small proportion of
transplants performed. In addition, only grafts from “ideal donors” are thought to be suitable to this
form of transplantation. Criteria supported by the UNOS for splitting currently include donor age less
than 40 years of age, on a single or no pressors, transaminases no greater than three times normal, and
a body mass index of 28 or less.
910
booksmedicos.org
Figure 37-12. A: In most cases, a choledochocholedochostomy is performed, possibly over an internal stent. B: Patients with a
diseased or unsuitable common bile duct may require biliary reconstruction with a Roux-en-Y choledochoenterostomy.
Living Donor Liver Transplantation

Experiences with deceased donor split liver transplantation as well as the success with living donor
kidney transplantation led to the adoption of the techniques for split liver transplantation to living
donor liver transplantation. The first living donor liver transplantation allowed an adult volunteer to
donate the left lateral segment of the liver to a child. Based on the success of living donation in the
pediatric population as well as the increased waiting list mortality rate for adults, these techniques have
also been applied to adult recipients receiving either the right or left lobe from an adult volunteer.61
Living donor liver transplantation was progressively developing in the United States until a well-
publicized donor mortality occurred.62 Living donor liver transplantation now accounts for
approximately 5% of all liver transplants performed in the United States. In Japan and other areas of
the Far East, where deceased donor transplantation has developed slower because of cultural difficulties
with the concept of brain death, living donor transplant are the rule rather than the exception.
Figure 37-13. Segmental anatomy of the liver as based on Couinaud nomenclature.
911
booksmedicos.org
Figure 37-14. Living donor right hepatic lobe allograft demonstrating the right hepatic vein (RHV), right portal vein (RPV), right
hepatic artery (RHA), and two right hepatic ducts.
In many respects, transplantation of a graft from a living donor is similar to transplantation of a

whole liver from a deceased donor. However, a bicaval technique is not possible given that the donor
vena cava is not available for replacement of the recipient’s retrohepatic inferior vena cava (Fig. 37-14).
Therefore, the recipient vena cava must be left intact. A direct hepatic vein to vena caval anastomosis is
used (Figs. 37-15 and 37-16). Establishing adequate outflow of hepatic venous blood is necessary to help
prevent edema of inadequately drained segments of the liver possibly leading to small-for-size
syndrome. Therefore, any accessory veins greater than 5 mm in diameter should be reconstructed either
by direct anastomosis to the vena cava or using an interposition graft. In addition, the length of the
portal vein, hepatic artery, and bile duct on the donor graft is considerably shorter than that available
from a deceased donor. Therefore, during the recipient hepatectomy, considerable care should be given
to preserving the length of the recipient bile duct as well as the right and/or left hepatic artery and
portal vein which are intended for future anastomosis.
Figure 37-15. Left lateral segment (segments II and III) living donor transplantation. A: Donor operation. B: Recipient operation
completed.
912
booksmedicos.org
Figure 37-16. Right lobe (segments V to VIII) living donor transplantation. A: Donor operation. B: Recipient operation completed.
Auxiliary Liver Transplantation

Under select circumstances, there is a good rationale for placing the donor allograft in a heterotopic
rather than orthotopic position, leaving the native liver in place. This procedure is known as auxiliary
liver transplantation. Auxiliary liver transplantation has occasionally been used for cases in which liver
transplantation is indicated for somatic genetic deficiency but the native liver is otherwise normal in all
other respects. It is also been used in cases of FHF where the liver candidate is expected to die in the
near future without transplant but if adequate time was allowed, the native liver may recover and
return to normal. In this situation, immunosuppression can slowly be weaned, the transplanted liver will
atrophy, and the recipient can be taken off of all immunosuppression. Figure 37-17 demonstrates one
technique used. Another option, auxillary partial orthotopic liver transplantation (APOLT) has been
developed. For this technique, part of the native liver is resected, often the right trisegment, leaving
only the left lateral segment intact. The donor liver is then transplanted in an orthotopic position. If the
native left lateral segment recovers, immunosuppression can be weaned leading to hypertrophy of the
left lateral segment and involution of the allograft.
Complications
3 The degree of preoperative debilitation and the complexity of the operative procedure make
complications following liver transplantation very common. Prompt recognition and treatment are
essential. However, the usual signs or symptoms that would be expected in the general population are
often absent or present to a lesser degree, and therefore, a high level of suspicion must be maintained.
Early warnings, such as fever, leukocytosis, or pain may be suppressed as a result of
immunosuppression. In addition, the burden of immunosuppression predisposes to additional problems
not usually encountered in other areas of surgery. Complications associated with immunosuppression,
which are predominantly infectious, are detailed in another chapter. In the following sections, some of
the major surgical complications that occur after liver transplantation are described.
Primary Nonfunction
4 About 2% to 4% of transplanted livers function so poorly in the immediate postoperative period, from
an unknown etiology that death is likely in the absence of retransplantation and is referred to as
primary nonfunction. Most cases of primary nonfunction likely occur as a result of ischemic injury,
occurring either in the donor or the recipient,63 or from poor preservation. Donor factors known to
predispose to primary nonfunction include allograft steatosis, advanced donor age, and prolonged cold
ischemic time. In addition, donor race and the need for portal vein reconstruction have also been
demonstrated to be risk factors for primary nonfunction.64
Early evidence for primary nonfunction include poor bile production of the liver intraoperatively,
refractory acidosis, progressive coagulopathy, and hepatic encephalopathy. In a short period of time,
these early signs are often followed by acute renal insufficiency and eventually cardiopulmonary
collapse. Serial factor V levels may be helpful to determine if a liver allograft is functioning in a patient
who has received a massive transfusion of fresh frozen plasma. In this setting, the INR may reflect
transfused coagulation factors rather than factors synthesized by the liver graft. Fresh frozen plasma
contains relatively little factor V because this factor is relatively unstable in cold storage. Therefore, a
steady increase in the factor V level suggests production by the liver rather than transfusion with fresh
frozen plasma.
913
booksmedicos.org
Liver transplant recipients in the United States with primary nonfunction, currently defined as those
who were transplanted within 7 days and are anhepatic developed an AST above 3,000 along with
either an INR above 2.5 and/or an acidosis, can be relisted as a status 1A. Patients listed as a status 1A
receive regional priority over less ill patients and frequently wait only a period of few days for an
appropriate donor to become available. Despite this preferential listing for retransplantation, primary
nonfunction is associated with a mortality rate of more than 50%.64
Postoperative Hemorrhage
Postoperative hemorrhage requiring laparotomy occurs in approximately 5% to 15% of liver transplant
recipients. Postoperative bleeding should be suspected in any liver recipient during the immediate
posttransplant period that develops tachycardia, volume-dependent hypotension, oliguria, and
abdominal distention. Because many liver transplant recipients may have had a large volume of ascites
preoperatively (sometimes more than 10 to 20 L), a considerable amount of bleeding may occur before
developing an abdominal compartment syndrome. In general, attempts to correct coagulopathy should
be made and reexploration should occur in patients with refractory hypotension, abdominal
compartment syndrome, or ongoing need for blood transfusion. At exploration, a specific bleeding point
often cannot be identified, suggesting that bleeding may be related more to coagulopathy than failure of
surgical hemostasis. Therefore, waiting until coagulopathy is corrected before reexploration may be
wise assuming that the recipient is otherwise reasonably stable.
Figure 37-17. Heterotopic auxiliary liver transplantation using a reduced-size allograft.
Hepatic Artery Thrombosis

The incidence of hepatic artery thrombosis ranges from 1% to 2% up to 10% in some populations. The
incidence of hepatic artery thrombosis is higher in pediatric recipients as well as recipients of living
donors or split livers. Other risk factors include receiving a liver from a donor who is significantly
smaller than the recipient, the need for reconstructive arterioplasty in the presence of nonstandard
donor anatomy, acute rejection within the first week posttransplant, placement of cytomegalovirus
(CMV)-positive organs into CMV-negative recipients, and a recipient history of smoking.65 The
association between rejection and hepatic artery thrombosis may be the result of a decrease in hepatic
914
booksmedicos.org
arterial flow that occurs when the liver is swollen and edematous or to release procoagulations into the
microcirculation in association with the inflammatory injury of graft rejection.
Hepatic artery thrombosis can occur in the early, arbitrarily defined as within 30 days, or late
posttransplant periods. Early hepatic artery thrombosis is usually identified within the first 10 days
posttransplant. The diagnosis is suspected in the setting of unexpectedly high liver enzymes, an
elevation in liver enzymes rather than a gradual decline, or poor synthetic function during the first
week to 10 days posttransplant. Other signs of biliary ischemia from hepatic arterial thrombosis include
the development of biliary leaks, strictures, or intrahepatic abscesses. Doppler ultrasonography is
usually used to confirm flow within the extrahepatic and intrahepatic arteries. If inappropriate
waveforms or no flow is identified, the diagnosis can be confirmed by angiography or reexploration. At
exploration, flow can be restored within the hepatic artery approximately 80% of the time if the
diagnosis is made early. However, despite restoring arterial flow, many of these recipients will still
develop biliary complications.
Hepatic artery thrombosis that occurs months to years following liver transplantation does not always
lead to graft failure. Although some patients develop biliary strictures and/or hepatic abscesses,
approximately a third of patients do well without intervention.66
The arterial blood flow in the reconstructed hepatic artery is an important determinant of long-term
patency. It is believed that children are predisposed to hepatic artery thrombosis because they have
smaller vessels and lower mean arterial blood pressure than adults. Pediatric patients with an arterial
diameter of less than 3 mm have the highest incidence of hepatic artery thrombosis. However, the
experience with pediatric living donor transplantation, where very small arteries are routinely
encountered, has indicated that with microsurgical technique it is possible to achieve a low hepatic
artery thrombosis rate.67
A postoperative hypercoagulable state associated with hepatic transplantation may predispose to
hepatic artery thrombosis. Relatively poor hepatic production of natural regulatory anticoagulants, such
as proteins C and S and antithrombin III, immediately after transplantation promotes coagulation
because production of procoagulant factors, such as factor V and VII, occurs more rapidly after
revascularization.68 This observation has prompted some centers to administer fresh frozen plasma as a
source of antithrombin III and proteins C and S in the postoperative period. Most centers recommend
prophylactic aspirin to prevent hepatic artery thrombosis in children.
Portal Vein Thrombosis

Postoperative portal vein thrombosis is much less common than hepatic artery thrombosis, occurring in
1% to 3% of cases. A higher incidence of portal vein problems is seen in patients that have had previous
portal vein operations or prior thrombosis of the portal system. Factors that decrease antegrade portal
flow also predispose to portal vein thrombosis. Patients with chronic portal hypertension often
spontaneously develop large retroperitoneal collaterals from the portal venous system to the renal vein
and inferior vena cava. A previous surgically created splenorenal shunt should be disconnected at the
time of transplantation because it usually is associated with reduced flow through the portal vein. This
can be accomplished easily during a liver transplant by dissecting down the vena cava and ligating the
left renal vein at its origin. This maneuver does not compromise the function of the left kidney. This
maneuver can also be useful to improve portal flow if preoperative imaging discloses large spontaneous
portosystemic shunts to the left renal vein.
Portal vein thrombosis should be suspected when the recipient develops symptoms of portal
hypertension or ascites that is unusually difficult to control. Doppler ultrasound examination is usually
the first diagnostic tool, but magnetic resonance imaging is also an option, as are standard mesenteric
arteriography with portal phase views and direct percutaneous transhepatic portography. Transhepatic
portography is particularly useful if a stenosis, rather than thrombosis, is identified because it is possible
to both measure the pressure gradient across a stenotic area and treat a stenotic area with angioplasty
and/or stent placement.
When portal vein thrombosis is identified in the immediate postoperative period, reexploration and
attempted thrombectomy are usually indicated. Thrombectomy is more likely to be successful if a
technical flaw in the anastomosis is present and can be corrected. When performing thrombectomy, it is
advisable to avoid using balloon embolectomy catheters to remove clot from the mesenteric venous
system, because these veins are very fragile and rupture of mesenteric veins deep in the mesentery can
be catastrophic.
Hepatic Vein or Inferior Vena Cava Stenosis
915
booksmedicos.org
Thrombosis of the inferior vena cava is a rare complication after liver transplantation, but hepatic vein
outflow obstruction occurs in 2% to 4% of patients. Restrictions of hepatic blood flow may result from
kinking of the suprahepatic cava. This is particularly problematic when the donor is small relative to the
recipient and when the suprahepatic anastomosis is left long. Hepatic outflow problems can present
with ascites and renal dysfunction. Presentation may be early in the first week after transplantation or
months later. The diagnosis may be suspected on the basis of Doppler ultrasonography, but definitive
diagnosis usually requires inferior cavography with measurement of pressure gradients. The incidence
of caval complications utilizing the piggyback technique appears to be higher than the incidence with
the bicaval technique, at approximately 4%.69 Outflow stenosis appears to be more common if the
combined orifice of two, rather than three, hepatic veins is used for the anastomotic site on the
recipient when the piggyback technique is used. In many cases, hepatic vein or suprahepatic caval
stenosis can be successfully treated noninvasively with the use of balloon angioplasty and stenting.70,71
Biliary Leak or Stricture

Biliary leak or obstruction is a common surgical complication encountered after hepatic transplantation
with an incidence of approximately 10% to 30%.56,72 Most biliary complications probably relate to
ischemia of the donor biliary tree (Fig. 37-18). The transected donor bile duct is totally dependent on
arterial flow from the liver graft. Therefore, when a biliary leak is identified, it is appropriate to
interrogate the hepatic vasculature to rule out the presence of hepatic artery stenosis or thrombosis.
Although anastomotic biliary complications can result in mortality from sepsis, these most commonly
lead to short-term morbidity. The initial management of biliary complications can generally be
nonoperative. In most cases, the problem can be both diagnosed and treated by ERCP. If the biliary
reconstruction was made using a Roux-en-Y hepaticojejunostomy, of if ERCP is unsuccessful, biliary
leaks can be diagnosed and treated by interventional radiology using percutaneous transhepatic
cholangiography and percutaneous placement of a biliary stent. In addition to stenting the anastomosis,
it may be necessary to place a percutaneous drain if there is a significant extrahepatic collection of bile.
In cases where initial studies show a large defect and in cases where the leak is not controlled through
percutaneous measures, operative revision may be indicated.
Figure 37-18. Bile leak (arrow) from the choledochocholedochostomy after hepatic transplantation.
Biliary obstruction resulting from anastomotic strictures can also generally be managed
nonoperatively by using percutaneous cholangioplasty or ERCP. When anastomotic strictures persist
beyond two attempts at balloon dilatation and stent replacement, operative repair may be an option as
long as the entire biliary stricture is extrahepatic and there are no intrahepatic strictures.
While anastomotic strictures are less likely to cause long-term morbidity, intrahepatic biliary
strictures, also referred to as intrahepatic cholangiopathy, can be progressive and lead to allograft
dysfunction, cholangitis, and ultimately to either death or retransplantation. Intrahepatic
cholangiopathy is largely related to ischemic injuries and occurs in the setting of hepatic artery
thrombosis and occurs in approximately 20% of donation following cardiac death (DCD) liver recipients.
Intra-Abdominal Sepsis
Intra-abdominal sepsis presents as diffuse peritonitis or localized abscess and occurs in about 5% of
916
booksmedicos.org
patients who undergo liver transplantation. The most common cause of peritonitis is leakage of the
biliary anastomosis. Abscesses may also develop spontaneously in the right upper quadrant or elsewhere
in the abdomen. Most isolated infected fluid collections can be managed by percutaneous placement of
drains guided by ultrasound or CT scanning, along with broad-spectrum intravenous antibiotics.
Generalized infected ascitic fluid is managed with paracentesis and antibiotics. Surgical drainage may be
necessary if leakage of enteric contents is suspected based on the finding of extravasated oral contrast in
the peritoneal cavity on CT scan, or if the patient does not respond to percutaneous drainage.
Neurologic Complications
A number of preoperative and postoperative factors predispose to impaired consciousness and seizure
activity after transplantation. Patients who have significant preoperative encephalopathy are more
likely to suffer from postoperative neurologic symptoms. In the extreme, patients who are in hepatic
coma from fulminant liver failure can sometimes take weeks to regain complete consciousness. Patients
undergoing liver transplants are also at risk for watershed cerebral infarcts if significant intraoperative
hypotension occurs. The effects of transient cerebral ischemia are worsened by the large amount of
intravenous fluids that are often necessary during and after transplantation, which can exacerbate
cerebral edema. Air embolism is also a risk if venous bleeding occurs from the inferior vena cava or
hepatic veins at a time when the patient is relatively hypovolemic. If the patient has a patent foramen
ovale, air embolism can result in cerebral ischemia if large bubbles lodge in the cerebral circulation. If
the patient fails to awaken promptly after transplantation, and particularly if the transplant is
functioning well, an urgent CT scan of the head should be obtained to rule out intracranial hemorrhage
and to assess the degree of cerebral edema.
Seizures are reasonably common after transplantation. The calcineurin inhibitors cyclosporine and
tacrolimus both lower seizure threshold and are associated with seizures following liver transplantation.
Patients with a history of seizures are particularly predisposed to postoperative seizure activity. Seizures
are treated with benzodiazepines acutely. Many long-term anticonvulsants alter the metabolism of
calcineurin inhibitors. Therefore, levetiracetam is often used in substitution for these other
anticonvulsants. To prevent recurrence of seizure activity it is usually necessary to decrease the dosage
of calcineurin inhibitor to a lower target blood level. Frequently it is also necessary to change to a
different calcineurin inhibitor altogether, or even to change the patient’s maintenance
immunosuppression to a regimen that does not include a calcineurin inhibitor.
REJECTION AND IMMUNOSUPPRESSION

5 For reasons that are not understood, liver transplant recipients require less immune suppression than
patients with other types of allografts, such as heart, lung, and kidney recipients. This is somewhat
surprising given that the mass of the liver is so great compared with the mass of the other organs. With
current immunosuppressive therapy, graft loss from rejection is rare.
Antibody-Mediated Rejection
The liver is relatively resistant to injury from recipient antibodies, regardless of whether they are
present at the time of transplant or develop later. This is very different compared with renal and cardiac
recipients who experience rapid graft destruction, termed hyperacute rejection, if performed in a patient
who has complement-fixing antibodies directed against the donor organ in significant concentrations at
the time of transplantation. Hepatic graft injury from pre-existing antibodies directed at donor ABO
determinants does occur, but in a much less pronounced fashion than in the context of renal
transplantation. The overall results of ABO-incompatible liver transplants are somewhat inferior to
those of ABO-compatible transplantations, but only by about a 10% to 20% decrease in 1-year graft
survival rates compared to ABO-compatible grafts. Some of this decrease in graft survival rate may be
due to the fact that ABO-incompatible transplants are usually performed only in dire circumstances
where the patient is so ill that he or she may not survive the wait for a compatible organ. Because
preformed antibodies do not seem to be clinically important, most transplantation programs do not
perform prospective cross-matches between recipient serum and donor cells before transplantation, and
determination of recipient and donor HLA type is no longer considered mandatory.
Why the liver is less susceptible to antibody-mediated destruction than the kidney is not clearly
understood. One factor may be the vastly different microcirculation that the liver has compared with
917
booksmedicos.org
the kidney, with a preponderance of sinusoidal channels and a smaller capillary network. It is probable
that antibody-mediated injury affects blood flow through the delicate capillary network of the kidney
more than it does to the liver sinusoids. In addition, each hepatocyte is exposed to two sinusoidal
channels, presumably permitting survival if only one sinusoid is occluded. Finally, differences in HLA
antigen expression are known to exist in the two organs, with the kidney the more antigenic of the two.
Cell-Mediated Rejection
6 Typical acute rejection in liver transplant recipients is usually cell mediated and occurs frequently but
is effectively blunted by antirejection therapy. Acute rejection occurs most commonly in the first two
postoperative months. In modern practice, cell-mediated rejection is a less common cause of graft loss
than are primary nonfunction or hepatic artery thrombosis. Still, the effectiveness of antirejection
treatment assumes a relatively early diagnosis and treatment of acute rejection, which is in turn the
result of careful monitoring by the transplantation physician and compliance by the patient with
frequent laboratory testing. Treatment of acute rejection with enhanced immunosuppressive therapy is
highly effective, and an episode of rejection does not affect long-term graft survival. This is very
different from renal transplantation, where an episode of rejection decreases long-term graft survival
markedly.
The diagnosis of cell-mediated rejection is made primarily on a histologic basis. Clinical features can
include low-grade fever and malaise, but frequently the patient is completely asymptomatic. Laboratory
evaluation of peripheral blood may demonstrate leukocytosis and occasionally eosinophilia. Biochemical
changes associated with rejection include elevated and rising levels of serum transaminases and alkaline
phosphatase. A prolonged serum prothrombin time and an abnormal serum bilirubin also suggest the
possibility of rejection, but frequently these parameters are normal if rejection is detected early. Any of
these findings should prompt a biopsy.
Figure 37-19. Acute rejection of a liver transplant. A: A portal tract is expanded by a polymorphous inflammatory infiltrate
consisting of large and small lymphocytes, plasma cells, macrophages, and neutrophils. The bile ducts (arrows) are damaged and
inflamed. B: A central vein from the same biopsy exhibits endothelialitis, characterized by swollen endothelial cells and infiltrating
lymphocytes. (From Thung SN, Gerber MA. Histopathology of liver transplantation. In: Fabry TL, Klion FM, eds. Guide to Liver
Transplantation. New York: Igaku-Shoin Medical Publishers; 1988.)
The diagnosis of cell-mediated rejection rests on the finding of a triad of portal lymphocytosis,
endotheliitis (subendothelial deposits of mononuclear cells), and bile duct infiltration and damage (Figs.
37-19 and 37-20). Various classification schemes have been devised to grade the severity of the
rejection process based on the degree of cellular involvement or injury in these areas. Cell
characterization studies have documented that the cells in the portal triads are primarily T cells, with
fewer macrophages and neutrophils. Bile duct epithelial cells appear to be a prime target of immune
attack, and they are known to express large amounts of class II HLA antigen.
If the recipient has hepatitis C, it is critical that recurrent hepatitis C is differentiated from acute
rejection. At times the difference can be subtle, and a pathologist with experience in the interpretation
of allograft biopsies is extremely valuable. Enhanced immunosuppression is associated with accelerated
rates of hepatitis C viral replication; it is, therefore, important that immunosuppression is kept to a
minimum for these patients.
918
booksmedicos.org
Chronic Rejection
7 Chronic rejection is characterized by relentless immune attack on small bile ducts. Clinically, the
pattern is one of gradual elevation of alkaline phosphatase and bilirubin, in the absence of obstruction
of the large bile ducts. Histologically, small bile ducts are obliterated or completely absent, with a less
pronounced cellular infiltrate than is seen with acute rejection. This finding has been termed vanishing
bile duct syndrome when bile ducts are absent in 15 of 20 portal triads examined.73 The loss of small bile
ducts is partly the result of lymphocyte-directed attack on biliary epithelium. Relative to other cells in
the liver, biliary epithelium tends to express more class I antigen. Thus, biliary epithelial cells are
vulnerable targets for host attack because of their antigenicity. Loss of bile ducts may also occur
indirectly as the result of ischemia secondary to immune-mediated obliteration of small to medium
arteries. As in the case of renal transplantations, there is no effective treatment for chronic rejection
except retransplantation.
Immunosuppression Induction and Maintenance

Multiple immunosuppressive protocols achieve acceptable suppression of allograft rejection for liver
transplant recipients. Induction with antithymocyte globulin is no longer considered to be mandatory
but is used at some centers. Similarly prednisone therapy, once considered a mainstay of a successful
immunosuppressive protocol, is no longer considered absolutely necessary and when used is often
tapered off rapidly. Treatment with a calcineurin inhibitor, either cyclosporine or tacrolimus is still
considered to be imperative for most liver transplant recipients. These agents are associated with
significant long-term morbidity, particularly the development of chronic renal failure. Dosages of these
agents have gradually been reduced both to prevent renal insufficiency and to avoid the rapid and
aggressive recurrence of hepatitis C infection. Induction antibody therapy with either polyclonal
antilymphocyte preparations or with inhibitors of the receptor for IL-2 are still used commonly in the
perioperative setting to avoid the nephrotoxicity associated with the immediate use of calcineurin
inhibitors.
Figure 37-20. Arterial lesion of chronic hepatic rejection. Subintimal foam cells, intimal sclerosis, and myointimal hyperplasia
obliterate the arterial lumen. (From Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1999.)
Because immunosuppression predisposes to infection, prophylactic anti-infective drugs are usually

administered. Trimethoprim–sulfamethoxazole, dapsone, or pentamidine is recommended to prevent
Pneumocystis carinii infection. Oral Mycostatin or fluconazole therapy is used to prevent fungal
infections, particularly esophageal Candida albicans. Either ganciclovir or valganciclovir is prescribed for
patients who are at risk for CMV infection, which includes any patient exposed to CMV in the past and
any patient transplanted with organs from a donor who has been exposed to CMV. Patients who are
CMV negative who receive CMV-negative organs are not at high risk for CMV infection but should still
receive prophylaxis against disseminated herpes simplex infections with acyclovir therapy. The duration
of prophylactic anti-infective therapy has not been rigorously defined by evidenced-based trials and is
therefore dependent on each center’s experience with the prevalence of these infections in its patient
population.
Treatment of Acute Rejection

Despite the overall effectiveness of the regimen described, acute rejection does occur and must be
treated promptly. Several options are available for treatment of acute rejection, depending on the
clinical circumstances. Traditionally, high doses of methylprednisolone are administered (usually 500
919
booksmedicos.org
mg to 1 g) intravenously on a daily basis for 3 days. This treatment is effective in reversing most acute
rejection episodes. Alternatively, increased doses of oral prednisone, a calcineurin inhibitor, or the
addition of an antimetabolite drug, such as mycophenolate mofetil, will also reverse most episodes of
rejection, particularly if the rejection is mild. Rejection that is resistant to these maneuvers or severe is
treated with antilymphocyte therapy, either a monoclonal antibody directed at the T3 determinant
common to all mature T cells (Orthoclone, OKT3) or polyclonal antilymphocyte treatments such as
Atgam or Thymoglobulin. These treatments are typically administered daily for 5 to 10 days. These
agents are highly effective, and it is unusual to lose an allograft secondary to acute rejection. However,
these treatments are associated with profound and long-lasting immunosuppression, and it is usually
advisable to restart prophylactic anti-infective therapies when they are initiated.
RESULTS
8 The patient survival rate following liver transplantation in the United States at 1 year is more than
85% for adults and nearly 90% for children. Patients who survive the first year following a liver
transplantation experience approximately a 3% annual mortality rate thereafter, so 3-year survival rates
for adults and children are currently 78% and 83%, respectively.
The most important predictors of survival following liver transplantation are whether the patient has
previously undergone transplantation and whether the patient was in the intensive care unit at the time
of transplantation. Although not as important as the condition of the patient at transplantation, the
cause of liver failure is also an important determinant of success. Five-year survival varies from
approximately 60% for patients transplanted for malignancy to 70% for patients transplanted for viral
and alcoholic cirrhosis. The best 5-year survival rates of around 80% are seen with patients transplanted
for metabolic liver disease, biliary atresia, and cholestatic liver diseases (PBC and PSC).37 The volume
of liver transplants performed at a given transplant center is also associated with patient survival, with
higher-volume programs exhibiting higher adjusted overall patient survival rates.74
References
1. Starzl TE, Groth CG, Brettschneider L, et al. Orthotopic homotransplantation of the human liver.
Ann Surg 1968;168:392–415.
2. Calne RY, Rolles K, White DJ, et al. Cyclosporin A initially as the only immunosuppressant in 34
recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet 1979;2:1033–1036.
3. Roberts MS, Angus DC, Bryce CL, et al. Survival after liver transplantation in the United States: a
disease-specific analysis of the UNOS database. Liver Transpl 2004;10:886–897.
4. Freeman RB Jr, Steffick DE, Guidinger MK, et al. Liver and intestine transplantation in the United
States, 1997–2006. Am J Transplant 2008;8:958–976.
5. O’Leary JG, Lepe R, Davis GL. Indications for liver transplantation. Gastroenterology
2008;134:1764–1776.
6. Punch JD, Hayes DH, LaPorte FB, et al. Organ donation and utilization in the United States, 1996–
2005. Am J Transplant 2007;7:1327–1338.
7. Centers for Medicare & Medicaid Services (CMS), HHS. Medicare and Medicaid programs;
conditions for coverage for organ procurement organizations (OPOs). Final rule. Fed Regist
2006;71:30981–31054.
8. Olthoff KM, Merion RM, Ghobrial RM, et al. Outcomes of 385 adult-to-adult living donor liver
transplant recipients: a report from the A2ALL Consortium. Ann Surg 2005;242:314–323, discussion
323–325.
9. Trotter JF, Wachs M, Everson GT, et al. Adult-to-adult transplantation of the right hepatic lobe
from a living donor. N Engl J Med 2002;346:1074–1082.
10. Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage
liver disease. Hepatology 2001;33:464–470.
11. Merion RM, Schaubel DE, Dykstra DM, et al. The survival benefit of liver transplantation. Am J
Transplant 2005;5:307–313.
12. Freeman RB GR, Harper A, Davis GL, et al. Model for end-stage liver disease (MELD) exception
920
booksmedicos.org
guidelines: results and recommendations from the MELD exception study group and conference
(MESSAGE) for the approval of patients who need liver transplantation with diseases not
considered by the standard MELD formula. Liver Transpl 2006;12:S128–S136.
13. Freeman RB, Wiesner RH, Edwards E, et al. Results of the first year of the new liver allocation
plan. Liver Transpl 2004;10:7–15.
14. Sass DA, Shakil AO. Fulminant hepatic failure. Liver Transpl 2005;11:594–605.
15. Stieber AC, Zetti G, Todo S, et al. The spectrum of portal vein thrombosis in liver transplantation.
Ann Surg 1991;213:199–206.
16. Roland ME, Barin B, Carlson L, et al. HIV-infected liver and kidney transplant recipients: 1- and 3-
year outcomes. Am J Transplant 2008;8:355–365.
17. Mindikoglu AL, Regev A, Magder LS. Impact of human immunodeficiency virus on survival after
liver transplantation: analysis of United Network for Organ Sharing database. Transplantation
2008;85:359–368.
18. Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. Gastroenterology
2014;146:1176–1192.
19. Wong SN, Chu CJ, Wai CT, et al. Low risk of hepatitis B virus recurrence after withdrawal of long-
term hepatitis B immunoglobulin in patients receiving maintenance nucleos(t)ide analogue therapy.
Liver Transpl 2007;13:374–381.
20. Chu CJ, Fontana RJ, Moore C, et al. Outcome of liver transplantation for hepatitis B: report of a
single center’s experience. Liver Transpl 2001;7:724–731.
21. Gaglio P, Singh S, Degertekin B, et al. Impact of the hepatitis B virus genotype on pre- and post-
liver transplantation outcomes. Liver Transpl 2008;14:1420–1427.
22. Bruno S, Stroffolini T, Colombo M, et al. Sustained virological response to interferon-alpha is
associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology
2007;45:579–587.
23. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with
interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.
Lancet 2001;358:958–965.
24. Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating
dosage regimen of antiviral therapy. Hepatology 2005;42:255–262.
25. Lake JR, Shorr JS, Steffen BJ, et al. Differential effects of donor age in liver transplant recipients
infected with hepatitis B, hepatitis C and without viral hepatitis. Am J Transplant 2005;5:549–557.
26. Fontana RJ, Hughes EA, Bifano M, et al. Sofosbuvir and daclatasvir combination therapy in a liver
transplant recipient with severe recurrent cholestatic hepatitis C. Am J Transplant 2013;13:1601–
1605.
27. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small
hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334:693–699.
28. Onaca N, Davis GL, Goldstein RM, et al. Expanded criteria for liver transplantation in patients with
hepatocellular carcinoma: a report from the International Registry of Hepatic Tumors in Liver
Transplantation. Liver Transpl 2007;13:391–399.
29. Schwartz M. Liver transplantation for hepatocellular carcinoma. Gastroenterology 2004;127:S268–
S276.
30. Golfieri R, Cappelli A, Cucchetti A, et al. Efficacy of selective transarterial chemoembolization in
inducing tumor necrosis in small (<5 cm) hepatocellular carcinomas. Hepatology 2011;53:1580–
1589.
31. Kim WR, Stock PG, Smith JM, et al. OPTN/SRTR 2011 Annual Data Report: liver. Am J Transplant
2013;13(Suppl 1):73–102.
32. Finegold MJ, Egler RA, Goss JA, et al. Liver tumors: pediatric population. Liver Transpl
2008;14:1545–1556.
33. Mantel HT, Rosen CB, Heimbach JK, et al. Vascular complications after orthotopic liver
transplantation after neoadjuvant therapy for hilar cholangiocarcinoma. Liver Transpl 2007;13:1372–
1381.
34. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neoadjuvant chemoradiation, followed
by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology
921
booksmedicos.org
2012;143:88–98e3; quiz e14.
35. van Vilsteren FG, Baskin-Bey ES, Nagorney DM, et al. Liver transplantation for
gastroenteropancreatic neuroendocrine cancers: defining selection criteria to improve survival. Liver
Transpl 2006;12:448–456.
36. Burke A, Lucey MR. Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis and orthotopic
liver transplantation. Am J Transplant 2004;4:686–693.
37. Mas A, Rodes J. Fulminant hepatic failure. Lancet 1997;349:1081–1085.
38. O’Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic
failure. Gastroenterology 1989;97:439–445.
39. Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in fulminant hepatic failure:
an assessment of the Model for End-Stage Liver Disease (MELD) and King’s College Hospital
criteria. Liver Transpl 2007;13:814–821.
40. Yantorno SE, Kremers WK, Ruf AE, et al. MELD is superior to King’s college and Clichy’s criteria to
assess prognosis in fulminant hepatic failure. Liver Transpl 2007;13:822–828.
41. Barshes NR, Lee TC, Balkrishnan R, et al. Orthotopic liver transplantation for biliary atresia: the
U.S. experience. Liver Transpl 2005;11:1193–1200.
42. Sylvestre PB, Batts KP, Burgart LJ, et al. Recurrence of primary biliary cirrhosis after liver
transplantation: histologic estimate of incidence and natural history. Liver Transpl 2003;9:1086–
1093.
43. Maheshwari A, Yoo HY, Thuluvath PJ. Long-term outcome of liver transplantation in patients with
PSC: a comparative analysis with PBC. Am J Gastroenterol 2004;99:538–542.
44. Kayler LK, Rasmussen CS, Dykstra DM, et al. Liver transplantation in children with metabolic
disorders in the United States. Am J Transplant 2003;3:334–339.
45. Arguedas MR, Abrams GA, Krowka MJ, et al. Prospective evaluation of outcomes and predictors of
mortality in patients with hepatopulmonary syndrome undergoing liver transplantation. Hepatology
2003;37:192–197.
46. Ashfaq M, Chinnakotla S, Rogers L, et al. The impact of treatment of portopulmonary hypertension
on survival following liver transplantation. Am J Transplant 2007;7:1258–1264.
47. Swanson KL, Wiesner RH, Nyberg SL, et al. Survival in portopulmonary hypertension: Mayo Clinic
experience categorized by treatment subgroups. Am J Transplant 2008;8:2445–2453.
48. Pomfret EA, Fryer JP, Sima CS, et al. Liver and intestine transplantation in the United States, 1996–
2005. Am J Transplant 2007;7:1376–1389.
49. Eason JD, Gonwa TA, Davis CL, et al. Proceedings of Consensus Conference on Simultaneous Liver
Kidney Transplantation (SLK). Am J Transplant 2008;8:2243–2251.
50. Lodge JP, Jonas S, Jones RM, et al. Efficacy and safety of repeated perioperative doses of
recombinant factor VIIa in liver transplantation. Liver Transpl 2005;11:973–979.
51. Planinsic RM, van der Meer J, Testa G, et al. Safety and efficacy of a single bolus administration of
recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl
2005;11:895–900.
52. Dumortier J, Czyglik O, Poncet G, et al. Eversion thrombectomy for portal vein thrombosis during
liver transplantation. Am J Transplant 2002;2:934–938.
53. Tzakis AG, Kirkegaard P, Pinna AD, et al. Liver transplantation with cavoportal hemitransposition
in the presence of diffuse portal vein thrombosis. Transplantation 1998;65:619–624.
54. Charco R, Margarit C, Lopez-Talavera JC, et al. Outcome and hepatic hemodynamics in liver
transplant patients with portal vein arterialization. Am J Transplant 2001;1:146–151.
55. Lerut J, Ciccarelli O, Roggen F, et al. Cavocaval adult liver transplantation and retransplantation
without venovenous bypass and without portocaval shunting: a prospective feasibility study in
adult liver transplantation. Transplantation 2003;75:1740–1745.
56. Welling TH, Heidt DG, Englesbe MJ, et al. Biliary complications following liver transplantation in
the model for end-stage liver disease era: effect of donor, recipient, and technical factors. Liver
Transpl 2008;14:73–80.
57. Otte JB, de Ville de Goyet J, Alberti D, et al. The concept and technique of the split liver in clinical
transplantation. Surgery 1990;107:605–612.
922
booksmedicos.org
58. Brolsch CE, Stevens LH, Whitington PF. The use of reduced-size liver transplants in children,
including split livers and living related liver transplants. Eur J Pediatr Surg 1991;1:166–171.
59. Emond JC, Whitington PF, Thistlethwaite JR, et al. Transplantation of two patients with one liver.
Analysis of a preliminary experience with ‘split-liver’ grafting. Ann Surg 1990;212:14–22.
60. Humar A, Khwaja K, Sielaff TD, et al. Technique of split-liver transplant for two adult recipients.
Liver Transpl 2002;8:725–729.
61. Marcos A, Fisher RA, Ham JM, et al. Right lobe living donor liver transplantation. Transplantation
1999;68:798–803.
62. Miller C, Florman S, Kim-Schluger L, et al. Fulminant and fatal gas gangrene of the stomach in a
healthy live liver donor. Liver Transpl 2004;10:1315–1319.
63. Strasberg SM, Howard TK, Molmenti EP, et al. Selecting the donor liver: risk factors for poor
function after orthotopic liver transplantation. Hepatology 1994;20:829–838.
64. Oh CK, Sawyer RG, Pelletier SJ, et al. Independent predictors for primary non-function after liver
transplantation. Yonsei Med J 2004;45:1155–1161.
65. Pungpapong S, Manzarbeitia C, Ortiz J, et al. Cigarette smoking is associated with an increased
incidence of vascular complications after liver transplantation. Liver Transpl 2002;8:582–587.
66. Bhattacharjya S, Gunson BK, Mirza DF, et al. Delayed hepatic artery thrombosis in adult orthotopic
liver transplantation-a 12-year experience. Transplantation 2001;71:1592–1596.
67. Furuta S, Ikegami T, Nakazawa Y, et al. Hepatic artery reconstruction in living donor liver
transplantation from the microsurgeon’s point of view. Liver Transpl Surg 1997;3:388–393.
68. Stahl RL, Duncan A, Hooks MA, et al. A hypercoagulable state follows orthotopic liver
transplantation. Hepatology 1990;12:553–558.
69. Parrilla P, Sanchez-Bueno F, Figueras J, et al. Analysis of the complications of the piggy-back
technique in 1,112 liver transplants. Transplantation 1999;67:1214–1217.
70. Borsa JJ, Daly CP, Fontaine AB, et al. Treatment of inferior vena cava anastomotic stenoses with
the Wallstent endoprosthesis after orthotopic liver transplantation. J Vasc Interv Radiol 1999;10:17–
22.
71. Frazer CK, Gupta A. Stenosis of the hepatic vein anastomosis after liver transplantation: treatment
with a heparin-coated metal stent. Australas Radiol 2002;46:422–425.
72. Feller RB, Waugh RC, Selby WS, et al. Biliary strictures after liver transplantation: clinical picture,
correlates and outcomes. J Gastroenterol Hepatol 1996;11:21–25.
73. Wiesner RH, Batts KP, Krom RA. Evolving concepts in the diagnosis, pathogenesis, and treatment of
chronic hepatic allograft rejection. Liver Transpl Surg 1999;5:388–400.
74. Axelrod DA, Guidinger MK, McCullough KP, et al. Association of center volume with outcome after
liver and kidney transplantation. Am J Transplant 2004;4:920–927.
923
booksmedicos.org
Chapter 38
Cardiac Transplantation
Richard N. Pierson III
Key Points
1 Over the past 50 years, heart transplantation has evolved from public spectacle to accepted
therapeutic modality based on improved tools to diagnose rejection and infection and an expanded
armamentarium of treatment options.
2 Heart transplantation is offered to patients who are at higher risk of death without transplant than
with it, and for whom no other reasonable treatment options exist, while excluding those whose
comorbid conditions are likely to significantly limit length or quality of life.
3 The mortality rate for patients awaiting transplant has improved significantly over recent decades
due to improvements in (a) patient selection, (b) medical therapy of patients awaiting
transplantation, (c) mechanical support as a bridge to transplant, and (d) donor management and
allocation algorithms.
4 Of the four techniques for performing heart transplantation, orthotopic transplant using bicaval right
atrial connections has emerged as the most popular.
5 A “triple-drug” regimen including a calcineurin inhibitor, an antimitotic agent, and a steroid, with or
without antilymphocyte “induction,” is employed to prevent graft injury due to acute rejection.
6 Prophylaxis against opportunistic infections includes agents targeted at common bacterial, viral, and
protozoal pathogens.
7 Although the number of heart transplants performed worldwide has declined due to a donor organ
shortage, operative survival has improved over the past 20 years, and both patient and graft 1-year
survival rates now exceed 87% for adults.
8 Rejection and infection together account for most of the mortality during the first year after
transplant, whereas long-term survival is limited by cardiac allograft vasculopathy (a manifestation
of chronic rejection) and malignancy.
9 Current initiatives in the field include development of improved immunosuppression (perhaps
leading to graft “tolerance”) and alternatives to heart allotransplantation, such as “destination”
mechanical support or heart “xenografts” from genetically modified pigs.
1 Since 1964, clinical cardiac transplantation has evolved from a sensational, perilous experiment to
become conventional therapy for end-stage heart disease, the paradigm of successful but expensive
“high-tech” medicine. This remarkable transformation stemmed from fundamental surgical innovations
supported by incremental improvements in the diagnosis and management of common problems.
Current challenges revolve around donor supply and allocation, improving long-term outcomes,
developing alternative therapies, and related ethical issues.
HISTORICAL PERSPECTIVE
Based on significant contributions by many surgical pioneers,1–8 the first clinical heart transplant was
performed in 1964 by Hardy,9 who attempted to salvage a man dying from cardiogenic shock by
replacing his heart with one from a chimpanzee. Then, before the concept of brain death achieved wide
social or legal acceptance, in 1967 Christian Barnard et al.10 captured the imagination of the world with
the first operative survival, using the heart of a resuscitated cadaveric donor. This case, and many
others that were performed shortly thereafter, demonstrated not only the physiologic capacity of the
transplanted human heart allograft to support the recipient’s circulation but also the difficulty of
diagnosing and managing subsequent immunologic and infectious complications. After a worldwide
flurry of activity, generally dismal outcomes at many prominent cardiac surgery centers made clear the
924
booksmedicos.org
need for more thoughtful approaches to what was clearly a difficult constellation of problems beyond
effective circulatory support.
A few pioneering programs persisted in cautious clinical application supported by parallel laboratory
investigation. Recognizing the need for a more sensitive and specific diagnostic technique to diagnose
rejection, Phillip Caves, working with Shumway et al. at Stanford, developed the technique of
transvenous endomyocardial biopsy.11 Frequent, representative surveillance sampling of the graft
allowed early detection of pathogenic host immune responses. Perivascular lymphocytic infiltrates were
found to accurately diagnose acute cellular rejection in its presymptomatic phase; when detected early,
rejection usually responded to enhanced immunosuppression. Equally important, when rejection was not
seen, immunosuppression could be tapered to minimize drug toxicities and reduce the incidence of
opportunistic infection. Coupled with important advances in the diagnosis, prevention, and treatment of
infectious pathogens in immunosuppressed patients and in selection and management of patients with
end-stage heart failure, patient survival at 1 year improved gradually, from about 20% in the 1960s to
about 70% by 1980.12
However, even as recently as the early 1980s, when rejection persisted or recurred despite high-dose
steroids, alternative treatments (total lymphoid irradiation, intramuscular antilymphocyte preparations,
thoracic duct ligation, splenectomy) were often toxic or invasive and accompanied by a high incidence
of major short- and long-term complications. In this context the discovery and clinical development of
the first calcineurin inhibitor (CNI), cyclosporin A (CsA),13,14 catalyzed the next major improvement in
outcomes. CsA’s primary mechanism of action and toxicity profile were fundamentally different from
those of azathioprine, the most commonly used antimitotic agent, or anti-inflammatory steroids and
combination “triple” therapy allowed each agent to be used at lower doses and thus more safely.
Meanwhile, antithymocyte and antilymphocyte preparations were adapted for safe intravenous use,
either as prophylactic “induction” therapy (“quadruple therapy”) or as treatment for steroid-resistant
rejection. Based primarily on these pharmacologic innovations in the regulation of the immune
response, expected 1-year survival following heart transplant gradually rose from about 70% to almost
90% between 1980 and the present, despite increasing reliance on older donors for older and sicker
recipients.15,16
CANDIDATE EVALUATION
End-stage heart failure is the primary indication for heart transplantation in adults, with coronary artery
occlusive disease and myopathy of various etiologies each accounting for about 45% of cases.
Congenital heart disease is the primary indication for infants, whereas myopathy predominates in older
children.
2 heart transplant evaluation process seeks to identify patients who are at higher risk of death
without transplant than with it and for whom no other reasonable treatment options exist, while
excluding those whose comorbid conditions are likely to significantly limit length or quality of life. In
1993, a National Institutes of Health consensus conference developed recipient selection guidelines for
cardiac transplantation, based on objective criteria known to predict poor outcome without
transplantation17; these guidelines (Tables 38-1–38-3) continue to evolve in the context of improving
heart failure therapy.18–20 Among patients with heart failure symptoms, maximal oxygen consumption
(MVO2) is more sensitive and specific than ejection fraction in gauging prognosis, and blunted cardiac
output response to exercise may further stratify patients into high- and low-risk groups.18
When no clear survival advantage is apparent for transplantation or an alternative management
strategy, quality of life and other subjective factors are weighed. Contemporary studies defining
relative risks, along with basic considerations in the medical management of end-stage heart failure, are
well summarized in recent reviews.19,20
Table 38-1 Indications for Heart Transplant
925
booksmedicos.org
Table 38-2 Selection Criteria for Stratifying Risk and Survival Results
DONOR SELECTION AND MANAGEMENT

The ideal donor is a young, previously healthy individual without cardiac disease or hypertension, who
is well matched in size to the intended recipient and whose hemodynamics have been carefully managed
during the evolution of his or her lethal central nervous system (CNS) injury. Some programs have
advocated use of older donors, donors who may transmit infection or malignancy to the recipient, and
grafts with hypertensive myocardial hypertrophy for particular recipients.21 Some aggressive programs
have even proposed that hemodynamically significant coronary stenoses can be bypassed at the time of
transplant.22 These approaches to donor selection are associated with less favorable short- and long-term
outcomes, but the increased risk may be considered acceptable for patients in whom the short-term
prognosis is poor without transplant.15,23,24 Successful use of hearts resuscitated after cessation of
cardiac activity in the donor has recently been described, and may prove to be safely enabled by
functional and metabolic evaluation during normothermic ex vivo perfusion.25 Survival of genetically
modified pig hearts beyond 2 years in a preclinical model demonstrates significant progress toward an
alternative potential solution to the organ donor shortage.26
Donor management requires skill and experience to successfully address the complex physiologic
perturbations associated with brain death. Reflex hypertensive and hypotensive responses to intracranial
pressure changes, fluid and electrolyte imbalances consequent to the diabetes insipidus from pituitary
death, and additional stresses related to hemorrhage, trauma, and surgery often cause hemodynamic
and metabolic instability, which may injure a previously healthy heart. The neurohumoral milieu of CNS
catastrophe may also adversely affect other fundamental cell regulatory functions, such as those
dependent on thyroid hormone. Despite controversy regarding the mechanisms involved, thyroid
926
booksmedicos.org
hormone is often administered to the donor as a continuous infusion, hoping to correct a “sick
euthyroid” syndrome and optimize cardiac metabolism prior to explant. Although evidence to date is
largely anecdotal, inotrope requirements can often be reduced after thyroid infusion is begun, and
donor hemodynamic lability is less common, suggesting improved cardiac and vasoregulatory
function.27,28
Table 38-3 Contraindications to Cardiac Transplantation
Cardiac echocardiography has become a standard component of donor assessment to measure ejection
fraction and to exclude structural abnormalities or hypertrophy suggestive of hypertensive myopathy.
Cardiac catheterization may be requested for donors over age 45, especially for those with a strong
family history of coronary artery disease, for smokers, or when regional wall motion abnormalities are
appreciated on echocardiography.
MATCHING DONOR TO RECIPIENT

Once a potential donor is identified, priority among blood type–compatible recipients is determined first
by relative severity of illness (“status”) and then by length of time on the waiting list among those at
each status in the donor’s geographic area. In the United States, this information is currently tracked
and collated by a central, national registry operated by the United Network for Organ Sharing. The
heart is first offered to the program whose candidate has priority on the list and whose registered
height and weight range include the potential donor. Donor inotrope requirements and functional
927
booksmedicos.org
assessment, recipient pulmonary vascular resistance, possible infection transmission risks (known
hepatitis or potential human immunodeficiency virus [HIV] exposure in the donor), and other logistical
considerations (expected graft ischemic time) influence the recipient team’s decision regarding
acceptance of an organ for an individual patient. If the first program declines the offer for the first
patient, the process is repeated for the patient next on the list until the heart is accepted.
Tissue typing, the time-consuming process by which donor and recipient are matched for shared
transplant antigens, is not currently used for hearts. The probability is low of identifying a “close”
match among the relatively small number of blood type–compatible potential recipients within the
geographic radius (usually <1,500 miles) defined by a 4-hour projected ischemic time. In addition, the
demonstrated benefit of partial human leukocyte antigen (HLA) matching is small relative to the added
risk of prolonged graft ischemia, a risk augmented by increasing donor age.16,29
RECIPIENT MANAGEMENT BEFORE TRANSPLANT

3 The medical therapy of patients awaiting transplantation has improved significantly over the past
decade, centered around aggressive afterload reduction and diuresis, anticoagulation, and beta
blockade.18–20 This trend, coupled with improved mechanical support and improved donor allocation
algorithms (discussed later), has reduced the mortality rate for patients awaiting transplantation. As
waiting lists have grown faster than the donor pool and average time waiting has similarly escalated,
cardiac decompensation among patients on the waiting list is frequent. In most areas of the United
States and Europe, the majority of hearts go to patients who are sick enough to require hospitalization
for intensive diuresis and intravenous inotrope administration.15,16
When inotropic therapy proves inadequate, as gauged by progressive deterioration in renal and other
end-organ function, temporary intra-aortic balloon pump counterpulsation and mechanical ventilation
can stabilize some patients. These interventions are associated with important risks; the relative risk of
death is increased threefold in patients who are ventilator dependent at the time of transplant.15,16
Consequently, mechanical circulatory support using ventricular assist device (VAD) blood pumps has
emerged as an effective and generally preferred bridging strategy. Particularly in emergency
circumstances or in the setting of progressive or refractory extracardiac organ dysfunction, temporary
support with a paracorporeal (pump external to the body) VAD, an intravascular axial flow device
(Impella), or with a venoarterial extracorporeal membrane oxygenator (ECMO) device, is used as a
short-term “bridge to decision.” Fully implanted pumps are reserved for patients for whom end-organ
function seems likely to recover, and “bridge to transplant” (BTT) or definitive (“destination”) VAD
therapy is therefore deemed likely to extend life of a quality acceptable to the patient. Although many
VAD-bridged patients incur serious complications (stroke, renal or hepatic failure, systemic infection,
device malfunction) and some exhibit behaviors (noncompliance, substance abuse) that may preclude
transplantation, about three quarters are successfully transplanted, with excellent outcomes relative to
patients not requiring this intervention.16 Patients with biventricular failure can often be adequately
supported with left ventricular support, with or without addition of temporary paracorporeal right heart
support. Various total artificial heart devices can be implanted in place of the native heart and have
been applied successfully in small numbers.30,31 This approach is most likely to find a niche as an
alternative to heart transplantation in patients not supportable with a left VAD, such as those with fixed
pulmonary hypertension, although BTT is the only application currently clinically approved by FDA.
Over the past decade relatively small axial turbine (Jarvik 2000, HeartMate II) or bearing-free
centrifugal (HeartWare) continuous-flow (nonpulsatile) VADs have largely supplanted bulkier (Novacor)
or less durable (HeartMate I) pulsatile devices for both short-term paracorporeal (CentriMag) and
longer-term applications. Continuous-flow assist systems have shown sufficient promise in clinical trials
to earn FDA approval, with 1-year survival in both BTT patients and in carefully selected nontransplant-
eligible “destination therapy” patients now approaching that observed after heart transplantation.32,33
HEART PROCUREMENT
Cardiac allograft protection depends primarily on hypothermia, which reduces myocardial energy
requirements while the heart graft has no nutritive coronary blood flow. Other important principles
include avoidance of distention and warm ischemia in both the donor and the recipient and induction of
diastolic (flaccid) cardiac arrest. These goals are accomplished by interrupting systemic venous return
928
booksmedicos.org
for decompression, placing a clamp across the distal ascending aorta, and infusing a hyperkalemic
preservation solution proximal to the clamp, and thus selectively into the coronary arteries. Both the
inferior vena cava and left atrium are incised (“vented”) to prevent distention of either ventricle. Some
preservation solutions incorporating free radical scavenging molecules or other cytoprotective agents
are associated with improved early graft function.34,35
Every effort is made to minimize the ischemic interval – the time between initial interruption of
coronary flow by aortic cross-clamping in the donor and removal of the cross-clamp in the recipient –
since recipient morbidity and mortality increase with each additional hour of “cold ischemic time.”
Although laboratory studies and isolated clinical reports suggest that good results may be expected with
storage times of 8 hours or more using various preservation solutions, increased ischemic time remains
a strong and important independent risk factor for poor recipient outcome.15,16 Normothermic (∼34 to
37°C) ex vivo organ perfusion during transport is being explored in clinical trials as a potential
alternative to static cold storage (∼4°C).36
OPERATIVE RECIPIENT MANAGEMENT

Timing of the recipient operation requires careful coordination with the procurement team. Anesthesia
is induced after the donor heart is visually inspected and found suitable. Venous access is obtained,
which will permit rapid volume resuscitation and invasive cardiac monitoring after the new heart is
implanted. Prior cardiac surgery may complicate coordination of operative timing and is associated with
increased risk of bleeding.
Figure 38-1. Native cardiectomy and donor graft preparation. A: Recipient pericardium after institution of cardiopulmonary bypass
and ascending aortic occlusion, with caval snares secured. The diseased native heart can then be safely excised by transecting the
recipient aorta and pulmonary artery, and the atria divided as appropriate for the intended implant technique. Shown is the right
atrial incision for the traditional Lower/Shumway right atrial cuff. B: Posterior view of the explanted donor heart, indicating
various incisions used for atrial cuff preparation. Donor atrial cuff incisions made in preparation for traditional Lower/Shumway
biatrial implant are indicated by the heavy white dashed line. The superior vena cava (SVC) is ligated or oversewn. Right and left
pulmonary vein (light white dashed line) and superior vena cava (black dashed line) incisions are indicated for the total
atrioventricular implant technique. For the bicaval technique, the donor SVC (black dashed line) and inferior vena cava are retained
as for the total atrioventricular technique (Fig. 38-4), and the donor left atrial cuff trimmed as for the traditional biatrial approach
(heavy white dashed line).
929
booksmedicos.org
Figure 38-2. Traditional Lower/Shumway biatrial technique. A: Recipient cuffs, prepared for bicaval atrial implant technique.
After completion of the left atrial anastomosis (B), the right atrial cuffs are joined. Care is taken to avoid carrying the right atrial
incision or suture line close to the donor sinoatrial node, at the superior vena cava/right atrial junction (asterisk). C: Appearance of
the operative field after completion of great vessel anastomoses, weaning from cardiopulmonary bypass, and decannulation.
If appropriate, Coumadin effects are reversed with fresh frozen plasma, vitamin K, or prothrombin
complex concentrates. ε-Aminocaproic acid or tranexamic acid, and des-deoxyargine vasopressin
(DDAVP) are often used to inhibit fibrinolysis and promote coagulation at physiologically appropriate
sites, respectively, after prior cardiac surgery or associated with hepatic congestion. (Aprotinin, a serine
protease inhibitor formerly in routine use to prevent coagulopathic bleeding, was withdrawn from the
market because of safety concerns.) Increased inotropic infusion, antiarrhythmic agents, or mechanical
circulatory support may be required to maintain adequate systemic perfusion prior to institution of
cardiopulmonary bypass.
Vascular access for bypass is accomplished by cannulation of the superior and inferior vena cavae so
as to completely divert systemic venous blood to the cardiopulmonary bypass circuit. The ascending
aorta, common femoral, or subclavian artery is used for arterial return from the circuit to the patient.
Technical misadventures – such as entry into the heart or great vessels before bypass is established or
induction of ventricular arrhythmias – are more common with reoperative procedures, and can greatly
complicate the intraoperative course and postoperative management.
Once the proximate arrival of the donor heart is ensured, the recipient is placed on bypass and cooled.
Snares are secured around the caval cannulae, the ascending aorta clamped, and the native heart excised
(Fig. 38-1A). Vascular cuffs are preserved and tailored appropriately for implantation of the donor heart
(Figs. 38-2A, 38-3A, and 38-4A). The donor heart is then prepared according to the implant technique to
be used (Fig. 38-1B).
Implant techniques and the sequence of vascular anastomosis vary widely between surgeons, as do
strategies used to protect the ischemic organ during implantation. The biatrial orthotopic heart
transplant technique is simple, easy to teach, and still used by many surgeons (Fig. 38-2A–C).8 The
donor atria are spatulated open, trimmed if necessary, and laid over the recipient’s atrial remnants. The
left atrial suture line is everted to achieve endothelial apposition and to avoid leaving epicardial fat or
muscle exposed in the lumen as a potential nidus for thromboemboli. Sinoatrial node dysfunction can
usually be prevented by keeping the donor right atriotomy well anterior on the right atrial appendage,
930
booksmedicos.org
away from the sinoatrial node and its blood supply (Fig. 38-2B), and by optimizing graft preservation.35
Even if most of the dilated native atrium is excised, atrioventricular (AV) valve annular geometry may
be distorted, causing tricuspid regurgitation; or the area around the sinus node may be placed under
tension, leading to atrial arrhythmias or sinus node dysfunction.
Figure 38-3. Bicaval right atrial implant technique. A: During explantation of the native heart, the interatrial septum may be
excised, for end-to-end anastomosis of the cavae (B), or left in place (as in Fig. 38-2A), allowing the back walls of the donor cavae
to be laid into those of the recipient. C: Technique for pulmonary artery venting through an opening in the anterior aspect of this
anastomosis, which is useful for de-airing and decompressing the right heart. Alternatively, the aorta may be anastomosed earlier
in the operation and the aortic cross-clamp removed, to minimize graft ischemic time.
4 During the 1990s, these considerations led to evaluation of alternate atrial anastomotic techniques,
including bicaval right atrial connections (Fig. 38-3A–C) and total atrioventricular replacement (two
caval and two pulmonary vein anastomoses) (Fig. 38-4A, B). In a prospective, randomized trial
(bicaval)37 and several retrospective analyses,38,39 the incidence of atrial arrhythmias and AV valve
regurgitation was reduced, and hemodynamic results and survival were improved with either the
bicaval or total atrioventricular technique. Tricuspid valve annuloplasty may decrease early or later
tricuspid regurgitation and reduce the incidence of right heart dysfunction.40
Independent of whether the aorta or pulmonary artery connection is performed first, the anterior
aspect of the pulmonary artery anastomosis is usually left open or vented, to allow decompression of
the right heart after reperfusion (Fig. 38-3C). The size mismatch between donor and recipient aortas is
often dramatic, but can usually be accommodated by beveling the smaller vessel (usually the more
pliable donor) to increase its effective circumference and by distributing the discrepancy evenly over
the length of each anastomosis. Occasionally it is necessary to tailor down the larger vessel to reduce its
effective diameter, or to replace an aneurysmal ascending aorta with donor tissue or a prosthetic graft.
Functional supravalvular pulmonary stenosis is avoided by trimming back both donor and recipient
sufficiently to prevent redundancy or kinking.
An alternate “heterotopic” implantation technique places a second heart in the circulation, in parallel
931
booksmedicos.org
with the retained native heart.41 In principle, leaving the native heart affords protection in the event
that the graft fails. The operation is technically demanding, usually produces compressive atelectasis in
the right lung, and is associated with a high risk of stroke, perhaps due to stasis of blood in the native
heart.42 Notwithstanding, this surgical approach may be considered for patients with high pulmonary
vascular resistance unresponsive to vasodilators, and may in the future also find a role in the initial
application of cardiac xenografts.
After completion of the anastomoses, the heart is reperfused and allowed to resume contracting
without being required to function as a pump (“rested”) as the recipient and graft are rewarmed. Atrial
and ventricular pacing wires are placed. Cardiac output of the denervated transplant is highly dependent
on rate. In addition, the shorter cardiac filling time associated with higher heart rate prevents graft
distention. One commonly used protocol initiates isoproterenol prior to weaning from bypass at a dose
of 0.005 to 0.02 μg/kg/min, titrated to achieve a heart rate of about 110 beats/min.
Figure 38-4. Total atrioventricular transplant technique. A: Recipient pericardial well after preparation of bilateral pulmonary vein
pedicles and caval cuffs, for total atrioventricular heart transplant. B: Construction of left pulmonary vein anastomosis. As with
other left atrial anastomotic approaches, atrial walls or vein cuffs are everted to minimize exposure of thrombogenic fat or muscle
to the blood.
Patients with high preoperative pulmonary vascular resistance may be particularly difficult to wean
from cardiopulmonary bypass, even with excellent function of the donor heart, as the “normal” donor
right ventricle may acutely dilate and fail when confronted by a high-resistance pulmonary vascular
bed. Resting the recently ischemic heart on cardiopulmonary bypass, establishing a stable sinus or AV
sequentially paced rhythm, instituting inotropic support, and intra-aortic balloon counterpulsation are
useful in managing this problem. Traditional pharmacologic approaches to reducing pulmonary vascular
resistance, such as prostaglandins E1 or I2 and sodium nitroprusside, may cause transpulmonary shunting
of deoxygenated blood; these agents also reduce systemic vascular resistance and thus coronary
perfusion pressure. Inhaled nitric oxide or prostacyclin selectively dilates the pulmonary vascular bed
before being rapidly inactivated, and is very helpful to selectively reduce pulmonary vascular resistance
without adverse effects on systemic vascular resistance, oxygenation, or myocardial function.43,44 Poor
graft function may necessitate institution of mechanical support (VAD support of one or both ventricles,
or venoarterial ECMO) as a bridge to graft recovery or to retransplantation.
Postoperatively, ventilator and inotropic support is weaned, immunosuppression is instituted, and
diuretic and antihypertensive agents are initiated as necessary. When used, isoproterenol is continued
for about 5 days. Theophylline may be used transiently (for days to weeks after transplant) to sustain a
resting heart rate over 70. The first surveillance endomyocardial biopsy is typically performed 7 to 14
days after surgery and repeated about every 2 weeks for the first 3 months. Patient and caregiver
education with regard to medication schedules and physiologic monitoring facilitates early discharge for
patients without complications. Biologic monitoring of peripheral blood gene or protein expression or
lymphocyte function and electrical approaches to monitor the immune response to the graft have shown
promise to safely reduce dependence upon routine invasive monitoring.45–48
932
booksmedicos.org
IMMUNOSUPPRESSION
5 The goal of immunosuppressive therapy is to prevent immune-mediated injury to the graft while
minimizing associated complications, including opportunistic infection and drug-related toxicities. Most
programs employ a “triple-drug” regimen, including a CNI, an antimitotic agent, and steroids. This
approach allows each individual drug to be used within its therapeutic window (Table 38-4). Some
centers add antibody “induction” with anti-interleukin-2 (anti-IL-2) receptor antibodies, polyclonal
antilymphocyte serum, or other agents.15,16,49–54 Once wound healing has occurred, an inhibitor of the
mammalian target of rapamycin (mTOR) may be introduced.55 The mechanisms of action and side effect
profiles of these agents are well described in an earlier chapter of the transplantation section of this
text.
6 Medical management after heart transplantation is focused on anticipation and prevention of
common complications. Hypertension and hyperlipidemia are prevalent due to predisposition in the
recipient patient population and as side effects of various immunosuppressive agents. Prophylaxis
against opportunistic infections includes agents targeted at common protozoal and viral pathogens
(Table 38-4). Surveillance biopsies are performed according to a scheduled routine and additional
biopsies are performed to exclude rejection in the event of hemodynamic instability or unexplained
fever. Typically, patients are able to leave the hospital within 10 days of uncomplicated operation, to be
followed regularly in outpatient clinic. Monitored physical rehabilitation facilitates optimal
cardiovascular and musculoskeletal recuperation,56 and occupational rehabilitation may offer important
psychological and social benefits.
Table 38-4 Typical Immunosuppressive Protocol and Associated Medical

Treatment Following Adult Heart Transplantation
COMPLICATIONS
Complications of antirejection therapy relate primarily to the side effects of the specific
immunosuppressive agents currently used. Infections tend to occur in patients with the greatest degree
of preoperative debility and malnutrition, or in conjunction with additional stressors such as
perioperative bleeding or hepatorenal dysfunction. Bacterial pathogens are common in the first several
weeks, particularly in the lung and related to surgical or vascular access sites. Opportunistic viral and
fungal infections usually predominate later. Increasingly effective prophylaxis for cytomegalovirus and
herpes infections has markedly reduced the morbidity associated with these common pathogens. When
infection occurs, immunosuppression is tapered as aggressively as possible based on myocardial biopsy
933
booksmedicos.org
results.
Acute rejection occurs in the majority of patients and is graded histologically according to
standardized criteria developed by the International Society for Heart and Lung Transplantation
(ISHLT).57,58 When detected at an early histologic stage (ISHLT grade 1R, Fig. 38-5) in an asymptomatic
patient on surveillance biopsy, rejection will often respond to augmented oral steroids and/or an
increased dose of CNI. When a higher grade of rejection is found (Fig. 38-6), when the infiltrate fails to
resolve in response to initial interventions, or in the setting of depressed cardiac function or shock,
high-dose intravenous steroids are administered and antilymphocyte therapy often added. Inotropic or
mechanical support is instituted as needed in hopes of rescuing graft and patient. Antibody-mediated
“vascular” rejection is now a well-recognized entity that, when suspected or confirmed based on
immunohistochemical techniques or detection of increasing titers of antidonor antibody, may warrant
introduction of cyclophosphamide or other agents with increased activity against B cells.58
Figure 38-5. International Society for Heart and Lung Transplantation grade 1R – diffuse interstitial or focal perivascular infiltrate
with rare or absent myocyte damage is characteristic of mild acute cellular rejection.
Figure 38-6. International Society for Heart and Lung Transplantation grade 3R – multifocal cellular infiltrate with focal myocyte
necrosis, typical of severe acute cellular rejection.
Bradycardia is prevalent in the denervated heart for the first weeks after transplant, but a resting
heart rate over 70 can usually be achieved by initiating a β-agonist such as isoproterenol or
theophylline. Persistent bradycardia may be caused by ischemic, surgical, or immunologic injury to the
sinus or AV nodes or by amiodarone leaching from stores accumulated preoperatively in body fat;
pacemaker implantation may be necessary. Atrial flutter or fibrillation may occur spontaneously or
herald acute rejection. This dysrhythmia can be difficult to manage because vagal denervation
attenuates digoxin modulation of the typical rapid ventricular response. Most other agents traditionally
used to treat atrial arrhythmias depress AV node conduction or myocardial contractility, particularly
undesirable side effects in a recent heart recipient. Amiodarone is generally better tolerated, controls
heart rate and promotes conversion to sinus rhythm, and has been used widely in this circumstance once
absence of acute rejection has been confirmed.
Among patients who survive beyond the first year, the primary limits to long-term survival are
cardiac allograft vasculopathy (CAV) and malignancy15,16,24 (Fig. 38-7). Current understanding of the
pathogenesis of CAV is incomplete.59–61 Widely presumed to be a consequence of “chronic rejection,”
this process has an incidence of approximately 5% per year. CAV may cause progressive insufficiency of
coronary flow, myocardial infarction, and ultimately death. Recent research has drawn attention to the
934
booksmedicos.org
importance of donor stress associated with brain death and ischemia/reperfusion injury in the incidence
and severity of CAV in animal models.62 In contrast to the usual pattern of focal proximal lesions in
conventional atherosclerosis, coronary arteries are diffusely involved and conventional revascularization
techniques are not generally feasible. This process has proven stubbornly refractory to
immunosuppressive or antiproliferative interventions.55,63 Both CAV and increased risk of malignancy
would likely be prevented if durable tolerance were successfully induced, but this objectives has thus far
proven elusive for the heart as for other organs.64
RESULTS
7 Due to a decline in the number of donor hearts that are considered acceptable, the number of heart
transplants performed worldwide has declined, from a peak of about 4,070 in 1995 to fewer than 3,200
reported in each year since 2000, a 20% decrease. While some decrease in reporting from European
centers may have resulted from the absence of an incentive to contribute to international registries,
reported U.S. activity – which is federally mandated by organ allocation regulations – decreased by
about 15% between 1997 and 2004 despite a steady increase in average donor age.15,24 A slight upward
trend in U.S. heart transplant activity during the past decade (from 2,000 to 2,200 cases annually
between 2004 and 2014) may reflect the influence of a Health Resources and Services Administration
organ donor initiative,15,65,66 and implementation in 2006 of a donor allocation algorithm that
emphasizes recipient disease acuity over proximity to the donor hospital or other factors.
8 Operative survival in adults has improved over the past 20 years to above 90%, and both patient
and graft 1- and 5-year survival rates exceed 87% and 75%, respectively (Fig. 38-8).15,16 The most
important risk factors for death within the first year include previous transplant, increased donor age
(with age older than 60 conferring greater risk than age older than 45), need for ventilator or left VAD
support before transplant, and recipient age older than 60. Among common complications, rejection and
infection together account for most of the mortality during the first year and contribute approximately
equally (Table 38-5). Beyond the first year, malignancy including posttransplant lymphoproliferative
disease and chronic rejection emerge as prominent additional factors limiting long-term survival.
Extrapolating from current early results, more than 50% of recent recipients can expect to be alive 10
years after transplant, with actuarial graft half-life over 12 years.15,16,24,29
Repeat heart transplantation accounts for less than 2% of all heart transplants done. When performed
within the first 6 months, typically for early failure of the first graft, 1-year survival is less than 50%.
When performed later, usually for cardiac allograft vasculopathy, 1-year survival is over 80%, and has
improved significantly over the past decade. Overall, actuarial graft half-life following retransplant is
about 4.6 years, and is over 9 years in those who survive the first year.16 While these outcomes are
significantly inferior to other transplant indications, retransplantation offers significant survival
advantage for carefully selected patients.
Figure 38-7. Autopsy specimen of an epicardial coronary artery demonstrating a moderately severe concentric fibroproliferative
intimal lesion characteristic of cardiac allograft vasculopathy. (Courtesy of Dr. James Atkinson, Vanderbilt University School of
Medicine, Nashville, TN.)
935
booksmedicos.org
Figure 38-8. Heart Transplant Survival, 1980–2015. Survival following heart transplantation in recipients, grouped by era of
operation, analyzed by the Kaplan–Meier method. Operative survival accounts for much of the steady improvement in outcomes
over the past two decades. The subsequent rate of attrition appears to have changed little over the past 35 years, likely reflecting
the effect of competing influences such as an older, sicker recipient population and improving patient management strategies.
(Figure created from data provided by the United Network for Organ Sharing and International Society for Heart and Lung
Transplantation, including follow-up information available as of April 2015.) Current demographics and statistics may be found at
International Society for Heart and Lung Transplantation website (www.ishlt.org).
Table 38-5 Complications Following Heart Transplantation
Adolescent (11 to 17 year olds) pediatric heart transplantation recipients fare better (>80% 1-year
survival) than do younger children (1 to 10 year olds: ∼77%) or infants (younger than 1 year old:
∼68%). Less favorable short-term outcomes may be ascribed to pulmonary hypertension and anatomic
challenges posed by congenital heart disease, and to monitoring and compliance challenges
characteristic of these age groups. Nonetheless, the graft half-life for pediatric patients (11.4 to 13
years) is similar to that for adults.15,16,24,29
ETHICS
936
booksmedicos.org
Ethical considerations are important to every aspect of heart transplantation. The donor pool is limited
and appears to be shrinking despite extended donor acceptance criteria, restricting the number of
patients who can undergo transplantation. This shortage forces consideration of ways to limit recipient
candidacy (age limits), to increase the donor pool (presumed consent, advertising initiatives,
community outreach), and to develop alternatives (mechanical devices, xenografts, bioengineered
hearts).26,33,67–70
The heart transplant community has taken the lead in standardizing patient selection and management
guidelines and has established policies for equitable organ allocation. Those given an opportunity to
receive the “gift of life” are chosen from a much larger population who might benefit. Recipient
candidacy decisions are made by a multidisciplinary group based on objective and subjective input from
many individuals who come to know the patient and family in depth. Some recipient selection criteria
are fundamentally arbitrary: for example, age is retained as a criterion because of the limited supply of
donor organs and based on the consensus view that younger patients deserve preferred access. Recipient
selection criteria only become unfair if they are applied unequally or inconsistently at different
programs or between various regions of the country.
Some of the most difficult decisions made by the heart transplant team involve medically marginal
candidates with outstanding and effective social support or medically suitable candidates with marginal
social support. While the majority of such patients will do well, outcomes in either case can, on
average, be expected to fall below outcome benchmarks. For every marginal patient transplanted, a
candidate who meets all the criteria may die. Thus, the “right” decision for an individual patient is
difficult or impossible to know in advance and may conflict with the best interests of the population of
potential recipients.
CURRENT ISSUES
Quantifiable, objective measures of efficacy beyond survival, such as improvement in exercise capacity,
freedom from complications, and reduced costs are becoming the standards by which individual heart
transplantation programs are judged. Most important to the patient are subjective factors such as
quality of life and productivity, for which standardized measurement tools are being developed.
Meanwhile, the efficacy of any proposed alternative to transplantation must be measured against
survival, cost, and quality-of-life benchmarks established by this once-experimental procedure.71,72
The most important factor currently restricting the application of heart transplantation is the limited
supply of donor organs. Consent is obtained from the donor’s legal representatives in only about 25% to
50% of cases where hearts are appropriate based on acceptable physiologic parameters. Various
proactive approaches, such as institution of presumed consent, have been associated with high per
capita donation rates in some countries. However, presumed consent is ethically dubious and may
violate basic cultural or religious precepts of individuals or ethnic groups. An adverse societal response
to imposition of this unpopular approach as national policy might paradoxically cripple efforts to
maintain organ donation even at current levels. Well-conceived efforts to increase the rate of consent,
by passing laws requiring hospitals to facilitate and document the request, by allowing trained
individuals to manage the request process, and by educating the public about “the gift of life,” have
boosted per capita donation in several U.S. organ procurement regions.
9 Efforts to develop improved immunosuppressive drugs are important and are likely to yield
incremental near-term improvements in the incidence of chronic rejection. Ideally, one could induce
tolerance – permanent graft acceptance without requirement for indefinite immunosuppressive therapy.
Modulation, rather than suppression, of host responses to donor antigens may allow achievement of this
goal.73,74
Even if every physiologically suitable donor heart were available, only a minority of patients for
whom transplantation would offer a survival advantage could be cared for using this modality. As
technical innovations and management strategies evolve to address issues related to transcutaneous
power delivery, thromboembolism, infection risk, and reliability, definitive “destination” therapy with
VADs has become a viable option for some patients.33 Progress has also been made toward use of
porcine “xenografts” in man. The initial immunologic barrier, hyperacute rejection, appears
surmountable using organs from pigs genetically modified to express human complement regulatory
proteins and “knocked out” for the gene encoding Galα1,3Gal, the main carbohydrate target recognized
by human antipig antibodies.26,69,75–79 Control of subsequent antipig antibody responses and coagulation
937
booksmedicos.org
pathway dysregulation phenomena has been achieved in animal models, with recent survival of
multitransgenic heart grafts beyond 2 years using an “experimental” but clinically applicable
immunosuppressive regimen.26 Meanwhile, fully life-supporting function of renal xenografts (for 3
months) and heart xenografts (for 1 month) have been demonstrated in primates using an intensive
regimen of “conventional” immunosuppressive agents.78,79
Heart transplantation is one of the most resource-intensive modalities in modern medicine when
assessed as cost per year of life saved. The procedure itself, the increasingly common in-hospital and/or
VAD bridge care before transplantation, and maintenance of program infrastructure are very expensive.
Ongoing pharmacy charges and surveillance procedure costs are also substantial. Paradoxically, patients
physically able to return to work often cannot do so because they rely on medical disability benefits to
pay for medications and follow-up care. Whether heart transplantation will continue to receive wide
support is a function of societal acceptance of these costs, as currently reflected by coverage policies
established by public and private health care insurers.71 In the future the application of heart
transplantation and related technologies may be limited more by what society chooses to afford, rather
than what is medically possible.
References
1. Carrel A, Guthrie CC. The transplantation of veins and organs. Am Med (Philadelphia) 1905;10:1101.
2. Carrel A. The surgery of blood vessels. Bull Johns Hopkins Hosp 1907;18:18.
3. Neptune WB, Cookson BA, Bailey CP, et al. Complete homologous heart transplantation. Arch Surg
1953;66:174–178.
4. Webb WR, Howard HS, Neely WA. Practical methods of homologous cardiac transplantation. J
Thorac Surg 1959;37:361–366.
5. Goldberg M, Berman EF, Akman LC. Homologous transplantation of the canine heart. J Int Coll Surg
1958;30:575–586.
6. Cass MH, Brock R. Heart excision and replacement. Guys Hosp Rep 1959;108:285–290.
7. Demikhov VP. Experimental Transplantation of Vital Organs [in Russian]. Haigh B, trans-ed. New
York, NY: Consultant’s Bureau; 1962.
8. Lower RR, Stofer RC, Shumway NE. Homovital transplantation of the heart. J Thorac Cardiovasc
Surg 1961;41:196–204.
9. Hardy JD, Chavez CM, Kurrus FE, et al. Heart transplantation in man: developmental studies and
report of a case. JAMA 1964;188:1132–1140.
10. Barnard CN. The operation. A human cardiac transplant: an interim report of a successful operation
performed at Groote Schuur Hospital, Cape Town. S Afr Med J 1967;41:1271–1274.
11. Caves PK, Stinson EB, Braham AF, et al. Percutaneous transvenous endomyocardial biopsy. JAMA
1973;225:288–291.
12. Kaye MP, Elcombe SA, O’Fallon WM. The international heart transplantation registry. The 1984
report. J Heart Transplant 1985;4(3):290–292.
13. Calne RY, White DJ, Rolles K, et al. Prolonged survival of pig orthotopic heart grafts treated with
cyclosporin A. Lancet 1978;1:1183–1185.
14. Reitz BA, Bieber CP, Raney AA, et al. Orthotopic heart and combined heart and lung transplantation
with cyclosporin-A immune suppression. Transplant Proc 1981;13:393–396.
15. Colvin-Adams M, Smith JM, Heubner BM, et al. OPTN/SRTR 2013 Annual Data Report: heart. Am J
Transplant 2015;15(Suppl 2):1–28.
16. Lund LH, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for Heart
and Lung Transplantation: thirty-first official adult heart transplant report—2014; focus theme:
retransplantation. J Heart Lung Transplant 2014;33(10):996–1008.
17. O’Connell JB, Gunnar RM, Evans RW, et al. Task force 1: organization of heart transplantation in
the US. J Am Coll Cardiol 1993;22:8–14.
18. Chomsky DB, Lang CC, Rayos GH, et al. Hemodynamic exercise testing. A valuable tool in the
selection of cardiac transplantation candidates. Circulation 1996;94(12):3176–3183.
19. Mehra MR, Kobashigawa J, Starling R, et al. Listing criteria for heart transplantation: International
Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates
938
booksmedicos.org
—2006. J Heart Lung Transplant 2006;25(9):1024–1042.
20. Kinkhabwala MP, Mancini D. Patient selection for cardiac transplant in 2012. Expert Rev Cardiovasc
Ther 2013;11(2):179–191.
21. Jeevanandam V, Furukawa S, Prendergast TW, et al. Standard criteria for an acceptable donor heart
are restricting heart transplantation. Ann Thorac Surg 1996;62(5):1268–1275.
22. Drinkwater DC, Laks H, Blitz A, et al. Outcomes of patients undergoing transplantation with older
donor hearts. J Heart Lung Transplant 1996;15(7):684–691.
23. Tenderich G, Koerner MM, Stuettgen B, et al. Extended donor criteria: hemodynamic follow-up of
heart transplant recipients receiving a cardiac allograft from donors > or = 60 years of age.
24. Pierson RN III, Barr ML, McCullough KP, et al. SRTR report on the state of transplantation: thoracic
organ transplantation. Am J Transplant 2004;4(suppl 9):93–105.
25. Dhital KK, Iyer A, Connellan M, et al. Adult heart transplantation with distant procurement and ex-
vivo preservation of donor hearts after circulatory death: a case series. Lancet
2015;385(9987):2585–2591.
26. Mohiuddin MM, Singh AK, Corcoran PC, et al. Genetically engineered pigs and target-specific
immunomodulation provide significant graft survival and hope for clinical cardiac
xenotransplantation. J Thorac Cardiovasc Surg 2014;148(3):1106–1113; discussion 1113–1114.
27. Novitsky D, Cooper DK, Reichart B. Hemodynamic and metabolic responses to hormonal therapy in
brain-dead potential organ donors. Transplantation 1987;43:852–854.
28. Novitzky D, Mi Z, Sun Q, et al. Thyroid hormone therapy in the management of 63,593 brain-dead
organ donors: a retrospective analysis. Transplantation 2014;98(10):1119–1127.
29. Opelz G. Results of cardiac transplantation and factors influencing survival based on the
collaborative heart transplant study. In: Cooper DK, Miller LW, Patterson GA, eds. The
Transplantation and Replacement of Thoracic Organs. 2nd ed. Hingham, MA: Kluwer Academic Press;
1996:417–427.
30. Copeland JG, Smith RG, Arabia FA, et al. CardioWest Total Artificial Heart Investigators. Cardiac
Replacement with a total artificial heart as a bridge to transplantation. N Engl J Med
2004;351(9):859–867.
31. Cohn WE, Timms DL, Frazier OH. Total artificial hearts: past, present, and future. Nat Rev Cardiol
2015;12(10):609–617.
32. John R, Kamdar F, Liao K, et al. Improved survival and decreasing incidence of adverse events with
the HeartMate II left ventricular assist device as bridge-to-transplant therapy. Ann Thorac Surg
2008;86(4):1227–1234.
33. Jorde UP, Kushwaha SS, Tatooles AJ, et al. Results of the destination therapy post-food and drug
administration approval study with a continuous flow left ventricular assist device: a prospective
study using the INTERMACS registry (Interagency Registry for Mechanically Assisted Circulatory
Support). J Am Coll Cardiol 2014;63(17):1751–1757.
34. Vega JD, Ochsner JL, Jeevanandam V, et al. A multicenter, randomized controlled trial of Celsior
for flush and hypothermic storage of cardiac allografts. Ann Thorac Surg 2001;71(5):1442–1447.
35. Jeevanandam V, Barr ML, Auteri JS, et al. University of Wisconsin solution versus crystalloid
cardioplegia for human donor heart preservation. A randomized blinded prospective clinical trial. J
36. Ardehali A, Esmailian F, Deng M, et al. Ex-vivo perfusion of donor hearts for human heart
transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority
trial. Lancet. 2015;385(9987):2577–2584.
37. el Gamel A, Yonan NA, Grant S, et al. Orthotopic cardiac transplantation: a comparison of standard
and bicaval Wythenshawe techniques. J Thorac Cardiovasc Surg 1995;109(4):721–729.
38. Aziz T, Burgess M, Khafagy R, et al. Bicaval and standard techniques in orthotopic heart
transplantation: medium-term experience in cardiac performance and survival. J Thorac Cardiovasc
Surg 1999;118(1):115–122.
39. Trento A, Takkenberg JM, Czer LS, et al. Clinical experience with one hundred consecutive patients
undergoing orthotopic heart transplantation with bicaval and pulmonary venous anastomoses. J
939
booksmedicos.org
40. Jeevanandam V, Russell H, Mather P, et al. Donor tricuspid annuloplasty during orthotopic heart
transplantation: long-term results of a prospective controlled study. Thorac Surg 2006;82(6):2089–
2095
41. Cooper DK, Taniguchi S. Heterotopic heart transplantation—indications, surgical techniques and
special considerations. In: Cooper DK, Miller LW, Patterson GA, eds. Transplantation and
Replacement of Thoracic Organs. 2nd ed.Hingham, MA: Kluwer Academic Press; 1996:353–365.
42. Tagusari O, Kormos RL, Kawai A, et al. Native heart complications after heterotopic heart
transplantation: insight into the potential risk of left ventricular assist device. J Heart Lung
Transplant 1999;18(11):1111–1119.
43. Maxey TS, Smith CD, Kern JA, et al. Beneficial effects of inhaled nitric oxide in adult cardiac
surgical patients. Ann Thorac Surg 2002;73(2):529–532.
44. Khan TA, Schnickel G, Ross D, et al. A prospective, randomized, crossover pilot study of inhaled
nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients. J Thorac
Cardiovasc Surg 2009; 138(6):1417–1424.
45. Marboe CC, Billingham M, Eisen HJ, et al. Refining pathological classification of acute rejection in
cardiac allograft recipients: a multicenter study using peripheral blood gene expression profiling. J
Heart Lung Transplant 2004; 23(2S):S42.
46. Kobashigawa JA, Kiyosaki KK, Patel JK, et al. Benefit of immune monitoring in heart transplant
patients using ATP production in activated lymphocytes. J Heart Lung Transplant 2010;29(5):504–
508.
47. Deng MC, Elashoff B, Pham MX, et al. IMAGE Study Group. Utility of gene expression profiling
score variability to predict clinical events in heart transplant recipients. Transplantation
2014;97(6):708–714.
48. Knosalla C, Grauhan O, Muller J, et al. Intramyocardial electrogram recordings (IMEG) for
diagnosis of cellular and humoral mediated cardiac allograft rejection. Ann Thorac Cardiovasc Surg
2000;6(2):89–94.
49. Starnes VA, Oyer PE, Stinson EB, et al. Prophylactic OKT3 used as induction therapy for heart
transplantation. Circulation 1989;80(5 Pt 2):III79–III83.
50. Gelder T, Baan CC, Balk AH, et al. Blockade of the interleukin (IL)-2/IL-2 receptor pathway with a
monoclonal anti-IL-2 receptor antibody (BT563) does not prevent the development of acute heart
allograft rejection in humans. Transplantation 1998;65(3):405–410.
51. Carey JA, Frist WH. Use of polyclonal antilymphocytic preparations for prophylaxis in heart
transplantation. J Heart Transplant 1990;9(3 Pt 2):297–300.
52. Aliabadi A, Grömmer M, Cochrane A, et al. Induction therapy in heart transplantation: where are
we now? Transpl Int 2013;26(7):684–695.
53. Penninga L, M⊘ller CH, Gustafsson F, et al. Immunosuppressive T-cell antibody induction for heart
transplant recipients. Cochrane Database Syst Rev 2013;12:CD008842.
54. Mazimba S, Tallaj JA, George JF, et al. Infection and rejection risk after cardiac transplantation
with induction vs. no induction: a multi-institutional study. Clin Transplant 2014;28(9):946–952.
55. Eisen HJ, Kobashigawa J, Starling RC, et al. Everolimus versus mycophenolate mofetil in heart
transplantation: a randomized, multicenter trial. Am J Transplant 2013;13(5):1203–1216.
56. Kobashigawa JA, Leaf DA, Lee N, et al. A controlled trial of exercise rehabilitation after heart
transplantation. N Engl J Med 1999;340(4):272–277.
57. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the
standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant
2005;24(11):1710–1720.
58. Berry GJ, Burke MM, Andersen C, et al. The 2013 International Society for Heart and Lung
Transplantation Working Formulation for the standardization of nomenclature in the pathologic
diagnosis of antibody-mediated rejection in heart transplantation. J Heart Lung Transplant 2013;
32(12):1147–1162.
59. Pierson RN III, Miller GM. Late graft failure: lessons from clinical and experimental thoracic organ
transplantation. Graft 2000;3(2):88–93.
60. Caforio AL, Tona F, Fortina AB, et al. Immune and nonimmune predictors of cardiac allograft
vasculopathy onset and severity: multivariate risk factor analysis and role of immunosuppression.
940
booksmedicos.org
Am J Transplant 2004;4(6):962–970.
61. Valantine H. Cardiac allograft vasculopathy after heart transplantation: risk factors and
management. J Heart Lung Transplant 2004;23(5S):S187–S193.
62. Schmid C, Heemann U, Tilney NL. Factors contributing to the development of chronic rejection in
heterotopic rat heart transplantation. Transplantation 1997;64(2):222–228.
63. Kaufman DB, Shapiro R, Lucey MR, et al. Immunosuppression: practice and trends. Am J Transplant
2004;4(suppl 9):38–53.
64. Pierson RN 3rd. Tolerance after heart transplantation: the Holy Grail, or an attainable goal? Heart
Fail Clin 2007;3(1):17–29.
65. Marks WH, Wagner D, Pearson TC, et al. Organ donation and utilization, 1995–2004: entering the
collaborative era. Am J Transplant 2006;6(5):1101–1110.
66. Shafer TJ, Wagner D, Chessare J, et al. US organ donation breakthrough collaborative increases
organ donation. Crit Care Nurse Q 2008;31(3):190–210.
67. Rose EA, Gelijns AC, Moskowitz AJ, et al. Long-term mechanical left ventricular assistance for end-
stage heart failure. N Engl J Med 2001;345(20):1435–1443.
68. Cooper DK, Keogh AM, Brink J, et al. Report of the Xenotransplantation Advisory Committee of the
International Society for Heart and Lung Transplantation: the present status of xenotransplantation
and its potential role in the treatment of end-stage cardiac and pulmonary diseases. J Heart Lung
Transplant 2000;19:1125–1165.
69. Pierson RN 3rd, Dorling A, Ayares D, et al. Current status of xenotransplantation and prospects for
clinical application. Xenotransplantation 2009; 16(5):263–280.
70. Tapias LF, Ott HC. Decellularized scaffolds as a platform for bioengineered organs. Curr Opin Organ
Transplant 2014;19(2):145–152.
71. Evans RW. Socioeconomic aspects of heart transplantation. Curr Opin Cardiol 1995;10(2):169–179.
72. Evans RW. The economics of big game hunting: using a rifle to get a clear shot at transplantation.
73. Weaver TA, Charafeddine AH, Kirk AD. Costimulation blockade: towards clinical application. Front
Biosci 2008;13:2120–2139.
74. Ferrer IR, Hester J, Bushell A, et al. Induction of transplantation tolerance through regulatory cells:
from mice to men. Immunol Rev 2014;258(1):102–116.
75. Cozzi E, White DJ. The generation of transgenic pigs as potential organ donors for humans. Nat
Med 1995;1(9):964–966.
76. McGregor CG, Davies WR, Oi K, et al. Cardiac xenotransplantation: recent preclinical progress with
3-month median survival. J Thorac Cardiovasc Surg 2005;130(3):844–851.
77. Kuwaki K, Tseng YL, Dor FJ, et al. Transplantation of hearts from α1,3-galactosyl-transferase gene-
knockout (GalT-KO) pigs into baboons. Nat Med 2005;11:29–31.
78. Zaidi A, Schmoeckel M, Bhatti F, et al. Life-supporting pig-to-primate renal xenotransplantation
using genetically modified donors. Transplantation 1998;65(12):1584–1590.
79. Schmoeckel M, Bhatti FN, Zaidi A, et al. Orthotopic heart transplantation in a transgenic pig-to-
primate model. Transplantation 1998;65(12):1570–1577.
941
booksmedicos.org
Chapter 39
Pulmonary Transplantation
Jules Lin and Andrew C. Chang
Key Points
1 Candidates for lung transplantation have significant functional impairment that interferes with their
activities of daily living. In patients with restrictive or obstructive pulmonary disease, gas exchange
is impaired requiring supplemental oxygen while in pulmonary vascular disease, manifestations of
right ventricular failure predominate.
2 Initiation of the Lung Allocation Score (LAS) has decreased waitlist times and waitlist mortality
while posttransplant survival has continued to improve. With an increased emphasis on waitlist
survival and transplant benefit, there has been a shift in the primary diagnosis from emphysema to
pulmonary fibrosis.
3 Patients being listed for transplant are sicker than in the past with an increasing percentage of
patients with an LAS score >50, and with acute inpatient evaluations becoming more common, it is
critical to avoid deconditioning by using aggressive physical therapy, early tracheostomy, and
ambulatory extracorporeal membrane oxygenation (ECMO) when necessary.
4 Advances in donor management and lung preservation have increased the number and quality of
donor lungs and is likely responsible for the increase in the number of lung transplants performed
over the last 10 years. Ex vivo perfusion of marginal donor lungs and the use of DCD lungs
(donation after cardiac death [DCD]) may allow further increases in the percentage of recoverable
lungs.
5 Posttransplant lung injury results from the ischemic insult and subsequent reperfusion of the donor
lung as well as the host immunologic response and other mediators of non–alloimmune-related
injury.
6 By the end of the first year after transplantation, approximately 80% of recipients report no
limitations in activity.
7 Long-term survival after lung transplant is lower when compared to outcomes after transplantation
of other solid organs. The lack of effective medical therapy for chronic rejection remains a
significant barrier and is the focus of ongoing research.
8 Reflux in lung transplant patients has been associated with aspiration, impaired lung function, and
decreased survival. Antireflux surgery decreases immune factors associated with bronchiolitis
obliterans syndrome (BOS), preserves overall pulmonary function, and can be safely performed in
lung transplant patients.
INTRODUCTION
The first lung transplant was performed by James Hardy in 1963 at the University of Mississippi in a
patient with lung cancer who died 18 days later from renal failure.1 Over 40 lung transplants were
performed in the next 20 years with no long-term survivors. With time, pulmonary vascular and
bronchial anastomotic techniques were refined including the telescoping bronchial anastomosis and
wrapping the anastomosis with omentum to provide neovascularization. Steroids were found to inhibit
bronchial healing,2 and with the availability of cyclosporine and its decreased toxicity,3 the first
successful lung transplant was performed in 1983 by Joel Cooper at the University of Toronto. The
number of lung transplants continues to increase with approximately 3,640 lung transplants performed
worldwide in 2011.4 Pulmonary transplantation comprises 4% of the organs transplanted in the United
States.
Over the past 30 years, outcomes have improved dramatically, but even with advances in
immunosuppression, surgical technique, and perioperative and posttransplant care, long-term survival
942
booksmedicos.org
following pulmonary transplantation remains less than that of other solid organ transplants. The major
factors limiting long-term survival include donor availability, recipients with more advanced disease,
infection, acute rejection, impaired anastomotic healing,5 and chronic rejection with bronchiolitis
obliterans.6 Survival continues to increase, and the median survival in 2013 was up to 5.6 years from
5.3 years in 2010.4,7
The lung has a dual blood supply as a result of distinct bronchial and pulmonary arterial circulation.
Bronchial artery reanastomosis has been proposed as a way to decrease ischemia to the anastomosis, but
since bronchial artery anatomy and caliber vary greatly, most transplant surgeons have not advocated
reanastomosis in order to limit prolonged ischemia times. Bronchial anastomotic healing is dependent
on retrograde perfusion from collaterals from the pulmonary arterial circulation. Consequently, the
bronchial anastomosis is more profoundly ischemic after transplantation and susceptible to airway
dehiscence, typically within 3 weeks after transplantation. The combination of anastomotic ischemia
and other factors such as infection and postreperfusion edema hindered initial efforts to develop
successful clinical programs in pulmonary transplantation.
The first combined heart and lung transplantation was performed successfully in 1981, but this
procedure is currently rarely performed, with only 23 performed in the United States in 2013.
Combining cardiac and pulmonary transplantation introduced new issues including those associated with
heart transplantation, especially accelerated coronary artery atherosclerosis. Impaired tracheal
anastomotic healing is less common, possibly because the bronchial artery collaterals in the subcarinal
space are preserved. The discrepancy between available donor organs and the increasing number of
patients on the waiting list for heart or lung transplantation as well as lower short- and intermediate-
term survival among heart–lung transplant recipients compared to heart or lung transplant alone are
factors which have decreased the performance of heart–lung transplantation.
Investigators have defined factors contributing to failure in pulmonary transplantation.8 These factors
include a significant detrimental effect of corticosteroids on airway healing. Investigators have also
shown that cyclosporine did not have this adverse effect and that delaying the administration of
maintenance corticosteroids was advantageous. Wrapping the bronchial anastomosis with a pedicle of
omentum was initially thought to encourage capillary growth and promote airway healing, although
this has not correlated with a reduction in anastomotic dehiscence.9
Another factor contributing to the improved success of lung transplantation was recognition of the
importance of careful recipient selection. Most early attempts at pulmonary transplantation involved
critically ill, ventilator-dependent patients who had already suffered significant physical debilitation.
Poor short-term outcomes highlighted the importance of assessing preoperative functional status and
implementing intense pulmonary rehabilitation pretransplant. Thorough patient evaluation and
preparation, in addition to advances in operative techniques and immunosuppression, have improved
outcomes and broadened the indications for pulmonary transplantation.
As lung transplantation became more widely accepted in the treatment of end-stage lung diseases, the
worsening discrepancy between donor organ availability and patients listed for transplantation resulted
in increasing waitlist mortality. Initial lung allocation policies were based on ABO blood type
compatibility, geographic proximity to the donor hospital, and the accumulated waiting time since
listing. In 1998, the Final Rule was issued by the U.S. Department of Health and Human Services
requiring increased organ sharing with development of an organ allocation system that would be more
equitable and that would reduce the use of waitlist time as a criterion for allocation.10 In 2005, the Lung
Allocation Score (LAS) was implemented, incorporating waiting list and posttransplant survival
probabilities, in order to minimize waiting list mortality, increase the benefit of transplantation among
recipients, and ensure equitable allocation of lungs to lung transplantation candidates. Since
implementation of the LAS, there has been a dramatic reduction in the duration of median waiting list
time prior to transplantation, from 792 days in 2004 to 199 and 132 days in 2005 and 2006,
respectively.11 Waiting list mortality also declined from 134.6 per 1,000 patient-years in 2004 to 114.9
per 1,000 patient-years and 97.2 per 1,000 patient-years in 2005 and 2006, respectively.
INDICATIONS
1 Transplantation is indicated for patients with isolated organ dysfunction who have limited life
expectancy despite maximal medical therapy (Table 39-1). A patient should be referred for lung
transplantation when expected survival after transplant exceeds the expected survival without
transplantation. Improvements in patient selection, operative techniques, organ preservation,
943
booksmedicos.org
immunosuppression, and posttransplant management have led to better survival after transplantation.
The overall median survival after transplantation is approximately 5 years, and the timing of transplant
is an important consideration for maximizing transplant benefit. Prior to May 2005, allocation of donor
lungs was based on time on the waiting list. With the large discrepancy between the number of listed
transplant candidates and the limited availability of donor lungs, referral for transplant often occurred
well before patients had become severely debilitated from poor respiratory function. With the
institution of the LAS, the severity of disease has become a more important factor than waitlist times
alone.
Lung transplantation can also provide considerable palliation for dyspnea. Due to the limited
availability of donors, quality-of-life improvement has been considered secondary to survival benefit,
although improved outcomes in terms of oxygen dependence, physical activity, and return to work
remain important in assessing the success of pulmonary transplantation.
CONTRAINDICATIONS
Table 39-2 lists absolute and relative contraindications to lung transplant. The absolute
contraindications are consistent with the risks associated with immunosuppression and the physical and
social challenges of maintaining a complex medical regimen after transplantation. With respect to body
mass index (BMI), extremes in weight have been associated with lower short-term survival in heart
transplant patients.12 These findings have been reinforced by studies of lung transplantation where
extremes in BMI have been shown to confer a three- to fivefold increase in 90-day mortality.13,14
Overall survival for patients over the age of 65 is significantly lower than for younger cohorts.15,16 A
consensus report in 2006 recommended that age >65 be a relative contraindication17 due to lower
survival with a median survival of 3.6 years and a 5-year survival of 38%. Many centers will limit
listing recipients to those who are 65 years of age or younger. Despite this, the number of transplants in
older patients has continued to increase, and single-institution studies have demonstrated similar 1- and
3-year survival in highly selected older patients.18–20 Since the implementation of the LAS, recipients
age 65 or older have increased most rapidly from 2.9% in 1998 to 19% in 2008 and 25.9% in
2012.4,21–23
Postoperative recovery after lung transplant can be particularly challenging. Incisional pain, impaired
ventilatory mechanics, malnutrition, and deconditioning directly impact lung function as with any
pulmonary operation. In the early days of lung transplantation, it became apparent that posttransplant
survival was poor for ventilator-dependent patients or those with immunosuppression-related
myopathy. Preoperative pulmonary rehabilitation and improved selection of ambulatory patients led to
a significant improvement in survival in the 1990s. With improvements in critical care, pulmonary
transplantation may still be appropriate in highly selected ventilator-dependent patients as
demonstrated in small single-center series including patients who have had rapid deterioration in lung
function and who have had only brief periods of debilitation. Adjuncts to mechanical ventilatory
support, particularly tracheostomy or venovenous extracorporeal membrane oxygenation (ECMO),24
may allow patients to continue efforts to maintain preoperative conditioning. While patients with end-
stage extrapulmonary organ dysfunction are generally not candidates for lung transplant, limited
experience has demonstrated acceptable survival in patients with coronary artery disease amenable to
coronary artery bypass grafting or percutaneous coronary intervention.25
Table 39-1 Pulmonary Disease Diagnosis Groups
Table 39-2 Contraindications to Lung Transplantation
944
booksmedicos.org
Disease-Specific Indications
Disease-specific indications for lung transplantation are listed in Table 39-3.
Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) was the most common indication for lung
transplantation prior to the institution of the LAS score, accounting for 35.4% of transplants from 1990
to 2004 and decreasing to 30.9% after 2005.15 Advances in medical therapy for patients with
emphysema that can prolong survival include smoking cessation, long-acting bronchodilators, oxygen
supplementation, optimization of nutrition, pulmonary rehabilitation, and vaccination for pneumonia
and influenza. In addition, lung volume reduction surgery confers a survival benefit in patients with
upper lobe–predominant disease, impaired exercise capacity, and the absence of high-risk factors
including forced expiratory volume in 1 second (FEV1) less than 20% or carbon monoxide diffusing
capacity (DLCO) less than 20%.26 Patients who deteriorate despite maximal therapy and who are not
candidates for lung volume reduction should be referred for transplantation.
Factors associated with poor survival in patients with COPD include respiratory exacerbation with
hypercapnia, hypoxia, pulmonary hypertension, increasing age, decreasing FEV1, decreasing DLCO, and
increased BMI.27 A prospectively validated index based on body mass, airflow obstruction, degree of
dyspnea, and exercise tolerance (BODE) has been proposed as a robust predictor of mortality in patients
with COPD. A BODE index of greater than 7 on a scale from 0 to 10 was associated with a median
survival of 3 years.28
Idiopathic Pulmonary Fibrosis

Usual interstitial pneumonia (UIP) is the pathologic correlate of idiopathic pulmonary fibrosis (IPF) and
is the most common subtype of interstitial lung disease. While IPF accounted for 28% of single lung
transplants and 14% of bilateral lung transplants from 1995 to 2007, pulmonary fibrosis has become the
most common indication for lung transplantation after the initiation of the LAS with 32% of all lung
transplants performed for IPF in 2006 and 36.5% in 2013.16,29
Table 39-3 Disease-specific Considerations for Lung Transplantation
945
booksmedicos.org
Although the options for effective medical therapy for IPF are limited and patient mortality is high
with a median survival of 3 to 4 years following diagnosis, patients experience a variable clinical
course, with some patients progressing rapidly and others with a more gradual decline. Risk factors for
poor survival include a pathologic diagnosis of UIP as opposed to other types of interstitial lung disease,
severe fibrosis by high-resolution CT scan, the presence and severity of pulmonary hypertension, and
acute pulmonary exacerbations.
Assessment of pulmonary function and exercise capacity can also be used to identify patients at higher
risk for mortality. A baseline DLCO of less than 39% and a greater than 10% decrease in DLCO or
forced vital capacity (FVC) over a 6- to 12-month period are associated with an increased risk of
death.30,31 Oxygen desaturation and a shorter 6-minute walk distance independently predicted increased
mortality in patients with pulmonary fibrosis.32
Lung transplant improves survival and quality of life in patients with end-stage interstitial lung
disease with a median survival of 4.5 years which may be affected by the increased age at diagnosis.33
Prior to the LAS, IPF patients had the highest waitlist mortality rate34,35 and decreased survival in the
early posttransplant period compared to other diagnoses.36 The development of pulmonary hypertension
significantly increases the risk of complications and decreases survival.37 LAS scores have increased
since 2005 for patients with IPF to 43.3 compared to 38.3 with no change in postoperative mortality
while waiting times have decreased from 266 days to 78 days.29
Cystic Fibrosis/Bronchiectasis/Infection-Related End-Stage Lung Disease

Cystic fibrosis (CF) is the third most common indication for lung transplantation, accounting for 16.3%
of lung transplants performed in the last 15 years with a median survival of 7.8 years, with most
recipients undergoing bilateral transplantation due to the risk of bacterial seeding of the transplanted
lung.16 Colonization of the airway with resistant organisms is common in these patients and is not an
absolute contraindication to transplantation, although sepsis is an absolute contraindication. Single-
institution studies have identified colonization with Burkholderia cepacia genomovar III (redesignated as
Burkholderia cenocepacia) to be associated with a 30% to 40% increase in posttransplant mortality,
although this finding has not been validated in a multi-institutional setting.
Among patients with pulmonary disease due to CF, the time course of respiratory deterioration is
highly variable making the criteria for pulmonary transplantation in this population difficult to define
by risk modeling. Deterioration of FEV1 to below 30% of predicted remains an indication for referral for
evaluation, although not necessarily for immediate listing.38,39 Other factors to consider include
946
booksmedicos.org
increasing oxygen requirements, hypercapnia, and pulmonary hypertension.40
Pulmonary Artery Hypertension

Idiopathic pulmonary artery hypertension (PAH) has a median survival of less than 3 years if untreated,
and the cause of death in most patients is progressive right-sided heart failure. Pulmonary hypertension
was a more common indication for transplantation in the past, and after the initiation of the LAS, the
percentage of transplant patients waitlisted has decreased from 14.7% in 2002 to 10.8% in 2007 and
6.4% in 2012.23 There has been some concern that the LAS may not adequately prioritize these patients.
Increasing use of medical vasodilator therapy including inhaled iloprost and oral sildenafil, prostacyclin
analogs, phosphodiesterase 5 inhibitors, endothelin receptor antagonists, and guanylate cyclase
stimulators have improved survival in this population and may also be responsible for the decrease in
transplants performed for PAH. Patients with a history of right heart failure or poor pretreatment
functional status and those with either no response or functional deterioration despite vasodilator
therapy should be referred for transplantation. Recent guidelines emphasize progressive deterioration of
right heart function despite maximal medical therapy as an indication for referral.40
Cardiac index is an independent predictor for improvement in survival in patients with PAH.7 Patients
with left ventricular heart failure requiring inotropic support may not be suitable candidates for
pulmonary transplantation alone but instead should be considered for heart–lung transplantation.
Patients with PAH made up 23% of heart-lung transplant recipients from 2000 to 2012.4
Lung Allocation and Transplant Benefit

Lung Allocation Score
The goal of the lung allocation system should be to maximize the net benefit for donated lungs. Before
1995, allocation was based solely on wait times, geography, and blood type. In 1995, an exemption was
created for an additional 90 days for idiopathic pulmonary fibrosis due to increased mortality for these
patients on the waitlist. However, this did not account for differences in mortality for other pulmonary
diseases. The allocation system preferentially selected patients with a longer survival, and the waitlist
times were greater than 2 years for the majority of listed patients. Due to the increasing number of
waitlist deaths, the Final Rule was instituted in 1998 and mandated that medical necessity be considered
in organ allocation.35,41
In compliance with the Final Rule, the LAS was developed and has been one of the most significant
changes in the practice of lung transplantation over the past 10 years. The LAS was implemented in
2005 and takes into account the urgency (1-year risk of dying on the waitlist without a transplant) and
utility (1-year survival posttransplant) giving a net transplant benefit. The normalized LAS ranges from
0 (lowest priority) to 100 (highest priority) for recipients older than 12. The waitlist mortality is given
a greater weight in the LAS score. Variables included in the LAS score are listed in Table 39-4.
Lung allocation currently depends on the LAS, blood type, recipient and donor size, geographic
location, and age, with donor lungs being offered first to local candidates who are ABO identical and
then to patients that are ABO compatible. The donor lungs are then offered to zones A–E, increasingly
further away from the donor center. Since the initiation of the LAS, PaCO2 values and bilirubin were
added in 2008 while FVC was removed for all groups except group D. The bilirubin has a high impact
on potential recipients with idiopathic pulmonary hypertension (group B).
Table 39-4 Selected Components of the Lung Allocation Score
947
booksmedicos.org
Transplant Benefit
Egan et al.10 analyzed over 4,000 patients on the lung transplant waiting list in order to identify
markers of waitlist mortality in the Scientific Registry of Transplant Recipients (SRTR).The listing
diagnoses for these patients, including COPD, IPF, CF, and PAH, accounted for 80% of the transplants
performed at the time. Transplant candidate demographics, hemodynamic parameters, measures of
pulmonary function, and other clinical variables were used to create a regression model. Substantial
differences in waitlist mortality were found, with patients listed for emphysematous diseases
experiencing a 1-year waitlist mortality of less than 14% compared with 1-year waitlist mortality
between 28% and 33% among patients listed with the other three primary diagnoses. These results were
confirmed in the International Society of Heart and Lung Transplantation (ISHLT) Registry data from
2005 showing that patients with IPF, PAH, and sarcoidosis had an increased relative risk for 1-year
waitlist mortality and a waitlist mortality of 9.7%, 13.1%, 17.8%, and 23.1% for group A, B, C, and D
diagnostic groups from 2001 to 2002.15 Before the LAS, patients with COPD were more likely to
undergo transplantation since they had a greater chance of surviving to transplant; however, after the
initiation of the LAS, incorporating waitlist urgency into lung allocation, IPF has now become the most
common indication for lung transplant.
2 The LAS has had a clear impact on waitlist outcomes in lung transplantation. The number of active
waitlist patients declined by 54% since early listing no longer conferred an advantage. Waiting time to
transplantation has decreased from 792 days in 2004 to 141 days in 2007. The median waitlist time in
2012 was 4 months with 65.3% of recipients transplanted within 1 year.23 Mortality rates on the
waiting list have decreased since implementation of the LAS but have started to increase recently to
15.4 per 100 waitlist years from 2010 to 2012, possibly due to an overall increase in the acuity and age
of patients on the waiting list.23 The median age of recipients has increased from 45 years in 1985 to 55
years after the institution of the LAS, with 27.2% of recipients older than 65 in 2012.4,22,23 According to
a recent report, 20.7% of patients on the waiting list were older than 65 in 2012 compared with 2.5% in
2002 (Fig. 39-1).23
An analysis of all transplant patients with COPD, IPF, and CF from 1992 to 1994 demonstrated a
survival benefit for patients with IPF and CF but not with COPD.42,43 A similarly powered analysis of
the European transplant experience demonstrated a survival benefit for all lung transplant groups.44
Other studies have also called into question the transplant benefit for children with CF listed between
1992 and 2002.45 Overall early survival (30-day and 1-year) has slowly improved since 1995, which has
continued through the implementation of the LAS in 2005 with improvements in operative and
postoperative care. A predictive model for posttransplant survival was also developed.10 When these
models were applied to evaluate survival in 2,484 patients with these four primary diagnoses, factors
including increasing recipient age, intensive care unit (ICU) admission, and the need for mechanical
ventilation were significant predictors of 1-year mortality.
Other risk factors for earlier posttransplant mortality included donor/recipient BMI, recipient
creatinine, bilirubin, and PA systolic pressure. Malnutrition increases morbidity and mortality after lung
transplant. An albumin less than 3 g/dL has been correlated with an increased mortality at 1 year46; 9%
to 25% of lung transplant patients are malnourished. Allen et al.47 found decreased survival in patients
who were either under- or overweight.
Results of studies evaluating posttransplant survival after initiation of the LAS are conflicting. Since
948
booksmedicos.org
the initiation of the LAS, sicker patients are being transplanted (Fig. 39-1), and an increasing LAS has
been associated with a lower 1-year survival. Transplanted patients with an LAS score less than 35 had a
1-year survival of 85.7%, whereas those with an LAS score greater than 60 had a 1-year survival of
71.3%.48 The median LAS continues to increase to 40.8 in 2011 with 6.3% of patients with LAS scores
greater than 50 compared with a median LAS of 36.6 in 2005 with less than 2% greater than 50.49 A
study in 2008 showed an increased incidence of primary graft dysfunction and increased ICU stays after
initiation of the LAS although the 1-year survival was similar.50 McCue et al.51 reported no difference in
posttransplant morbidity with a small statistically significant improvement in 1-year survival. One-year
survival improved from 70% in 1988 to 1994 to 87% from 2007 to 2012.22,23 Thabut et al.52 evaluated
the survival benefit of transplant patients with CF after initiation of the LAS and found that lung
transplant decreased the risk of death by 69%, and a higher LAS was associated with an increased
survival benefit.
Reevaluation and revision of the criteria that determine the LAS remains one of the objectives of the
Thoracic Organ Transplantation Committee of the OPTN. Data will continue to be analyzed through
large studies including REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial
Hypertension Disease Management) and the Lung Retrospective Data Collection Projects, and the LAS
will continue to evolve to maximize the net lung transplant benefit.53,54 The first comprehensive
revision of the LAS was approved in November 2012 by the OPTN Board of Directors but has yet to be
implemented. The revision includes changes to the variables included in the LAS such as cardiac index,
CVP, and serum creatinine and the weight given to each variable in the LAS calculation. These changes
will have the greatest effect on patients in diagnosis group B.53
Figure 39-1. Since the initiation of the Lung Allocation Score (LAS) in 2005, the percentage of waitlist patients older than 65 has
markedly increased. Patients are also sicker with an increasing percentage of patients with an LAS score >50. Meanwhile, COPD
(group A), with a lower waitlist mortality, has decreased as an indication for lung transplant while idiopathic pulmonary fibrosis
(group D) has grown to become the most common indication. (Adapted from the 2012 OPTN/SRTR Annual Report.)
Critically Ill Patients

Before the institution of the LAS, critically ill patients were at a disadvantage because the primary
criterion was time on the waiting list. Under the LAS, the risk of waitlist mortality carries a greater
weight than posttransplant survival.10 A study by Russo et al.49 evaluated associations between the LAS
and postoperative morbidity and mortality. They found that an LAS of greater than 75 was correlated
with a decreased 1-year survival and increased perioperative complications. There was no difference in
mortality at 1 and 3 years. With the LAS, there has been some concern that the increased impact of
predicted waitlist mortality will result in allocation of donor lungs to patients with a lower
posttransplant survival. Russo et al.49found that patients with an LAS score between 90 and 100 had a
survival rate of 1.56 years while those between 80 and 90 LAS had a survival of 2.28 years. A higher
LAS score was also associated with primary graft dysfunction (PGD) and decreased graft survival.22 The
rate at which the LAS changed over a patient’s course affected survival with changes greater than five
associated with a worse survival.55
Extracorporeal Membrane Oxygenation

The use of ECMO can be lifesaving in cases of severe PGD posttransplant. Some centers prefer
venoarterial ECMO in order to reduce blood flow to the donor lung thus limiting the degree of
pulmonary edema56 while others prefer venovenous ECMO due to the lower complication rate. ECMO is
now available in more than 200 centers.57,58 Using ECMO as a bridge to lung transplant has been
associated with poor outcomes in the past.59–61 However, outcomes have improved with developments
in oxygenator technology using polymethylpentene membranes to reduce plasma leakage, dual lumen
cannulas and smaller pumps and oxygenators allowing ambulatory ECMO, centrifugal pumps, and
949
booksmedicos.org
improvements in critical care.
In venovenous ECMO blood is drawn from the central venous system, passed through the pump and
oxygenator, and returned to the right atrium. Newer dual lumen cannulas allow this to be performed
through a single cannulation site, often using the jugular vein. Patients with high pulmonary arterial
pressures and right heart failure may require conversion to venoarterial ECMO or an atrial septostomy.
In venoarterial ECMO, blood is withdrawn from a central vein and returned to a peripheral or central
artery providing hemodynamic and respiratory support. The configuration and cannulation depend on
the patient’s needs and mobility. Venovenous ECMO is a good choice in patients with hypercapnic or
hypoxemic respiratory failure without significant right heart dysfunction, such as most patients with CF.
A single dual lumen cannula with insertion in the jugular vein allows patients to ambulate. Physical
therapy should be consulted as soon as possible. Ambulating patients require close coordination with the
ECMO specialist, respiratory therapist, nursing, and the critical care team. Some patients can be
extubated while on ECMO, with the goal to keep patients comfortable so they are able to participate in
physical therapy. It is also important to avoid blood transfusions when possible to avoid development of
antibodies that can limit donor organ availability, only transfusing patients when the hemoglobin is <6
g/dL, if there is hemodynamic instability, or if patients are hypoxemic despite ECMO support. For CO2
clearance alone, a pumpless system driven by the patient’s own arterial pressure can be used with groin
cannulation, decreasing ventilator-induced trauma.62,63
Venovenous ECMO may be insufficient for patients with significant right heart dysfunction and
pulmonary hypertension. Venoarterial ECMO or pulmonary artery to left atrial cannulation may be
more beneficial by unloading the right ventricle. Central cannulation is avoided when possible to
prevent complicating the subsequent lung transplant. Femoral arterial cannulation makes ambulation
more difficult and does not oxygenate the carotids and coronary arteries as well. Axillary arterial
cannulation using a 6- to 8-mm vascular graft provides more effective upper body oxygenation.
3 Since the initiation of the LAS, patients on mechanical ventilation have higher scores and are more
likely to undergo a transplant. These patients are also more likely to be deconditioned and have
decreased posttransplant survival. In a study from 2010, patients undergoing transplant on mechanical
ventilation had a significantly lower survival of 57% versus 70% at 1 year, although survival is similar
after 6 months.64 Ambulatory ECMO can be used to help prevent deconditioning of these patients prior
to transplant.
The decision-making process must include a multidisciplinary team including the ECMO and critical
care intensivist, transplant surgeon, pulmonologist, and social work. The goals of care include
establishing adequate CO2 removal, oxygenation, and circulatory support. Whether ECMO is being used
as a bridge to recovery or to lung transplant should be established when possible before initiating
ECMO. Factors to consider include the patient’s age, the underlying pulmonary disease, social support,
other organ dysfunction, the presence of infection, and variables affecting the potential waiting times
including the patient’s size and panel of reactive antibodies (PRA). Patients who have completed their
transplant evaluation or are in the process of being evaluated, younger patients, and those who were
listed prior to an acute exacerbation generally have better outcomes. Timing is important and the
initiation of ECMO should not be delayed to the point where the patient is no longer a transplant
candidate due to deconditioning. Their pulmonary disease should have progressed to the point where it
is unlikely that they will improve, but patients must have sufficient functional reserve. Active
bacteremia or highly resistant infections are contraindications. Patients with renal, hepatic, and cardiac
failure are also not candidates for ECMO. It is important to carefully discuss the decision to proceed to
ECMO with the patient and family, as well as considering the possibility of withdrawal from ECMO in
the event that the patient is no longer a transplant candidate due to complications including sepsis,
renal, liver, or left heart failure, stroke, or worsening functional status despite circulatory support.
Daily clinical assessment is important to ensure that the patient continues to meet transplant criteria.
Due to the severity of pulmonary disease, patients with an LAS that is greater than 90 have a
postoperative mortality that is higher than expected. In a study from 2005, ECMO was used as a bridge
to transplant in 31 patients with 25 surviving to transplantation.65 The 2-year survival rate was 74% in
both the unsupported and the bridge to transplant groups. The rate of PGD was higher in the ECMO
group.65 In a study from 2013, 31 patients were successfully bridged to lung transplant, including 19
who were ambulatory, with an 80% 3-year survival.66 In another study, 30 of 36 patients on ECMO
were bridged to lung transplant with a 2-year survival rate of 60.5%. Survival was greater among
patients with CF at 71% compared to idiopathic pulmonary fibrosis at 27.3%.67 The duration of ECMO
also affects morbidity and mortality. One study showed a 76% 1-year survival with patients on ECMO
950
booksmedicos.org
less than 14 days having a significantly improved survival.68 Fuehner et al. evaluated 26 patients
bridged to lung transplant compared to 34 historical control patients on mechanical ventilation. Survival
at 6 months was higher in the ECMO group at 80% versus 50%.69 While transplant outcomes for
patients undergoing ECMO as a bridge to transplant have been acceptable, larger cohort studies are
needed to optimize selection criteria for patients bridged to transplant.
DONOR CONSIDERATIONS
Donor Selection
While the number of lung transplants has steadily increased, with 1,830 transplants in 2011, and waitlist
times and waitlist death rates have decreased, the total number of patients on the waitlist has continued
to increase to 2,200 highlighting the shortage of acceptable donors. The reasons that fewer lungs are
available compared to other organs are multiple. Death from head injury or intracranial bleeding may
lead to neurogenic pulmonary edema, while chest trauma can result in contusions or pneumothorax. All
brain-dead donors are intubated and at risk for aspiration and nosocomial pneumonia, especially if there
is a prolonged interval between hospitalization and declaration of brain death. In addition,
hemodynamic instability, whether from herniation or trauma, often results in significant volume
resuscitation that can contribute to acute lung injury. Criteria for an ideal lung donor include age <55
years, less than 20 pack-year smoking history, < 48 hours on the ventilator, a PaO2:FiO2 ratio >300,
and no evidence of edema or infection (Table 39-5).70,71
Bronchoscopy allows for direct examination of the bronchial tree and for microbiologic examination
of the bronchoalveolar lavage (BAL), the results of which may influence later treatment of the recipient.
Chest radiography and computed tomography are useful to evaluate for effusions, pulmonary infiltrates,
consolidation, and contusions that could contribute to donor hypoxemia. Unlike other solid organ
transplants, lungs are unique in carrying a relatively high risk of infection (i.e., pneumonia) following
transplant. Because all brain-dead patients have endotracheal tubes and are on mechanical ventilation,
there is a high likelihood that the airway is either colonized with bacteria or that there is ongoing
pulmonary infection.
Not infrequently, the donor lungs may not be suitable because of infiltrates when all other organs are
acceptable. Significant infiltrates typically preclude the use of donor lungs. However, a bilateral lung
transplant may still be considered, in a recipient with a higher LAS, when there is a small infiltrate in
one lung without evidence of purulent secretions and the contralateral lung appears normal. In addition,
unilateral pulmonary infiltrates do not necessarily preclude use of the normal contralateral lung for a
single lung transplant.72
Aspiration at the time of the initial insult resulting in brain death is a common cause of pulmonary
infiltrates in potential donors. Signs of aspiration may not be evident on a chest radiograph for 24 to 48
hours, underscoring the importance of the bronchoscopic examination. Characteristic early
bronchoscopic evidence of aspiration includes erythematous tracheobronchial mucosa, purulent
secretions, and occasionally the presence of food particles.
Table 39-5 Criteria for Ideal Lung Donors
Major pulmonary contusion resulting from blunt chest trauma may also eliminate lungs from donor
consideration, but minor to moderate unilateral contusions are often acceptable. Evaluating the full
951
booksmedicos.org
extent of the contusions at the time of donor procurement can be difficult because the interval from
injury to determination of brain death and donation may be short. Although the detrimental effect on
gas exchange caused by a pulmonary contusion is usually transient, further bleeding into the lung
parenchyma could occur if cardiopulmonary bypass is required to perform the transplant. Pulmonary
edema may occur as a result of massive head injury and may be exacerbated by donor management
protocols directed at maintaining satisfactory perfusion and function of nonpulmonary organs.
The limitation in overall donor organ availability is further compounded by the relatively smaller
number of usable donor lungs. The standard criteria for an acceptable donor lung are particularly
stringent (Table 39-5).73 There are limited data available to validate these criteria, and multiple single-
institution retrospective reports evaluating “extended criteria” donors have shown conflicting short- and
long-term outcomes for almost every criterion. Clinically, these selection criteria provide an overall
indication of the quality of the donor lungs. When multiple criteria are not met, the risks of
transplanting such lungs likely outweigh the benefits. However, if one aspect of the donor lungs is
marginal, the lungs may still be acceptable, and the risks must be weighed against recipient acuity and
the likelihood of receiving another offer, taking the patient’s size and antigenic status into account.
There are several caveats that have come into “standard” practice. Although leukocytes or occasional
bacteria on sputum Gram stain can be acceptable, the presence of gross pus or fungal elements confers a
high risk of perioperative complications.74 In the annual report of lung transplant outcomes, increasing
donor age modestly increased the risk of 5-year mortality.16 Analysis of a large cohort of more than 750
lung and heart–lung recipients demonstrated significantly worse long-term survival with ischemic times
greater than 330 minutes. Hazard ratios for death were threefold higher in patients with ischemic times
of 8 hours and nearly eightfold higher when ischemia reached 10 hours.75 The detrimental effects of
older donor age and longer ischemic times appear to be additive.76
Donor Management
4 Despite the inability to identify “extended” donor criteria that reliably provide acceptable grafts,
donor management optimization has allowed an increase in donor recovery and is likely responsible for
the increase in the overall number of transplants performed over the last decade.The number of donor
lungs recovered has increased from 0.25 lungs per donor in 2000 to 0.39 lungs per donor in 2012.23
Algorithm 39-1 outlines the donor management algorithm used at the University of Michigan. Key
principles include the early use of steroids and thyroxine to prevent neurogenic pulmonary edema and
to maintain cardiovascular stability, aggressive alveolar recruitment with positive end-expiratory
pressure (PEEP) for patients with a partial pressure of arterial oxygen (PaO2) less than 350 mm Hg,
optimization of intravascular volume, maneuvers to prevent aspiration, and lung-protective ventilation
utilizing high frequency, low tidal volumes, and PEEP to prevent volutrauma and barotrauma to the
lungs. Using these maneuvers has been shown to double the organ recovery rate without detrimental
effects on 30-day or 1-year survival.77
Investigators at the Texas Organ Sharing Alliance identified 330 potential lung donors over a 4-year
period preceding initiation of an active donor management protocol and 381 potential donors managed
on the protocol in the subsequent 4 years.77 Overall, 1.7 organs per donor were procured in 19%
(136/711) of potential donors. Prior to initiation of the management protocol, organ procurement
occurred in only 12% (38/330), recovering 1.6 lungs per donor. In contrast, with lung-protective donor
management, organ procurement occurred in 26% (98/381), recovering 1.7 organs per donor.
952
booksmedicos.org
Algorithm 39-1. The donor management algorithm used at the University of Michigan in coordination with the organ procurement
organization, Gift of Life. Optimal PEEP is determined by increasing PEEP 2 cm of H2O every 3 to 5 minutes until compliance
decreases. Recruitment maneuvers include CPAP at 30 cm of H2O for 30 seconds every 20 minutes × 3. P/F, PaO2/FiO2; IBW,
ideal body weight; TV, tidal volume; APRV, airway pressure release ventilation; CPAP, continuous positive airway pressure.
Following initial organ acceptance, the lungs might be declined if the procurement team identifies
significant purulent secretions during bronchoscopy, if arterial blood gases deteriorate significantly to a
P/F ratio <300 or if the donor lungs are found to have poor compliance. On-site measurement of
selective pulmonary vein blood gases at the time of donor procurement can aid the procuring team in
determining whether donor hypoxemia is due to unilateral or bilateral lung compromise.78 Size of the
donor lungs is less important when the recipient suffers from emphysema, in which each hemithorax is
large, compared to pulmonary fibrosis, in which the hemithorax can be significantly contracted. The
most important size consideration is a reasonable match between donor and recipient height.
Lung Preservation
Unlike the kidney, liver, or pancreas, immediate acceptable function of the transplanted lung is vital for
survival of the recipient. PGD occurs in 10% to 25% of cases and is the most common cause of 30-day
mortality after lung transplantation. PGD is associated with higher rates of chronic rejection
(bronchiolitis obliterans syndrome [BOS]) and correlates with increased 1- and 5-year mortality.79
5 Ischemia-reperfusion injury refers to the cellular and architectural changes that occur after cross-
clamp of the donor aorta to release of the recipient pulmonary arterial clamp (ischemic phase) through
the immediate restoration of systemic gas exchange (reperfusion phase). Minimizing ischemia-
reperfusion injury is crucial to ensuring good early graft function. Advances in donor lung preservation
techniques have led to more consistent quality of the donor allograft and lower rates of PGD.
Current preservation techniques depend on cold static preservation to decrease metabolic activity
using topical cooling and cold pulmonary perfusion. A major development in lung preservation has been
the widespread clinical use of a preservation solution specifically designed for lung procurement.
Traditional preservation solutions such as Euro-Collins solution were designed to maintain intracellular
ion balance and cell wall integrity. Low-potassium dextran (Perfadex, Vitrolife, Goteborg, Sweden) has
953
booksmedicos.org
an extracellular fluid ion balance and has been shown to have beneficial effects on endothelial cell
function and pulmonary microcirculation. Five single-institution reports have demonstrated significantly
better initial lung function with low-potassium dextran, while one study showed no difference.80
The donor allograft is cooled to minimize cellular metabolism while maintaining vital cellular
function. Although small animal studies have demonstrated better postischemic function at preservation
temperatures between 15°C and 23°C, practical limits have led to the common practice of cooling to 4°C
to 8°C (the temperature of ice water). Other techniques that have traditionally been employed to ensure
rapid homogeneous cooling of the lung include topical cooling, antegrade flush through the pulmonary
artery, and techniques to maintain patency of the microcirculation including the administration of
prostaglandins prior to cross-clamp and the maintenance of ventilation after cross-clamp. Retrograde
flush through the pulmonary veins purges the pulmonary and bronchial circulations, has a more
homogeneous distribution, and can evacuate pulmonary arterial clots or fat emboli. Clinically,
retrograde perfusion in combination with the antegrade flush has been shown to improve immediate
posttransplant oxygenation.81
Optimal storage techniques have also evolved. After flushing of the pulmonary circulation, the lungs
are recruited to expand atelectatic areas, and the trachea is stapled and divided prior to separation from
the donor and storage for transport. Methods of lung recruitment have been studied in animal models
and have shown that ventilation with less than 50% oxygen and maintenance of airway pressure
between 15 and 20 cm H2O have beneficial effects on capillary leak, lipid peroxidation, and
barotrauma.82–84
Lung injury likely results not only from the ischemic insult but also from reperfusion of the ischemic
lung. Several experimental models of acute lung injury implicate oxygen free radicals as a factor in
reperfusion injury. A significant early increase in lung permeability is seen after an ischemic period
followed by reperfusion, which improves within several hours. After single lung transplantation,
changes in the contralateral, nonischemic lung are presumably the result of substances released during
reperfusion of the ischemic lung. Animal models have demonstrated that gradual pressure-controlled
reintroduction of blood flow and a protective ventilation strategy of high frequency and low tidal
volume reduce lung injury.85,86
Expanding the Donor Pool

Ex Vivo Lung Perfusion
Currently only 20% of brain death donor lungs are used for transplantation due to damage from trauma
or complications related to brain death and critical care including barotrauma and edema.87,88 The
number of patients on the waiting list exceeds the number of donor lungs available. With current cold
static preservation techniques, it is difficult to assess lung function after organ procurement.
Normothermic ex vivo lung perfusion (EVLP) (Fig. 39-2) allows for objective evaluation of marginal
lungs in an optimized environment leading to improved utilization of available donor lungs.
Early attempts at EVLP failed due to the development of pulmonary edema.89 Steen et al.90 initially
evaluated EVLP as a means to evaluate donor lungs from uncontrolled donation after cardiac death
(DCD) circumstances. They developed an optimized colloid lung perfusate solution that keeps fluid
within the intravascular space and also provides nutrition during lung perfusion (Steen Solution, XVIVO,
Sweden).91 The perfusion period was initially short, at around 60 minutes, and the solution was mixed
with red blood cells. The Toronto group first described stable long-term perfusion for 12 hours using an
acellular Steen solution, protective perfusion with only 40% of the cardiac output, and physiologic left
atrial positive pressure.92
Lung injury is reflected in the development of pulmonary edema during EVLP. Parameters used to
evaluate the donor lungs include the perfusate pO2, airway pressure, lung compliance, and pulmonary
vascular resistance. While PaO2 is one of the most important in vivo donor parameters, pO2 is less useful
ex vivo. Dynamic compliance is the most sensitive parameter for the development of pulmonary edema
ex vivo.93 Parameters are monitored over a 3- to 4-hour period, and it is important to take the trends
into account in addition to the absolute values. A delta pO2 (pulmonary vein pO2 – pulmonary artery
pO2) of greater than 300 mm Hg on 100% is used as criteria for lung acceptance for transplantation.
Chest x-rays, bronchoscopies, and deflation tests are also performed.
954
booksmedicos.org
Figure 39-2. The donor lungs have been placed on ex vivo lung perfusion with pulmonary arterial and left atrial cannulation and
the change in pO2, compliance, and pulmonary vascular resistance will be evaluated to determine if the lungs are acceptable for
transplantation.
Several prospective trials have recently been completed or are underway including the NOVEL trial
(United States; XVIVO), the HELP trial (Toronto; XVIVO), the INSPIRE and EXPAND trials (Europe and
the United States; Transmedics), the Perfusix trial (United States; Perfusix), the Vienna trial (Vienna;
XVIVO), and the DEVELOP trial (United Kingdom; Vivoline). Different technologies and techniques are
used in the various trials. While the NOVEL, HELP, DEVELOP, EXPAND, and Perfusix trials are
evaluating extended criteria lungs, the INSPIRE and Vienna trials are evaluating standard criteria lungs.
In the HELP trial, 80% of the lungs from brain dead and DCD donors that were not initially acceptable
for transplantation were transplanted after EVLP with outcomes equivalent to standard controls.94,95
The incidence of PGD grade 3, airway complications, and the need for ECMO has been <5%.
EVLP also provides the potential for rehabilitating injured lungs. Specific therapies could be used
depending on the type of lung injury. Terbutaline increases clearance of alveolar fluid during EVLP96
while applying surfactant to porcine lungs injured by aspiration improved graft function.97 Treatment of
donor lungs with high-dose antibiotics could also be useful with the large number of lungs rejected for
pneumonia.98,99 For donors with acute pulmonary emboli, tissue plasminogen activator has been used to
lyse emboli with good outcomes after transplant.100 Gene therapy with IL-10 is also being studied using
adenoviral vectors in rejected donor lungs and has shown improved function.101 In addition, the
application of stem cells has been reported to restore endothelial barrier permeability after lung
injury.102
Donation after Cardiac Death

DCD may be valuable in increasing the donor pool with only 20% of donor lungs acceptable for
transplant. The lung is unique compared to other organs since it does not depend solely on perfusion for
oxygen, and cell viability can be maintained by mechanical ventilation after cardiac arrest. Cadaveric
lungs have been shown experimentally to remain viable for 1 hour to 90 minutes after arrest with
function declining after 2 hours although this does not account for the agonal phase, which can vary in
duration and the degree of hypoxia and hypotension.103–105 On the other hand, DCD donor lungs may
actually have better function, since they are not exposed to the catecholamine surge and neurogenic
pulmonary edema associated with brain death and may be less sensitive to ischemia-reperfusion
injury.106 The Toronto group reported that lungs from brain-dead donors had higher levels of
proinflammatory cytokines than DCD lungs.107
Currently only 2% of DCD lungs are utilized in the United States.108 However 13.3% of lung
transplants in the United Kingdom and 22.5% in Canada are from DCD donors.109 DCD donors are
classified using the Maastricht classification into four groups: I, dead on arrival; II, failed resuscitation;
III, awaiting cardiac arrest; IV, cardiac arrest in a brain-dead donor.110 Controlled DCD (category III and
IV) is the approach of choice and includes withdrawal of life support in the ICU or operating room so
the organs can be allocated in advance with the ability to evaluate graft function and discuss donation
with the family. DCD donors generally have an irreversible cerebral injury, high spinal cord injury, or
end-stage muscular disorder and are expected to die within 1 hour of the withdrawal of support.
Predictive models have been developed to predict the potential for expiration based on the need for
pressors, cardiopulmonary status, age, BMI, Glasgow Coma Scale, peak and inspiratory pressures, and
the PaO2/FiO2 ratio.111–113
Death of the donor, with irreversible cessation of respiration and circulation, must be declared before
organ retrieval can begin, and the retrieval process must not alter or hasten death. One of the main
955
booksmedicos.org
differences from brain death donation is the addition of a warm ischemia period. The length of the
agonal phase, from the withdrawal of care until the declaration of death which includes a 2- to 5-minute
no touch period after circulatory arrest, varies among donors and is associated with impaired graft
function and longer hospital stays.114,115 Most DCD protocols limit the agonal phase to 60 minutes for
lung donation. Heparin is generally given before cardiac arrest although some donor hospitals restrict
its use since heparin can hasten death in donors with intracranial hemorrhage. Heparin given postarrest
can prevent pulmonary thromboemboli, and retrograde perfusion is helpful in clearing any emboli116,117
with no difference in thrombus formation.118–121 After arrest, the donor lungs can be rapidly cooled
topically, through chest tubes or after exposure of the lungs, followed by antegrade perfusion with cold
Perfadex and retrograde perfusion through the pulmonary veins.
EVLP may increase the use of DCD lungs by allowing evaluation after cardiac death in optimized
conditions, which is especially useful in DCD cases since in vivo evaluation is more limited and the
warm ischemia time is variable. There is also the potential to improve lung function. The Toronto group
transplanted lungs using 20 donor lungs placed on EVLP, including 9 DCD lungs, with no significant
difference in 30-day mortality, ICU or hospital length of stay. Although the use of EVLP remains
controversial since DCD lung transplants can also be performed with good outcomes without
EVLP.108,109
The first successful lung transplant from a DCD donor was reported in 1995.122 Early and midterm
outcomes after transplantation of lungs from controlled DCD donors are comparable to standard lung
transplantation.123–125 Although the incidence of PGD grade 3 was not significantly different, in some
series there was a trend toward increased early graft dysfunction with improvement within 72 hours
and more frequent ECMO usage.125,126 The incidence of BOS is similar but was more frequent in the
brain death group at 1 year in a series from the Netherlands.127 In a series of uncontrolled DCDs from
Madrid, the incidence of BOS at 5 years was 45%, which was significantly higher, although outcomes
were improved after using EVLP to evaluate donor lung function.128
TRANSPLANTATION OPERATION
Single Versus Bilateral Lung Transplant
Over the past decade the ratio of bilateral lung transplants has continued to increase from 49.9% of all
lung transplants in 2002 to 67.3% in 2012.23 Bilateral lung transplant is required for septic lung
diseases, including CF, due to the risk of contaminating the transplanted lung. Whether to perform a
single or bilateral lung transplant for other diseases remains controversial, and short- and long-term
outcomes as well as benefits to society should be considered.129,130 While double lung transplants may
provide greater benefits to the recipient, single lung transplants may maximize the benefit to society by
allowing two patients to be transplanted.
The decision to proceed with single or bilateral lung transplantation depends on several factors
including the primary diagnosis, the presence of pulmonary hypertension, recipient age, and donor lung
availability. Patients with chronic infection, such as those with CF or immunoglobulin deficiency
disorders, require bilateral transplant. Single lung transplantation can be considered for patients with
restrictive physiology (pulmonary fibrosis), particularly if there is no evidence of secondary pulmonary
hypertension. The decision on which side to transplant is based on both donor lung availability and the
recipient’s quantitative ventilation perfusion scan.
In patients with end-stage obstructive lung disease, specifically emphysema, there was concern
initially that single lung transplantation would be associated with altered physiology due to
hyperventilation of the overly compliant native lung and that mediastinal shift would result in
significant ventilation and perfusion mismatch and compromised function of the transplanted lung. It
has been demonstrated that single lung transplantation is acceptable in patients with emphysema,131
especially for older patients, with significant improvements in mean 6-minute walk results (Fig. 39-3).
However, bilateral lung transplant recipients appear to have greater improvement in FEV1 at 3-month
(Fig. 39-4) and 1-year follow-up.132
A single lung transplant is simpler technically and avoids a sternotomy. While some studies have
found improved early 30-day and 3-month survival with single lung transplant,133,134 others have found
no difference in survival135,136 or other postoperative outcomes including mechanical ventilation and
ICU stay.137,138 Bilateral lung transplantation, when indicated, has been simplified by the development
and refinement of the sequential rather than the en bloc double lung technique, which required a
956
booksmedicos.org
tracheal anastomosis with cardiopulmonary bypass and resulted in significant perioperative morbidity
and mortality.139 Bilateral sequential lung transplant can be approached either by median sternotomy or
bilateral thoracotomies using cardiopulmonary bypass when necessary depending on the degree of
pulmonary hypertension and impairment in gas exchange. A bilateral thoracosternotomy (“clamshell”)
incision permits easier exposure of the hilum especially on the left but tends to be more painful.
Figure 39-3. Mean 6-minute walk results for patients undergoing single lung transplantation for emphysema. There is significant
improvement at 6 weeks with continued improvement after 12 weeks.
Figure 39-4. Comparison of the percent predicted forced expiratory volume in 1 second (FEV1) in 14 patients undergoing single
and 10 patients undergoing bilateral pulmonary transplantation for chronic obstructive pulmonary disease.
In patients with pulmonary hypertension, single lung transplantation historically had been felt to be
adequate to unload the right ventricle by reducing pulmonary artery pressures leading to improved
right ventricular function. Although no significant survival benefit has been demonstrated between
patients receiving single, bilateral, or heart–lung transplantation, most patients undergo bilateral
sequential transplantation unless there is evidence for inotrope-dependent left ventricular heart
failure.140 Patients with pulmonary arterial hypertension listed for lung transplantation tend to be
younger, and thus may be more likely to obtain more durable improvement in lung function following
bilateral lung transplantation. In addition, perioperative management and improved hemodynamic
performance appear to be facilitated by bilateral rather than single lung transplantation. Although
seemingly contradictory, bilateral lung transplantation for this population also might improve organ
utilization, since marginal bilateral lungs are likely more readily available than an “ideal” single donor
lung.
Bilateral lung transplant results in greater improvements in spirometry.129,141 A study by Anyanwu et
al. shows that over 3 years, quality of life was improved to a greater degree after bilateral versus single
lung transplant while Gerbase et al. found no significant difference in quality of life.129 Meyer et al.136
evaluated 2,260 patients undergoing lung transplant for COPD in the United Network for Organ Sharing
(UNOS) database and found that long-term survival was better following bilateral lung transplant for
recipients less than 60. Thabut et al.142 evaluated 9,883 patients with COPD and found that median
survival was longer after bilateral transplant but not for patients older than 60. Nwakanma143 also
found no significant difference in long-term survival in 1,656 patients older than 60.
In a study of 821 patients with IPF, there was no significant difference in survival between single and
bilateral lung transplants with a trend favoring single lung transplant.133 Force et al. evaluated 3,860
patients with IPF in the UNOS database and found no survival advantage on multivariate analysis, but
the 1-year survival for those living at least 1 year was greater after bilateral transplant. Risk factors for
early mortality included recipient age greater than 57 and donor age greater than 36.144 The authors
concluded that bilateral transplant should be considered for younger patients with IPF. Patients
undergoing bilateral transplant from 1994 to 2011 had a greater median survival compared to single
957
booksmedicos.org
lung transplants (6.9 vs. 4.6 years).145
Bilateral transplant has also been found to have a survival benefit in sicker patients with a higher LAS
with a 14.4% lower 1-year mortality after a bilateral transplant.146 Black et al.147 evaluated 8,778
patients in the UNOS database and found that in patients with an LAS >75, the 1-year survival was
significantly lower in patients undergoing a single lung transplant. While several smaller studies have
found an increased risk of BOS after single lung transplant,129,130,148 Meyer et al.,136 found no difference
in the risk of BOS in 2,260 patients with COPD in the UNOS database at 3-year follow-up.
While no randomized or prospective, controlled studies have been performed, the ratio of bilateral
lung transplants has continued to increase over the past decade. Based on the available data, our
approach has been to perform bilateral lung transplants in most patients younger than 60 while a single
lung transplant is performed in older patients with IPF or COPD especially if pulmonary pressures are
only mildly elevated and there is a significant difference in perfusion between the two lungs.
OPERATIVE TECHNIQUE
Single Lung Transplantation
In the recipient operation, a standard fourth intercostal space posterolateral thoracotomy is performed.
In patients with emphysematous disease, a muscle-sparing axillary thoracotomy can be performed, but
this approach might not afford suitable exposure for patients who have significant volume loss due to
severe pulmonary fibrosis, a previous thoracotomy, or pleurodesis. The groin should always be included
in the sterile field. If necessary, cardiopulmonary bypass can be performed by cannulating the femoral
vessels in the groin or the right atrium and ascending aorta either through a right thoracotomy or a
clamshell incision. The hilar dissection (Fig. 39-5) differs from that of a pneumonectomy in that the
main pulmonary artery should be mobilized and divided distal to the origin of the first segmental trunk,
and the pulmonary veins should be divided at the main segmental tributaries as they return to the
superior or inferior veins. Care should be taken to preserve the peribronchial lymphatic and areolar
tissue in order to maintain the vascular supply of the mainstem bronchus just proximal to the origin of
the upper lobe bronchus. In addition, injury to the phrenic nerve must be avoided, especially in the
setting of pleural adhesions from previous surgery, severe emphysema, or pulmonary fibrosis, to avoid
diaphragmatic dysfunction, which can adversely affect posttransplant functional recovery.
The donor lung is prepared by dissecting the left atrial cuff and the proximal pulmonary artery from
the surrounding tissues. Retrograde perfusion is then administered by perfusing the superior and
inferior pulmonary veins with cold Perfadex while the lung is still inflated. The bronchial cuff is
prepared by transecting the mainstem bronchus approximately two cartilaginous rings from the orifice
of the upper lobe bronchus to maximize retrograde perfusion to the bronchial anastomosis.
Implantation of the donor lung begins with the anastomosis between the donor and recipient
bronchus. An end-to-end anastomosis is performed with a running 4-0 polydioxanone suture on the
membranous airway and figure-of-eight 4-0 polydioxanone sutures to reapproximate the cartilaginous
airway.149,150 Absorbable sutures are used rather than polypropylene to reduce the risk of suture
granuloma formation. The peribronchial areolar and lymphatic tissue can be reapproximated between
the donor and recipient, particularly anteriorly, in order to separate the bronchial and pulmonary
arterial anastomoses. Advocates of bronchial arterial revascularization with a native internal mammary
artery have reported decreased bronchial anastomotic complications in small series, but this technique
has not received widespread acceptance due to the increased complexity and ischemic times.151–153
958
booksmedicos.org
Figure 39-5. Mobilization of the hilum of the right lung. The pulmonary artery is encircled, and the first branch is ligated and
divided. The superior and inferior pulmonary veins have been exposed. Both the artery and veins are taken as close to the lung as
possible. The bronchus is divided at the level of the takeoff of the upper lobe to minimize ischemia of the airway.
The vascular anastomoses are then performed sequentially using running 4–0 or 5–0 nonabsorbable
polypropylene sutures. Our preference has been to first perform the left atrial anastomosis followed by
the pulmonary arterial anastomosis. The pericardium is opened around the left atrial cuff allowing the
left atrium to be clamped centrally to the branch point of the superior and inferior veins. The recipient
pulmonary vein stumps are prepared by unifocalization into one left atrial cuff to reduce the risk of
pulmonary venous obstruction. In constructing the pulmonary arterial anastomosis, care must be taken
to trim the donor pulmonary artery to the appropriate length to avoid kinking of the low-pressure
vessel. Once the vascular anastomoses are completed, the lungs are gently ventilated as the vessels are
deaired with the patient in the Trendelenburg position, first removing the pulmonary arterial clamp
followed by the left atrial clamp prior to tying the anastomotic sutures. The chest is closed in standard
fashion.
Bilateral Lung Transplantation

The technique of double lung transplantation has evolved considerably since the late 1980s from an en
bloc technique to a bilateral, sequential technique.139,154 With the patient in the supine position, this
operation can be performed through a median sternotomy, bilateral thoracosternotomy (clamshell)
incision (Fig. 39-6), bilateral anterior thoracotomies without sternal division, or bilateral muscle-sparing
axillary thoracotomies. The bilateral thoracosternotomy incision provides the widest exposure
facilitating dissection and mobilization of the hilar structures as well as cannulation of the right atrium
and ascending aorta if cardiopulmonary bypass is necessary. This exposure is particularly important in
recipients with diffuse dense pleural adhesions as is often seen in patients with chronic infections with
bronchiectasis or CF, previous pleurodesis, or with severe apical adhesions after lung volume reduction
in patients with emphysema.
959
booksmedicos.org
Figure 39-6. Patient positioning for a bilateral, sequential lung transplant. Bilateral anterior thoracotomies are made in the fourth
intercostal space with a transverse sternotomy when needed for exposure (clamshell incision).
Although both lungs are replaced, the operation can often be performed without cardiopulmonary
bypass unless the recipient has significant pulmonary hypertension or severely limited gas exchange. By
replacing the lung with the least function first, based on the quantitative ventilation perfusion scan,
oxygenation and ventilation can be maintained by the native lung. If the patient is unable to tolerate
single lung ventilation due to inadequate gas exchange or worsening right ventricular dysfunction with
increasing pulmonary hypertension (near or suprasystemic), then cardiopulmonary bypass is initiated. If
recipient hemodynamics are significantly impaired during retraction and exposure of the left atrial
anastomosis, particularly during left lung recipient pneumonectomy and implantation, opening the
recipient pericardium can be sufficient to permit safe manual cardiac retraction or application of an
apical cardiac stabilizer.155 In patients with severe mediastinal shift due to volume loss from pulmonary
fibrosis, cardiopulmonary bypass may be necessary to provide sufficient cardiac decompression in order
to obtain adequate exposure to complete the anastomoses.
The donor lungs are prepared leaving a cuff of left atrium around the pulmonary veins on each side.
The recipient pneumonectomy is performed one side at a time with the patient maintained using single
lung ventilation of the contralateral lung. Each donor lung is implanted using the same technique as
described for single lung transplantation. The bronchial anastomosis is completed first, followed by the
left atrial and pulmonary arterial anastomoses. Once perfusion and ventilation are restored to the first
implanted lung, this lung then supports the patient while the remaining lung is removed and the second
lung is implanted.
RESULTS
1. Based on OPTN data, 27,043 lung transplants were performed between 1988 and 2013. In 2012,
52.5% of transplanted patients were from diagnosis group D, including pulmonary fibrosis, which is
now the most common indication for lung transplant (Fig. 39-1).23 LAS scores continue to increase
with 12.7% of transplant candidates with an LAS of 50 to 100 in 2006 compared to 22.5% in 2012. Of
those patients listed, only 2% were listed for a heart–lung transplant. In 2012, 1,783 lung transplants
were performed with 68% bilateral transplants and 5.5% retransplants. By the end of the first year
after transplantation, approximately 80% of recipients report no limitations in activity.
6 Overall, survival after transplant has steadily improved with time. Between 1988 and 1994, median
survival was 3.9 years while the median survival in 2012 was 5.3 years.23 For patients who survived at
least 1 year, the survival was 6.7 years. In this most recent era of lung transplant, the overall 1-year
960
booksmedicos.org
survival rate following lung transplant was 81.4% and the 5-year survival was 53.5%. Patients receiving
bilateral lung transplant survive significantly longer than patients after single lung transplant (median
survival of 6.2 vs. 4.5; p < 0.0001). In general, younger recipients have a longer survival than older
patients. Patients with CF have the best median survival (6.4 years) as they comprise a younger
population and in general will receive two lungs secondary to their infectious lung disease. Median
survival for patients with pulmonary fibrosis is significantly lower at 4.1 years, and that of patients with
COPD is 5 years.
For all recipients, the factors associated with the highest risk of 1-year mortality were the era in
which patients were transplanted, intravenous inotropes, and mechanical ventilation. The most
significant risk factor for 5-year mortality was the development of BOS within the first year of
transplant.16
IMMUNOSUPPRESSION
Immunosuppression is initiated in the immediate perioperative period and continued for the remainder
of the recipient’s life. Regimens typically include a calcineurin inhibitor, either cyclosporine or
tacrolimus; a purine synthesis antagonist, either azathioprine or mycophenolate mofetil; and a
corticosteroid, either methylprednisolone (intravenous) or prednisone (oral). In an open-label
randomized trial of 90 patients who received either cyclosporine or tacrolimus,156 subjects who were
treated with tacrolimus experienced significantly less acute rejection. Lymphocytic bronchitis was also
less frequent among patients receiving tacrolimus. In addition, fewer patients developed stage 0-p BOS
(not statistically significant). The investigators used a composite endpoint including cumulative acute
rejection score, cumulative lymphocytic bronchitis score, or the development of BOS stage 0-p (10% or
greater decrease in FEV1). No difference in graft survival was seen. Although diabetes was slightly more
prevalent among subjects treated with tacrolimus, there were no differences observed between the two
treatment groups in terms of hypertension, chronic renal disease, posttransplant malignancy, or total
number of infections. In 2012, more than 90% of lung transplant recipients were treated with
tacrolimus.23 Rapamycin (sirolimus) is a serine/threonine kinase inhibitor that can be used as a second-
line agent for treatment of acute rejection, sometimes in combination with calcineurin inhibitors, but
such use is considered off-label and not recommended. In addition, rapamycin is absolutely
contraindicated in the early posttransplantation period because of an association with fatal bronchial
anastomotic dehiscence.
In other solid organs, use of induction (perioperative) antithymocyte regimens appears to be
beneficial in reducing both acute and chronic rejection. There are limited data supporting the use of
such agents in lung transplantation. In a study of 44 patients randomized to conventional triple-drug
immunosuppression with or without rabbit antithymocyte globulin, a significant reduction in early acute
rejection from 41% to 5% was observed with the use of rabbit antithymocyte globulin, but there was no
apparent effect on the total number of rejection episodes. Compared to induction immunosuppression,
the time to onset of BOS was earlier and graft survival was worse with conventional therapy alone, but
these differences were not statistically significant. Several studies comparing antithymocyte globulin
with T-cell–specific interleukin-2 (IL-2) receptor (CD25) monoclonal antibody suggest that outcomes,
including early acute rejection and freedom from rejection, are equivalent157 if not worse158,159 for
patients treated with IL-2 receptor antibody. Treatment-related complications, particularly
cytomegalovirus infection, appear to be equivalent for these induction agents. These studies do not
provide sufficient evidence, and lack sufficient power, to determine whether their use is beneficial for
the prevention of acute or chronic rejection. However, the use of induction therapy has increased from
23% in 1998 to 55% in 2012 with IL-2 receptor antagonists being the most commonly used agents.23
COMPLICATIONS
Complications after pulmonary transplantation occur frequently, may be severe, and occasionally result
in death (Table 39-6). Compared to other solid organ transplants, lung recipients have the highest rates
of rehospitalizations for complications at 43.7 per 100 patients.23 Intraoperative complications include
technical problems with the vascular or bronchial anastomoses, injury to the phrenic or recurrent
laryngeal nerves, and myocardial infarction. Early postoperative complications include PGD, infection,
and problems with airway healing and acute rejection. The most common late complications are
961
booksmedicos.org
infection and bronchiolitis obliterans (chronic rejection). Intra-abdominal complications are not
uncommon while wound infection occurs rarely. Two important issues regarding standard
immunosuppressive therapy are the various side effects associated with these agents and their
interactions with other commonly prescribed medications.160 Despite the progress made in operative
techniques and early postoperative care, noninfectious, nonpulmonary complications related to long-
term immunosuppression remain common. Five years after transplant, 66.7% of patients have
hypertension, 53.8% hyperlipidemia, 49.8% renal dysfunction, 42.5% diabetes, and 18.3% have
developed a malignancy with the risk of cancer three- to fourfold higher in patients after
transplant.23,161
Table 39-6 Complications
Causes of recipient death can be categorized according to the time frame in which they occur. Early
deaths (less than 30 days following transplant) most commonly result from primary graft failure
(28.2%).16 Infection is the second most common cause of early death (20.3%), followed by heart failure
(11.1%). Rejection accounts for 4.3% of deaths in the early posttransplantation period. Hemorrhage and
airway dehiscence each are responsible for 8.3% of early postoperative deaths. Infection accounts for
about 39.5% of deaths within the first year of transplant (after 90 days). About one-third of deaths
result from manifestations of chronic rejection and obliterative bronchiolitis, the single most significant
barrier to long-term survival following lung transplantation. Respiratory failure and malignancy are the
next most common causes of late mortality.
Primary Graft Dysfunction

Mild, transient pulmonary edema is common in the freshly transplanted allograft. In approximately 15%
of cases, the injury is sufficiently severe to cause PGD. While ischemia-reperfusion injury is the likely
cause, surgical trauma and lymphatic disruption may also be contributing factors. The diagnosis rests on
the presence of widespread infiltrates on chest radiographs, severe hypoxemia within 72 hours after
transplantation, and the exclusion of other causes of graft dysfunction, such as volume overload,
pneumonia, rejection, occlusion of the venous anastomosis, and aspiration. Treatment is supportive
relying principally on conventional mechanical ventilation. Independent lung ventilation, inhaled nitric
oxide, and ECMO have been used as adjunctive measures. Mortality rates of up to 60% have been
reported, and among those who survive, the recovery period is often prolonged, but achievement of
normal allograft function is possible. The results of emergency retransplantation in such cases have been
poor.160,162,163
The impact of PGD on lung transplant outcomes has been historically unclear due to variability in the
definition. A consensus statement in 2005 sought to standardize the definition and severity of PGD
(Table 39-7).164 Studies examining outcome utilizing the current grading system have demonstrated a
direct correlation with severity of PGD and ICU mortality, in-hospital mortality, 1-year survival, and
freedom from BOS.165,166
Table 39-7 Grading of Primary Graft Dysfunction Severity
962
booksmedicos.org
Rejection
Acute rejection episodes often occur soon after transplantation, usually between posttransplantation
days 5 and 7. Two or three rejection episodes can occur within the first month. Mild temperature
elevation, perihilar fluffy infiltrates, or a minimal decrease in oxygenation as measured by arterial
oxygen tension may indicate the onset of acute rejection. Because rejection occurs so frequently during
this period, the distinction between infection and rejection may be difficult. Often, the distinguishing
factor between these two entities is that rejection responds positively to the administration of
corticosteroids. Treatment of early rejection involves the use of bolus corticosteroids given on 3
consecutive days. Within 12 to 18 hours after the first corticosteroid dose symptoms relating to
rejection usually resolve including clearing of infiltrates on chest radiograph.
Transbronchial biopsies are performed to diagnose and monitor rejection, but the number of biopsies
required to maximize specificity is large. One group recommends obtaining 18 separate transbronchial
biopsy specimens to achieve 95% specificity. Transbronchial lung biopsy can also be used when the
issue of rejection versus infection is not resolved after steroid administration. Flexible bronchoscopy can
be performed at the bedside, and 6 to 10 separate biopsies can be obtained under fluoroscopic guidance.
When symptoms or signs of rejection persist despite adequate treatment, open lung biopsy may be
considered.
Infection
Infection in the posttransplantation period continues to be a significant cause of morbidity and mortality
and is the most common overall cause of death. Posttransplant prophylaxis strategies targeting gram-
positive and gram-negative bacteria, Pneumocystis pneumoniae, cytomegalovirus, and Aspergillus have
been shown to decrease the morbidity and mortality from infectious complications. Bacterial pneumonia
usually responds to appropriate antibiotic therapy, and patients are maintained on broad-spectrum
antibiotics until specificities are determined by culture from the donor and recipient bronchus sent at
the time of transplantation. Antibiotic administration is particularly important if one predominant
organism is grown from the donor bronchus, and the recipient is maintained on an appropriate
antibiotic or combination of antibiotics for at least 1 week. The most common organism recovered from
donor bronchial washings is Staphylococcus aureus. In a series of 32 transplants, this organism was
recovered from donors 11 times and subsequently from 4 transplant recipients.167 Other commonly
recovered pathogens include Enterobacter species and Candida albicans. The presence of organisms
cultured from donor bronchial washings, however, does not absolutely predict the development of
invasive infection in recipients. Less than half of recipients from whom organisms were recovered
developed invasive infections.
The second most significant pathogen is cytomegalovirus (CMV). The diagnosis of CMV is usually
made from culture of BAL fluid or tissue obtained from transbronchial lung biopsy. In the pulmonary
transplantation population, CMV pneumonitis is the predominant form of CMV infection, although CMV
enteritis and retinitis also occur. This observation corresponds to that seen in cardiac and
cardiopulmonary transplant recipients. About half of lung recipients develop documented CMV
infection. Ganciclovir has proved particularly effective and is the drug of choice for CMV infection in
this circumstance. The drug is well tolerated in most patients, with neutropenia accounting for most of
the toxicity. CMV prophylaxis with ganciclovir can be used for CMV-positive recipients or in those
recipients who receive a lung from a CMV-positive donor. The mortality rate from life-threatening CMV
infections treated with ganciclovir has been reported at 10%, far better than the 40% or greater
mortality reported before this agent was available.168 Life-threatening CMV infection can occur in CMV-
negative recipients who receive a lung from a CMV-positive donor (primary infection) or in recipients
who are already CMV positive (secondary infection). Cytolytic therapy especially with muromonab-CD3
is associated with an increased risk and severity of CMV infection. Mismatched donor–recipient CMV
status also appears to be a significant univariate risk factor for mortality following retransplantation.169
Attempts to match a CMV-negative recipient with a CMV-negative donor lung, given the shortage of
donor organs, can prolong candidate waiting times. Based on the 2012 OPTN Annual Data Report, the
963
booksmedicos.org
donor and recipient CMV status was either matched (positive-positive or negative-negative) or
mismatched with a CMV-positive recipient and a CMV-negative donor in 70% of lung transplants
performed from 2008–2012.23
An analysis of UNOS outcomes data demonstrated that donor–recipient CMV serologic mismatch,
particularly donor-positive/recipient-negative (D−/R–) serologic status, was a significant adverse risk
factor for posttransplantation mortality in earlier eras (1990 to 1994 and 1995 to 1999) but not in a
more recent era (2000 to 2004) of pulmonary transplantation, when compared with donor-
negative/recipient-negative transplants.170 These findings suggest that donor–recipient CMV mismatch
can be an adverse factor for posttransplant survival but that this effect can be significantly decreased
with the introduction of more effective CMV antiviral therapy.171
Infection with Aspergillus species is the most common fungal infection after lung transplant and occurs
in 15% to 35% of recipients. Overall mortality is high (52%), especially with invasive infections
(80%).172 Preemptive antifungal therapy has been shown to decrease the incidence of clinical fungal
infection from 69% to 31%.173
Airway Complications
Airway complications can significantly affect quality of life with repeated procedures, office visits, and
hospitalizations. Airway complications can be categorized by the time course of occurrence (early vs.
late) and the type of complication (stenosis, dehiscence, granulation, fistula, or infection). The incidence
of airway complications has decreased substantially over time. This is likely due to improvements in
lung preservation, surgical technique, and antibiotic prophylaxis. Airway complications are associated
with persistent ischemia, infection, and rejection.
During the early pulmonary transplantation experience, problems with airway healing occurred in
60% to 80% of patients and resulted in death in 2% to 3%.174 Patients often did well for the first 3
weeks after transplantation, and then the bronchial anastomosis dehisced, often with erosion into the
pulmonary artery. Bronchial anastomotic healing was initially facilitated by withholding maintenance
corticosteroids until after the first posttransplantation week and using an omental pedicle wrapped
around the anastomosis. Historically, most problems with airway healing occurred after en bloc double
lung transplants, which involves a tracheal anastomosis. Double lung transplantation required extensive
dissection in the subcarinal space, resulting in the disruption of a number of bronchial collateral vessels.
Since this operation was modified to one involving bilateral, sequential lung implantation with two
bronchial anastomoses, airway problems are now infrequent, occurring in 10% to 15%, and rarely result
in recipient deaths.175,176 The development of cyclosporine, advances in lung preservation, and better
postoperative care have also improved airway healing. Immunosuppression, especially with high-dose
steroids, may increase the risk of infection and decrease wound healing,177,178 and sirolimus should be
avoided perioperatively for 90 days due to significantly increased rates of airway dehiscence.178–180
The use of a telescoping bronchial anastomosis, in which the donor bronchus is intussuscepted into the
recipient bronchus or vice versa, obviated the need for the omental pedicle wrap, allowed for
immediate use of corticosteroids and reduced the anastomotic dehiscence rates. However, the
telescoping anastomosis can increase the rate of anastomotic stenosis with complications in up to
48%181 and a stenosis rate of 7%.181,182 Recently there has been a trend toward the use of primary end-
to-end anastomosis using figure-of-eight sutures with the anastomosis performed as close to the
secondary carina as possible.149,183 Initial results demonstrate a lower incidence of stenosis with an
equivalent rate of dehiscence of approximately 2%.149,150 Minimizing the length of the donor bronchus
is important since perfusion of the anastomosis depends initially on retrograde collaterals from the
pulmonary artery.184–186
Risk factors for airway complications include the duration of donor mechanical ventilation, height
mismatch, length of the donor bronchus, type of anastomosis, size mismatch, infections, airway
ischemia, immunosuppression used, PGD, positive pressure ventilation, and acute
rejection. 178,179,181,185,187 Infections may increase inflammation and decrease healing, and resistant
bacteria and fungal colonization are frequently present at the time of the anastomosis.
Management options depend on the type, location, timing, and severity of airway complication.
Complications can occur at the anastomosis or more distally in 2.5% to 3% of patients with the extreme
case being the vanishing bronchus syndrome with a mean survival of 25 months.188,189 Bronchial
stenosis is the most common and occurs in 1.6% to 32% of transplants.181,189,190 Necrosis and dehiscence
result in bronchial strictures. Some degree of dehiscence occurs in 1% to 10% of cases.191 Infections
such as Aspergillus and early rejection have also been associated with stenosis.192 Patients may present
964
booksmedicos.org
with cough, postobstructive pneumonia, dyspnea, atelectasis or lobar collapse on chest x-ray, and
worsening FEV1 on spirometry. Other types of airway complications include malacia, dehiscence, and
fistula. A persistent air leak, pneumothorax, or pneumomediastinum may suggest airway dehiscence,
and the most severe cases may require open repair, flap bronchoplasty, or even retransplant,193
although a partial dehiscence may heal without further intervention.
Chest CT with 3D reconstructions can be helpful in planning interventions.194,195 Bronchoscopy plays
a key role in diagnosing, and managing airway complications. Dilation can be performed using a
balloon, rigid bronchoscope, or various dilators including Savary or olive tip dilators. Balloon dilation is
the only procedure required in 26% of cases196 and relieves symptoms in 94% of patients,197 although
most patients require repeat procedures. Rigid bronchoscopic dilation allows for direct visualization of
the stricture and ventilation during dilation. Ablation can be performed with laser, argon plasma
coagulation, or cryotherapy. For refractory lesions, submucosal injection of steroids or topical
mitomycin-C may help prevent recurrence.198–200
Stenting should be considered when other more conservative interventions have failed. Stents can
provide symptomatic relief in 80% to 94% of patients with long-term patency in 45%.197,201 However,
complication rates up to 54% have been reported202–204 and should be carefully considered when placing
a foreign body in an immunocompromised patient. Bacterial colonization is seen in up to 78% of
cases,201,205,206 and complications include infection, granulation tissue, and stent migration. Stents have
also been associated with higher rates of respiratory infections in cancer patients.207 Metal stents can
become embedded in granulation tissue making removal hazardous. Covered stents should be used
when possible and should be removed once they are no longer needed. Stents can also be used to
temporarily cover a dehiscence to allow healing over several weeks208 although care must be taken not
to extend the injury during stent placement and removal.
Self-expanding stents are easy to place through a flexible scope; however, silicone stents offer certain
advantages including decreased granulation tissue, the ability to customize and modify the stents, and
the ease of removing the stents,209 although stent migration and mucous plugging are still possible. If
endoscopic therapies are unsuccessful, sleeve resection, lobectomy, and pneumonectomy have been
reported but carry significant risks of morbidity and mortality.
Bronchomalacia may occur with loss of cartilaginous support of the airway due to ischemia or
infection. Patients have a “barking” cough, shortness of breath, wheezing, and recurrent infections.
Bronchoscopy and dynamic CT with inspiration and expiration images are important for diagnosis.
Patients are treated with mucolytics and noninvasive positive pressure ventilation. In severe cases,
stents may be used and can increase spirometry results.196
The lungs have a dual blood supply with perfusion from systemic bronchial arteries as well as the
pulmonary arteries, although generally only the pulmonary arterial circulation is restored during
transplantation. The anatomy of the bronchial arteries is variable with 1 to 4 arteries arising from the
descending aorta and the upper right intercostal arteries.210 Bronchial artery revascularization may
improve airway healing and decrease airway complications.211–214 The largest series from Copenhagen
showed an improved 5-year survival of 69% after bronchial artery revascularization versus 57%
without.215 There are also studies showing decreased incidence of pulmonary infections and a trend
toward increased freedom from BOS at 24 months.216 Bronchial artery revascularization is technically
challenging, leading to longer ischemic times and increased risk of bleeding, and with the limited
published data, has not been widely adopted.
Bronchiolitis Obliterans
7 Acute and chronic rejection continues to be higher after lung transplant than other solid organs.
Bronchiolitis obliterans remains the leading cause of late mortality following lung transplantation with
nearly 30% of deaths beyond the first year of transplantation attributed to the fibroproliferative
changes and airway destruction of this disorder. BOS is present in the first year in 7.9% of patients and
in 43% by 5 years,23 and remains a significant cause of morbidity. Following heart–lung transplantation,
nearly 50% of deaths beyond the first year are attributable to bronchiolitis obliterans and pulmonary
graft failure.17
BOS is defined as a decline in FEV1 of greater than 20% from baseline determined on at least two
separate measurements obtained at least 3 weeks apart.217 The histologic appearance of bronchiolitis
obliterans is characterized by progressive small airway destruction, an inflammatory exudate, and
fibrosis. This complication is likely a form of chronic rejection, although its exact etiology remains
unknown. If diagnosed early, enhancing immunosuppression may either halt the process or slow its
965
booksmedicos.org
progression. Factors associated with BOS include repeated episodes of acute rejection, chronic rejection,
infection, and gastroesophageal reflux disease.218–220 It has been hypothesized that the development of
obliterative bronchiolitis in cardiopulmonary transplantation patients is related to a human major
histocompatibility complex (human leukocyte antigen)–A2 antigen mismatch. Others believe that CMV
infection or early lung injury, such as that arising from PGD, may be implicated.221 Once diagnosed, it
is important to increase immunosuppression to prevent what is usually an insidiously progressive
disorder. Unfortunately, in patients who have developed obliterative bronchiolitis and then undergo
retransplantation, the pathology can recur in the newly transplanted lungs. Obliterative bronchiolitis
remains the major problem in patients surviving for greater than 2 years following transplantation.
Overall, long-term survival for lung transplantation is not likely to improve significantly until effective
strategies for the prevention and treatment of obliterative bronchiolitis are identified.
New terminology has been recently introduced to include other chronic forms of decreased lung
function after transplant.222 Chronic allograft dysfunction, or CLAD, is defined as an irreversible decline
in FEV1 to < 80% of baseline. In addition to BOS, restrictive allograft syndrome presents with
restrictive findings on PFTs including a decline in total lung capacity to <90% of baseline and has a
worse survival than other patients with CLAD.223
GASTROESOPHAGEAL REFLUX
8 After lung transplantation, patients have a higher rate of gastroesophageal reflux disease,224 and the
incidence is increased after bilateral transplant and retransplantation.225,226 Reflux is found in 90% of
patients with CF7,227 and high rates of reflux and dysmotility are associated with connective tissue
disorders.228 Compared to nontransplant patients, pepsin is increased in BAL fluid in patients after lung
transplant.229,230 Increased reflux may be a result of immunosuppressive medications or changes from
the surgical procedure itself, possi bly due to the proximity of the vagus nerve.231–233 Reflux in lung
transplant patients has been associated with aspiration, impaired lung function, and decreased survival.
Bronchiolitis obliterans has been associated with gastroesophageal reflux.220,230,234–236 Cytokines and
cellular activation are increased in BAL fluid secondary to chronic gastroesophageal reflux and may lead
to the production of alloantigens and BOS.237,238 Decrease in mucociliary clearance in transplant patients
may also make the effects of aspiration worse.232,239 Reflux may lead to chemical injury,240 and bile
acids may inhibit immune mechanisms by lowering levels of surfactant involved in regulating cytokines
and the immune response.234 Studies have found an association between reflux and episodes of acute
rejection.230,235,237,241
Lung transplant patients with abnormal pH probe testing have an increased rate of decline in their
FEV1, and the decline is worse when patients do not undergo antireflux surgery.220 One study of 215
patients found that abnormal preoperative pH testing was associated with significantly decreased
survival.242 Nonacid reflux is also increased after lung transplant, and heartburn symptoms were poor at
predicting the presence of pepsin or bile in BAL fluid.243,244 In addition, suppressing acid with H2
blockers or proton pump inhibitors did not stop the effects of aspiration or the development of
bronchiolitis obliterans.245 Antacid therapy may result in silent aspiration and also contribute to
bacterial overgrowth, which could increase injury from aspiration.246 Thirty-six percent of patients with
reflux also had esophageal dysmotility.225 Gastroparesis is present in 50% of lung transplant patients
before transplant, increasing to 74% postoperatively; a significant number of patients return to normal
function with time.247
Antireflux surgery decreases both acid and nonacid reflux and can be safely performed in lung
transplant patients228,233,248,249 either prior to or after their transplant depending on their functional
status. Antireflux surgery decreases immune factors associated with BOS and preserves overall
pulmonary function220,233,250,251; data on any survival benefit is limited with only one study showing a
survival benefit at 1 year after early fundoplication within 90 days.252
FUTURE CONSIDERATIONS
The number of lung transplants continues to increase with 1,922 lung transplants performed in 2013 and
2,474 patients added to the waiting list. Pulmonary transplantation has evolved from an experimental
therapy to the standard of care for patients with certain end-stage pulmonary diseases. The number of
transplanted patients older than 65 has increased substantially over the past 10 years, and patients are
966
booksmedicos.org
sicker with a higher median LAS. Careful patient selection by a multidisciplinary team is essential. As
waitlisted patients become sicker, with acute inpatient evaluations becoming more common, the use of
ambulatory ECMO may increase to help prevent these patients from becoming deconditioned. Work
also continues on developing long-term paracorporeal support devices including the artificial lung.
Donor availability remains a limiting factor and efforts to increase the number of acceptable donor
lungs will continue including aggressive donor management, evaluation of marginal lungs using EVLP,
and consideration of DCD lungs. Future developments in EVLP may also allow biomarker assessment to
evaluate donor lung injury as well as therapeutic interventions during ex vivo perfusion.87 Research is
also being done to regenerate decellularized lung scaffolds using EVLP.253,254
References
1. Hardy JD. The first lung transplant in man (1963) and the first heart transplant in man (1964).
Transplant Proc 1999;31:25–29.
2. Samano MN, Minamoto H, Junqueira JJ, et al. Bronchial complications following lung
transplantation. Transplant Proc 2009;41:921–926.
3. Morris PJ. The impact of Cyclosporin A on transplantation. Adv Surg 1984;17:99–127.
4. Yusen RD, Christie JD, Edwards LB, et al. The Registry of the International Society for Heart and
Lung Transplantation: thirtieth adult lung and heart-lung transplant report–2013; focus theme: age.
J Heart Lung Transplant 2013;32:965–978.
5. Egan TM, Cooper JD. Lung transplantation. Ann Thorac Surg 1989;48:741–742.
6. Estenne M, Maurer JR, Boehler A, et al. Bronchiolitis obliterans syndrome 2001: an update of the
diagnostic criteria. J Heart Lung Transplant 2002; 21:297–310.
7. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for
Heart and Lung Transplantation: twenty-seventh official adult lung and heart-lung transplant
report–2010. J Heart Lung Transplant 2010;29:1104–1118.
8. Lima O, Cooper JD, Peters WJ, et al. Effects of methylprednisolone and azathioprine on bronchial
healing following lung autotransplantation. J Thorac Cardiovasc Surg 1981;82:211–215.
9. Khaghani A, Tadjkarimi S, al-Kattan K, et al. Wrapping the anastomosis with omentum or an
internal mammary artery pedicle does not improve bronchial healing after single lung
transplantation: results of a randomized clinical trial. J Heart Lung Transplant 1994;13:767–773.
10. Egan TM, Murray S, Bustami RT, et al. Development of the new lung allocation system in the
United States. Am J Transplant 2006;6:1212–1227.
11. Mulligan MS, Shearon TH, Weill D, et al. Heart and lung transplantation in the United States, 1997-
2006. Am J Transplant. 2008;8:977–987.
12. Grady KL, White-Williams C, Naftel D, et al. Are preoperative obesity and cachexia risk factors for
post heart transplant morbidity and mortality: a multi-institutional study of preoperative weight-
height indices. Cardiac Transplant Research Database (CTRD) Group. J Heart Lung Transplant
1999;18:750–763.
13. Culver DA, Mazzone PJ, Khandwala F, et al. Discordant utility of ideal body weight and body mass
index as predictors of mortality in lung transplant recipients. J Heart Lung Transplant 2005;24:137–
144.
14. Madill J, Gutierrez C, Grossman J, et al. Nutritional assessment of the lung transplant patient: body
mass index as a predictor of 90-day mortality following transplantation. J Heart Lung Transplant
2001;20:288–296.
15. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the International Society for
Heart and Lung Transplantation: twenty-eighth adult lung and heart-lung transplant report–2011. J
Heart Lung Transplant 2011;30:1104–1122.
16. Hertz MI, Aurora P, Christie JD, et al. Registry of the International Society for Heart and Lung
Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant 2008;27:937–
942.
17. Trulock EP, Edwards LB, Taylor DO, et al. Registry of the International Society for Heart and Lung
Transplantation: twenty-second official adult lung and heart-lung transplant report–2005. J Heart
Lung Transplant 2005;24:956–967.
967
booksmedicos.org
18. Mahidhara R, Bastani S, Ross DJ, et al. Lung transplantation in older patients? J Thorac Cardiovasc
Surg 2008;135:412–420.
19. Smith PW, Wang H, Parini V, et al. Lung transplantation in patients 60 years and older: results,
complications, and outcomes. Ann Thorac Surg 2006;82:1835–1841; discussion 1841.
20. Vadnerkar A, Toyoda Y, Crespo M, et al. Age-specific complications among lung transplant
recipients 60 years and older. J Heart Lung Transplant 2011;30:273–281.
21. Yusen RD, Shearon TH, Qian Y, et al. Lung transplantation in the United States, 1999-2008. Am J
Transplant 2010;10:1047–1068.
22. Valapour M, Paulson K, Smith JM, et al. OPTN/SRTR 2011 Annual Data Report: lung. Am J
Transplant 2013;13(suppl 1):149–177.
23. Valapour M, Skeans MA, Heubner BM, et al. OPTN/SRTR 2012 Annual Data Report: lung. Am J
Transplant 2014;14(suppl 1):139–165.
24. Baz MA, Palmer SM, Staples ED, et al. Lung transplantation after long-term mechanical ventilation :
results and 1-year follow-up. Chest. 2001;119:224–227.
25. Patel VS, Palmer SM, Messier RH, et al. Clinical outcome after coronary artery revascularization
and lung transplantation. Ann Thorac Surg 2003;75:372–377; discussion 377.
26. Fishman A, Martinez F, Naunheim K, et al. A randomized trial comparing lung-volume-reduction
surgery with medical therapy for severe emphysema. N Eng J Med 2003;348:2059–2073.
27. Oga T, Nishimura K, Tsukino M, et al. Analysis of the factors related to mortality in chronic
obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med
2003;167:544–549.
28. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and
exercise capacity index in chronic obstructive pulmonary disease. N Eng J Med 2004;350:1005–
1012.
29. De Oliveira NC, Osaki S, Maloney J, et al. Lung transplant for interstitial lung disease: outcomes
before and after implementation of the united network for organ sharing lung allocation scoring
system. Eur J Cardiothorac Surg 2012;41:680–685.
30. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic interstitial pneumonia: the prognostic
value of longitudinal functional trends. Am J Respir Crit Care Med 2003;168:531–537.
31. Mogulkoc N, Brutsche MH, Bishop PW, et al. Pulmonary function in idiopathic pulmonary fibrosis
and referral for lung transplantation. Am J Respir Crit Care Med 2001;164:103–108.
32. Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk
test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:1084–1090.
33. O’Beirne S, Counihan IP, Keane MP. Interstitial lung disease and lung transplantation. Semin Respir
Crit Care Med 2010;31:139–146.
34. Garrity ER, Moore J, Mulligan MS, et al. Heart and lung transplantation in the United States, 1996-
2005. Am J Transplant 2007;7:1390–1403.
35. OPTN/SRTR. Annual reports of the US organ procurement and transplantation network and the
scientific registry of transplant. recipients: transplant data 1999–2008. Bethesda, MD: Health
Resources and Services Administration, US Department of Health and Human Services; 2009.
36. Orens JB, Shearon TH, Freudenberger RS, et al. Thoracic organ transplantation in the United States,
1995-2004. Am J Transplant 2006;6:1188–1197.
37. Whelan TP, Dunitz JM, Kelly RF, et al. Effect of preoperative pulmonary artery pressure on early
survival after lung transplantation for idiopathic pulmonary fibrosis. J Heart Lung Transplant
2005;24:1269–1274.
38. Kerem E, Reisman J, Corey M, et al. Prediction of mortality in patients with cystic fibrosis. N Eng J
Med 1992;326:1187–1191.
39. Kreider M, Kotloff RM. Selection of candidates for lung transplantation. Proc Am Thorac Soc
2009;6:20–27.
40. Orens JB, Estenne M, Arcasoy S, et al. International guidelines for the selection of lung transplant
candidates: 2006 update–a consensus report from the Pulmonary Scientific Council of the
International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006;25:745–755.
41. Department of Health and Human Services. Final rule, 42 CFR 121: Organ procurement and
transplantation network. Federal Register 42 CFR (Part 121) 1999:56649–56661.
968
booksmedicos.org
42. Hosenpud JD, Bennett LE, Keck BM, et al. Effect of diagnosis on survival benefit of lung
transplantation for end-stage lung disease. Lancet 1998;351:24–27.
43. Titman A, Rogers CA, Bonser RS, et al. Disease-specific survival benefit of lung transplantation in
adults: a national cohort study. Am J Transplant 2009;9:1640–1649.
44. De Meester J, Smits JM, Persijn GG, et al. Lung transplant waiting list: differential outcome of type
of end-stage lung disease, one year after registration. J Heart Lung Transplant 1999;18:563–571.
45. Liou TG, Adler FR, Cox DR, et al. Lung transplantation and survival in children with cystic fibrosis.
N Eng J Med 2007;357:2143–2152.
46. Chamogeorgakis T, Mason DP, Murthy SC, et al. Impact of nutritional state on lung transplant
outcomes. J Heart Lung Transplant 2013;32:693–700.
47. Allen JG, Arnaoutakis GJ, Weiss ES, et al. The impact of recipient body mass index on survival after
lung transplantation. J Heart Lung Transpl 2010;29:1026–1033.
48. McCurry KR, Shearon TH, Edwards LB, et al. Lung transplantation in the United States, 1998-2007.
Am J Transplant 2009;9:942–958.
49. Russo MJ, Iribarne A, Hong KN, et al. High lung allocation score is associated with increased
morbidity and mortality following transplantation. Chest 2010;137:651–657.
50. Kozower BD, Meyers BF, Smith MA, et al. The impact of the lung allocation score on short-term
transplantation outcomes: a multicenter study. J Thorac Cardiovasc Surg 2008;135:166–171.
51. McCue JD, Mooney J, Quail J, et al. Ninety-day mortality and major complications are not affected
by use of lung allocation score. J Heart Lung Transplant 2008;27:192–196.
52. Thabut G, Christie JD, Mal H, et al. Survival benefit of lung transplant for cystic fibrosis since lung
allocation score implementation. Am J Respir Crit Care Med 2013;187:1335–1340.
53. OPTN. Proposal to revise the lung allocation score (LAS) system. 2013.
54. McGoon M, Miller D. REVEAL registry: registry to evaluate early and long-term PAH disease
management. Available at: http://clinicaltrials.gov/ show/NCT00370214. 2006.
55. Tsuang WM, Vock DM, Finlen Copeland CA, et al. An acute change in lung allocation score and
survival after lung transplantation: a cohort study. Ann Intern Med 2013;158:650–657.
56. Lang G, Aigner C, Winkler G, et al. Prolonged venoarterial extracorporeal membrane oxygenation
after transplantation restores functional integrity of severely injured lung allografts and prevents
the development of pulmonary graft failure in a pig model. J Thorac Cardiovasc Surg 2009;
137:1493–1498.
57. Rehder KJ, Turner DA, Hartwig MG, et al. Active rehabilitation during extracorporeal membrane
oxygenation as a bridge to lung transplantation. Respir Care 2013;58:1291–1298.
58. Turner DA, Cheifetz IM, Rehder KJ, et al. Active rehabilitation and physical therapy during
extracorporeal membrane oxygenation while awaiting lung transplantation: a practical approach.
Crit Care Med 2011;39:2593–2598.
59. Jackson A, Cropper J, Pye R, et al. Use of extracorporeal membrane oxygenation as a bridge to
primary lung transplant: 3 consecutive, successful cases and a review of the literature. J Heart Lung
Transplant 2008;27:348–352.
60. Nosotti M, Rosso L, Palleschi A, et al. Bridge to lung transplantation by venovenous extracorporeal
membrane oxygenation: a lesson learned on the first four cases. Transplant Proc 2010;42:1259–
1261.
61. Olsson KM, Simon A, Strueber M, et al. Extracorporeal membrane oxygenation in nonintubated
patients as bridge to lung transplantation. Am J Transplant 2010;10:2173–2178.
62. Strueber M, Hoeper MM, Fischer S, et al. Bridge to thoracic organ transplantation in patients with
pulmonary arterial hypertension using a pumpless lung assist device. Am J Transplant 2009;9:853–
857.
63. Fischer S, Simon AR, Welte T, et al. Bridge to lung transplantation with the novel pumpless
interventional lung assist device NovaLung. J Thorac Cardiovasc Surg 2006;131:719–723.
64. Gore A, Hatch O. National Organ Transplant Act of 1984. In: Senate 2048–98th Congress: Sec. 101-
Sec, vol. 401. Weekly Compilation of Presidential Documents, Presidential statement. Washington, DC:
1984:98–507.
65. Lewandowski K, Rossaint R, Pappert D, et al. High survival rate in 122 ARDS patients managed
according to a clinical algorithm including extracorporeal membrane oxygenation. Intens Care Med
969
booksmedicos.org
1997;23:819–835.
66. Kopp R, Dembinski R, Kuhlen R. Role of extracorporeal lung assist in the treatment of acute
respiratory failure. Minerva Anestesiol 2006;72:587–595.
67. Morris AH, Wallace CJ, Menlove RL, et al. Randomized clinical trial of pressure-controlled inverse
ratio ventilation and extracorporeal CO2 removal for adult respiratory distress syndrome. Am J
Respir Crit Care Med 1994;149:295–305.
68. Jurmann MJ, Haverich A, Demertzis S, et al. Extracorporeal membrane oxygenation as a bridge to
lung transplantation. Eur J Cardiothorac Surg 1991;5:94–97; discussion 98.
69. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as
bridge to lung transplantation. Am J Respir Crit Care Med 2012;185:763–768.
70. Meyers BF, Lynch J, Trulock EP, et al. Lung transplantation: a decade of experience. Ann Surg
1999;230:362–370; discussion 370-371.
71. Merlo C, Orens J. Selection of candidates for lung transplantation. Curr Opin Organ Transpl
2007;12:749–784.
72. Puskas JD, Winton TL, Miller JD, et al. Unilateral donor lung dysfunction does not preclude
successful contralateral single lung transplantation. J Thorac Cardiovasc Surg 1992;103:1015–1017;
73. Orens JB, Boehler A, de Perrot M, et al. A review of lung transplant donor acceptability criteria. J
74. Zenati M, Dowling RD, Dummer JS, et al. Influence of the donor lung on development of early
infections in lung transplant recipients. J Heart Transplant 1990;9:502–508; discussion 508–509.
75. Thabut G, Mal H, Cerrina J, et al. Graft ischemic time and outcome of lung transplantation: a
multicenter analysis. Am J Respir Crit Care Med 2005;171:786–791.
76. Weill D. Donor criteria in lung transplantation: an issue revisited. Chest 2002;121:2029–2031.
77. Angel LF, Levine DJ, Restrepo MI, et al. Impact of a lung transplantation donor-management
protocol on lung donation and recipient outcomes. Am J Respir Crit Care Med 2006;174:710–716.
78. Botha P, Trivedi D, Searl CP, et al. Differential pulmonary vein gases predict primary graft
dysfunction. Ann Thorac Surg 2006;82:1998–2002.
79. Arcasoy SM, Fisher A, Hachem RR, et al. Report of the ISHLT Working Group on Primary Lung
Graft Dysfunction part V: predictors and outcomes. J Heart Lung Transplant 2005;24:1483–1488.
80. de Perrot M, Keshavjee S. Lung preservation. Semin Thorac Cardiovasc Surg 2004;16:300–308.
81. Venuta F, Rendina EA, Bufi M, et al. Preimplantation retrograde pneumoplegia in clinical lung
transplantation. J Thorac Cardiovasc Surg 1999; 118:107–114.
82. DeCampos KN, Keshavjee S, Liu M, et al. Optimal inflation volume for hypothermic preservation of
rat lungs. J Heart Lung Transplant 1998;17:599–607.
83. Fukuse T, Hirata T, Ishikawa S, et al. Optimal alveolar oxygen concentration for cold storage of the
lung. Transplantation 2001;72:300–304.
84. Haniuda M, Hasegawa S, Shiraishi T, et al. Effects of inflation volume during lung preservation on
pulmonary capillary permeability. J Thorac Cardiovasc Surg 1996;112:85–93.
85. de Perrot M, Imai Y, Volgyesi GA, et al. Effect of ventilator-induced lung injury on the
development of reperfusion injury in a rat lung transplant model. J Thorac Cardiovasc Surg
2002;124:1137–1144.
86. Pierre AF, DeCampos KN, Liu M, et al. Rapid reperfusion causes stress failure in ischemic rat lungs.
J Thorac Cardiovasc Surg 1998;116:932–942.
87. Munshi L, Keshavjee S, Cypel M. Donor management and lung preservation for lung
transplantation. The Lancet. Respir Med 2013;1:318–328.
88. Punch JD, Hayes DH, LaPorte FB, et al. Organ donation and utilization in the United States, 1996-
2005. Am J Transplant 2007;7:1327–1338.
89. Jirsch DW, Fisk RL, Couves CM. Ex vivo evaluation of stored lungs. Ann Thorac Surg 1970;10:163–
168.
90. Steen S, Sjoberg T, Pierre L, et al. Transplantation of lungs from a non-heart-beating donor. Lancet
2001;357:825–829.
91. Steen S, Ingemansson R, Eriksson L, et al. First human transplantation of a nonacceptable donor
970
booksmedicos.org
lung after reconditioning ex vivo. Ann Thorac Surg 2007;83:2191–2194.
92. Cypel M, Yeung JC, Hirayama S, et al. Technique for prolonged normothermic ex vivo lung
perfusion. J Heart Lung Transplant 2008;27:1319–1325.
93. Yeung JC, Cypel M, Machuca TN, et al. Physiologic assessment of the ex vivo donor lung for
transplantation. J Heart Lung Transplant 2012;31:1120–1126.
94. Cypel M, Yeung JC, Machuca T, et al. Experience with the first 50 ex vivo lung perfusions in
clinical transplantation. J Thorac Cardiovasc Surg 2012;144:1200–1206.
95. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung
transplantation. N Eng J Med 2011;364:1431–1440.
96. Frank JA, Briot R, Lee JW, et al. Physiological and biochemical markers of alveolar epithelial
barrier dysfunction in perfused human lungs. Am J Physiol Lung Cell Mol Physiol 2007;293:L52–L59.
97. Inci I, Ampollini L, Arni S, et al. Ex vivo reconditioning of marginal donor lungs injured by acid
aspiration. J Heart Lung Transplant 2008;27:1229–1236.
98. Andreasson A, Karamanou DM, Perry JD, et al. The effect of ex vivo lung perfusion on microbial
load in human donor lungs. J Heart Lung Transplant 2014;33:910–916.
99. Boffini M, Bonato R, Rinaldi M. The potential role of ex vivo lung perfusion for the diagnosis of
infection before lung transplantation. Transpl Int 2014;27:e5–e7.
100. Machuca TN, Hsin MK, Ott HC, et al. Injury-specific ex vivo treatment of the donor lung:
pulmonary thrombolysis followed by successful lung transplantation. Am J Respir Crit Care Med
2013;188:878–880.
101. Cypel M, Liu M, Rubacha M, et al. Functional repair of human donor lungs by IL-10 gene therapy.
Sci Transl Med 2009;1:4ra9.
102. Lee JW, Fang X, Gupta N, et al. Allogeneic human mesenchymal stem cells for treatment of E. coli
endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A
2009;106:16357–16362.
103. Egan TM, Lambert CJ Jr, Reddick R, et al. A strategy to increase the donor pool: use of cadaver
lungs for transplantation. Ann Thorac Surg 1991;52:1113–1120; discussion 1120–1121.
104. Van Raemdonck DE, Jannis NC, De Leyn PR, et al. Warm ischemic tolerance in collapsed
pulmonary grafts is limited to 1 hour. Ann Surg 1998;228:788–796.
105. Greco R, Cordovilla G, Sanz E, et al. Warm ischemic time tolerance after ventilated non-heart-
beating lung donation in piglets. Eur J Cardiothorac Surg 1998;14:319–325.
106. Neyrinck AP, Van De Wauwer C, Geudens N, et al. Comparative study of donor lung injury in
heart-beating versus non-heart-beating donors. Eur J Cardiothorac Surg 2006;30:628–636.
107. Kang CH, Anraku M, Cypel M, et al. Transcriptional signatures in donor lungs from donation after
cardiac death vs after brain death: a functional pathway analysis. J Heart Lung Transplant
2011;30:289–298.
108. Wigfield CH, Love RB. Donation after cardiac death lung transplantation outcomes. Curr Opin Organ
Transplant 2011;16:462–468.
109. Levvey BJ, Harkess M, Hopkins P, et al. Excellent clinical outcomes from a national donation-after-
determination-of-cardiac-death lung transplant collaborative. Am J Transplant 2012;12:2406–2413.
110. Kootstra G, Daemen JH, Oomen AP. Categories of non-heart-beating donors. Transplant Proc
1995;27:2893–2894.
111. Bernat JL, D’Alessandro AM, Port FK, et al. Report of a National Conference on Donation after
cardiac death. Am J Transplant 2006;6:281–291.
112. Lewis J, Peltier J, Nelson H, et al. Development of the University of Wisconsin donation After
Cardiac Death Evaluation Tool. Prog Transplant 2003;13:265–273.
113. DeVita MA, Brooks MM, Zawistowski C, et al. Donors after cardiac death: validation of
identification criteria (DVIC) study for predictors of rapid death. Am J Transplant 2008;8:432–441.
114. Cypel M, Sato M, Yildirim E, et al. Initial experience with lung donation after cardiocirculatory
death in Canada. J Heart Lung Transplant 2009;28:753–758.
115. Snell GI, Levvey BJ, Oto T, et al. Early lung transplantation success utilizing controlled donation
after cardiac death donors. Am J Transplant 2008;8:1282–1289.
116. Okazaki M, Date H, Inokawa H, et al. Optimal time for post-mortem heparinization in canine lung
971
booksmedicos.org
transplantation with non-heart-beating donors. J Heart Lung Transplant 2006;25:454–460.
117. Akasaka S, Nishi H, Aoe M, et al. The effects of recombinant tissue-type plasminogen activator (rt-
PA) on canine cadaver lung transplantation. Surg Today 1999;29:747–754.
118. Keshava HB, Farver CF, Brown CR, et al. Timing of heparin and thrombus formation in donor lungs
after cardiac death. Thorac Cardiovasc Surg 2013;61:246–250.
119. Van De Wauwer C, Neyrinck AP, Geudens N, et al. Retrograde flush following warm ischemia in
the non-heart-beating donor results in superior graft performance at reperfusion. J Surg Res
2009;154:118–125.
120. Sanchez PG, Bittle GJ, Williams K, et al. Ex vivo lung evaluation of prearrest heparinization in
donation after cardiac death. Ann Surg 2013;257:534–541.
121. Brown CR, Shafii AE, Farver CF, et al. Pathologic correlates of heparin-free donation after cardiac
death in lung transplantation. J Thorac Cardiovasc Surg 2013;145:e49–e50.
122. D’Alessandro AM, Hoffmann RM, Knechtle SJ, et al. Successful extrarenal transplantation from non-
heart-beating donors. Transplantation 1995;59:977–982.
123. Mason DP, Brown CR, Murthy SC, et al. Growing single-center experience with lung transplantation
using donation after cardiac death. Ann Thorac Surg 2012;94:406–411; discussion 411–412.
124. Zych B, Popov AF, Amrani M, et al. Lungs from donation after circulatory death donors: an
alternative source to brain-dead donors? Midterm results at a single institution. Eur J Cardiothorac
Surg 2012;42:542–549.
125. De Oliveira NC, Osaki S, Maloney JD, et al. Lung transplantation with donation after cardiac death
donors: long-term follow-up in a single center. J Thorac Cardiovasc Surg 2010;139:1306–1315.
126. Puri V, Scavuzzo M, Guthrie T, et al. Lung transplantation and donation after cardiac death: a single
center experience. Ann Thorac Surg 2009;88:1609–1614; discussion 1614–1615.
127. Van De Wauwer C, Verschuuren EA, van der Bij W, et al. The use of non-heart-beating lung donors
category III can increase the donor pool. Eur J Cardiothorac Surg 2011;39:e175–e180; discussion
e180.
128. Gomez-de-Antonio D, Campo-Canaveral JL, Crowley S, et al. Clinical lung transplantation from
uncontrolled non-heart-beating donors revisited. J Heart Lung Transplant 2012;31:349–353.
129. Gerbase MW, Spiliopoulos A, Rochat T, et al. Health-related quality of life following single or
bilateral lung transplantation: a 7-year comparison to functional outcome. Chest 2005;128:1371–
1378.
130. Neurohr C, Huppmann P, Thum D, et al. Potential functional and survival benefit of double over
single lung transplantation for selected patients with idiopathic pulmonary fibrosis. Transpl Int
2010;23:887–896.
131. Kaiser LR, Cooper JD, Trulock EP, et al. The evolution of single lung transplantation for
emphysema. The Washington University Lung Transplant Group. J Thorac Cardiovasc Surg
1991;102:333–339; discussion 339–341.
132. Pochettino A, Kotloff RM, Rosengard BR, et al. Bilateral versus single lung transplantation for
chronic obstructive pulmonary disease: intermediate-term results. Ann Thorac Surg 2000;70:1813–
1818; discussion 1818–1819.
133. Meyer DM, Edwards LB, Torres F, et al. Impact of recipient age and procedure type on survival
after lung transplantation for pulmonary fibrosis. Ann Thorac Surg 2005;79:950–957; discussion
957–958.
134. Chang AC, Chan KM, Lonigro RJ, et al. Surgical patient outcomes after the increased use of
bilateral lung transplantation. J Thorac Cardiovasc Surg 2007;133:532–540.
135. Meyers BF, Lynch JP, Trulock EP, et al. Single versus bilateral lung transplantation for idiopathic
pulmonary fibrosis: a ten-year institutional experience. J Thorac Cardiovasc Surg 2000;120:99–107.
136. Meyer DM, Bennett LE, Novick RJ, et al. Single vs bilateral, sequential lung transplantation for
end-stage emphysema: influence of recipient age on survival and secondary end-points. J Heart Lung
Transplant 2001;20:935–941.
137. Minambres E, Llorca J, Suberviola B, et al. Early outcome after single vs bilateral lung
transplantation in older recipients. Transplant Proc 2008;40:3088–3089.
138. Gammie JS, Keenan RJ, Pham SM, et al. Single- versus double-lung transplantation for pulmonary
hypertension. J Thorac Cardiovasc Surg 1998;115:397–402; discussion 402–403.
972
booksmedicos.org
139. Pasque MK, Cooper JD, Kaiser LR, et al. Improved technique for bilateral lung transplantation:
rationale and initial clinical experience. Ann Thorac Surg 1990;49:785–791.
140. Toyoda Y, Thacker J, Santos R, et al. Long-term outcome of lung and heart-lung transplantation for
idiopathic pulmonary arterial hypertension. Ann Thorac Surg 2008;86:1116–1122.
141. Mason DP, Rajeswaran J, Murthy SC, et al. Spirometry after transplantation: how much better are
two lungs than one? Ann Thorac Surg 2008;85:1193–1201, 1201.e1–e2.
142. Thabut G, Christie JD, Ravaud P, et al. Survival after bilateral versus single lung transplantation for
patients with chronic obstructive pulmonary disease: a retrospective analysis of registry data.
Lancet 2008;371:744–751.
143. Nwakanma LU, Simpkins CE, Williams JA, et al. Impact of bilateral versus single lung
transplantation on survival in recipients 60 years of age and older: analysis of United Network for
Organ Sharing database. J Thorac Cardiovasc Surg 2007;133:541–547.
144. Force SD, Kilgo P, Neujahr DC, et al. Bilateral lung transplantation offers better long-term survival,
compared with single-lung transplantation, for younger patients with idiopathic pulmonary fibrosis.
Ann Thorac Surg 2011;91:244–249.
145. Anyanwu AC, McGuire A, Rogers CA, et al. Assessment of quality of life in lung transplantation
using a simple generic tool. Thorax 2001;56:218–222.
146. Weiss ES, Allen JG, Merlo CA, et al. Survival after single versus bilateral lung transplantation for
high-risk patients with pulmonary fibrosis. Ann Thorac Surg 2009;88:1616–1625; discussion 1625–
1626.
147. Black MC, Trivedi J, Schumer EM, et al. Double lung transplants have significantly improved
survival compared with single lung transplants in high lung allocation score patients. Ann Thorac
Surg 2014; 98:1737–1741.
148. Hadjiliadis D, Davis RD, Palmer SM. Is transplant operation important in determining
posttransplant risk of bronchiolitis obliterans syndrome in lung transplant recipients? Chest
2002;122:1168–1175.
149. Garfein ES, Ginsberg ME, Gorenstein L, et al. Superiority of end-to-end versus telescoped bronchial
anastomosis in single lung transplantation for pulmonary emphysema. J Thorac Cardiovasc Surg
2001;121:149–154.
150. Schroder C, Scholl F, Daon E, et al. A modified bronchial anastomosis technique for lung
transplantation. Ann Thorac Surg 2003;75:1697–1704.
151. Baudet EM, Dromer C, Dubrez J, et al. Intermediate-term results after en bloc double-lung
transplantation with bronchial arterial revascularization. Bordeaux Lung and Heart-Lung Transplant
Group. J Thorac Cardiovasc Surg 1996;112:1292–1299; discussion 1299–1300.
152. Pettersson G, Norgaard MA, Arendrup H, et al. Direct bronchial artery revascularization and en
bloc double lung transplantation–surgical techniques and early outcome. J Heart Lung Transplant
1997;16:320–333.
153. Sundset A, Tadjkarimi S, Khaghani A, et al. Human en bloc double-lung transplantation: bronchial
artery revascularization improves airway perfusion. Ann Thorac Surg 1997;63:790–795.
154. Lau CL, Patterson GA. Technical considerations in lung transplantation. Chest Surg Clin N Am.
2003;13:463–483.
155. Lau CL, Hoganson DM, Meyers BF, et al. Use of an apical heart suction device for exposure in lung
156. Hachem RR, Yusen RD, Chakinala MM, et al. A randomized controlled trial of tacrolimus versus
cyclosporine after lung transplantation. J Heart Lung Transplant 2007;26:1012–1018.
157. Mullen JC, Oreopoulos A, Lien DC, et al. A randomized, controlled trial of daclizumab vs anti-
thymocyte globulin induction for lung transplantation. J Heart Lung Transplant 2007;26:504–510.
158. Burton CM, Andersen CB, Jensen AS, et al. The incidence of acute cellular rejection after lung
transplantation: a comparative study of anti-thymocyte globulin and daclizumab. J Heart Lung
Transplant 2006;25:638–647.
159. Hachem RR, Chakinala MM, Yusen RD, et al. A comparison of basiliximab and anti-thymocyte
globulin as induction agents after lung transplantation. J Heart Lung Transplant 2005;24:1320–1326.
160. Arcasoy SM, Kotloff RM. Lung transplantation. N Eng J Med 1999;340:1081–1091.
161. Amital A, Shitrit D, Raviv Y, et al. Development of malignancy following lung transplantation.
973
booksmedicos.org
Transplantation 2006;81:547–551.
162. Christie JD, Kotloff RM, Ahya VN, et al. The effect of primary graft dysfunction on survival after
lung transplantation. Am J Respir Crit Care Med 2005;171:1312–1316.
163. Novick RJ, Stitt LW, Al-Kattan K, et al. Pulmonary retransplantation: predictors of graft function
and survival in 230 patients. Pulmonary Retransplant Registry. Ann Thorac Surg 1998;65:227–234.
164. Christie JD, Carby M, Bag R, et al. Report of the ISHLT Working Group on Primary Lung Graft
Dysfunction part II: definition. A consensus statement of the International Society for Heart and
Lung Transplantation. J Heart Lung Transplant 2005;24:1454–1459.
165. Prekker ME, Nath DS, Walker AR, et al. Validation of the proposed International Society for Heart
and Lung Transplantation grading system for primary graft dysfunction after lung transplantation. J
166. Whitson BA, Prekker ME, Herrington CS, et al. Primary graft dysfunction and long-term pulmonary
function after lung transplantation. J Heart Lung Transplant 2007;26:1004–1011.
167. Low DE, Kaiser LR, Haydock DA, et al. The donor lung: infectious and pathologic factors affecting
outcome in lung transplantation. J Thorac Cardiovasc Surg 1993;106:614–621.
168. Ettinger NA, Bailey TC, Trulock EP, et al. Cytomegalovirus infection and pneumonitis. Impact after
isolated lung transplantation. Washington University Lung Transplant Group. Am Rev Respir Dis
1993;147:1017–1023.
169. Novick RJ, Schafers HJ, Stitt L, et al. Recurrence of obliterative bronchiolitis and determinants of
outcome in 139 pulmonary retransplant recipients. J Thorac Cardiovasc Surg 1995;110:1402–1413;
170. Russo MJ, Sternberg DI, Hong KN, et al. Postlung transplant survival is equivalent regardless of
cytomegalovirus match status. Ann Thorac Surg 2007;84:1129–1134; discussion 1134–1135.
171. Monforte V, Lopez C, Santos F, et al. A multicenter study of valganciclovir prophylaxis up to day
120 in CMV-seropositive lung transplant recipients. Am J Transplant 2009;9:1134–1141.
172. Sole A, Salavert M. Fungal infections after lung transplantation. Transplant Rev 2008;22:89–104.
173. Husain S, Zaldonis D, Kusne S, et al. Variation in antifungal prophylaxis strategies in lung
transplantation. Transpl Infect Dis 2006;8:213–218.
174. Santacruz JF, Mehta AC. Airway complications and management after lung transplantation:
ischemia, dehiscence, and stenosis. Proc Am Thorac Soc 2009;6:79–93.
175. Shofer SL, Wahidi MM, Davis WA, et al. Significance of and risk factors for the development of
central airway stenosis after lung transplantation. Am J Transplant 2013;13:383–389.
176. Dutau H, Vandemoortele T, Laroumagne S, et al. A new endoscopic standardized grading system for
macroscopic central airway complications following lung transplantation: the MDS classification.
Eur J Cardiothorac Surg 2014;45:e33–e38.
177. Bloom RD, Goldberg LR, Wang AY, et al. An overview of solid organ transplantation. Clin Chest
Med 2005;26:529–543, v.
178. Schafers HJ, Wagner TO, Demertzis S, et al. Preoperative corticosteroids. A contraindication to
lung transplantation? Chest 1992;102:1522–1525.
179. Groetzner J, Kur F, Spelsberg F, et al. Airway anastomosis complications in de novo lung
transplantation with sirolimus-based immunosuppression. J Heart Lung Transplant 2004;23:632–638.
180. King-Biggs MB, Dunitz JM, Park SJ, et al. Airway anastomotic dehiscence associated with use of
sirolimus immediately after lung transplantation. Transplantation 2003;75:1437–1443.
181. Garfein ES, McGregor CC, Galantowicz ME, et al. Deleterious effects of telescoped bronchial
anastomosis in single and bilateral lung transplantation. Ann Transplant 2000;5:5–11.
182. Schmid RA, Boehler A, Speich R, et al. Bronchial anastomotic complications following lung
transplantation: still a major cause of morbidity? Eur Respir J 1997;10:2872–2875.
183. Murthy SC, Blackstone EH, Gildea TR, et al. Impact of anastomotic airway complications after lung
transplantation. Ann Thorac Surg 2007;84:401–409, 409.e401–e404.
184. Van De Wauwer C, Van Raemdonck D, Verleden GM, et al. Risk factors for airway complications
within the first year after lung transplantation. Eur J Cardiothorac Surg 2007;31:703–710.
185. Shennib H, Massard G. Airway complications in lung transplantation. Ann Thorac Surg 1994;57:506–
511.
974
booksmedicos.org
186. Mulligan MS. Endoscopic management of airway complications after lung transplantation. Chest
Surg Clin N Am 2001;11:907–915.
187. Murthy SC, Gildea TR, Machuzak MS. Anastomotic airway complications after lung transplantation.
Curr Opin Organ Transplant 2010;15:582–587.
188. Hasegawa T, Iacono AT, Orons PD, et al. Segmental nonanastomotic bronchial stenosis after lung
189. Marulli G, Loy M, Rizzardi G, et al. Surgical treatment of posttransplant bronchial stenoses: case
reports. Transplant Proc 2007;39:1973–1975.
190. Herrera JM, McNeil KD, Higgins RS, et al. Airway complications after lung transplantation:
treatment and long-term outcome. Ann Thorac Surg 2001;71:989–993; discussion 993–984.
191. Usuda K, Gildea TR, Pandya C, et al. Bronchial dehiscence. J Bronchology Interv Pulmonol
2005;12:164–165.
192. Castleberry AW, Worni M, Kuchibhatla M, et al. A comparative analysis of bronchial stricture after
lung transplantation in recipients with and without early acute rejection. Ann Thorac Surg
2013;96:1008–1017; discussion 1017–1008.
193. Kshettry VR, Kroshus TJ, Hertz MI, et al. Early and late airway complications after lung
transplantation: incidence and management. Ann Thorac Surg 1997;63:1576–1583.
194. Garg K, Zamora MR, Tuder R, et al. Lung transplantation: indications, donor and recipient
selection, and imaging of complications. Radiographics 1996;16:355–367.
195. Quint LE, Whyte RI, Kazerooni EA, et al. Stenosis of the central airways: evaluation by using
helical CT with multiplanar reconstructions. Radiology 1995;194:871–877.
196. Chhajed PN, Malouf MA, Tamm M, et al. Interventional bronchoscopy for the management of
airway complications following lung transplantation. Chest 2001;120:1894–1899.
197. De Gracia J, Culebras M, Alvarez A, et al. Bronchoscopic balloon dilatation in the management of
bronchial stenosis following lung transplantation. Respir Med 2007;101:27–33.
198. Brodeur I, Goulet I, Tremblay CS, et al. Regulation of the Fanconi anemia group C protein through
proteolytic modification. J Biol Chem 2004;279:4713–4720.
199. Erard AC, Monnier P, Spiliopoulos A, et al. Mitomycin C for control of recurrent bronchial stenosis:
a case report. Chest 2001;120:2103–2105.
200. Penafiel A, Lee P, Hsu A, et al. Topical mitomycin-C for obstructing endobronchial granuloma. Ann
Thorac Surg 2006;82:e22–e23.
201. Saad CP, Ghamande SA, Minai OA, et al. The role of self-expandable metallic stents for the
treatment of airway complications after lung transplantation. Transplantation 2003;75:1532–1538.
202. Madden BP, Loke TK, Sheth AC. Do expandable metallic airway stents have a role in the
management of patients with benign tracheobronchial disease? Ann Thorac Surg 2006;82:274–278.
203. Murgu SD, Colt HG. Complications of silicone stent insertion in patients with expiratory central
airway collapse. Ann Thorac Surg 2007;84:1870–1877.
204. Gildea TR, Murthy SC, Sahoo D, et al. Performance of a self-expanding silicone stent in palliation of
benign airway conditions. Chest 2006;130:1419–1423.
205. Bolliger CT, Sutedja TG, Strausz J, et al. Therapeutic bronchoscopy with immediate effect: laser,
electrocautery, argon plasma coagulation and stents. Eur Respir J 2006;27:1258–1271.
206. Kapoor BS, May B, Panu N, et al. Endobronchial stent placement for the management of airway
complications after lung transplantation. J Vasc Interv Radiol 2007;18:629–632.
207. Grosu HB, Eapen GA, Morice RC, et al. Stents are associated with increased risk of respiratory
infections in patients undergoing airway interventions for malignant airways disease. Chest
2013;144:441–449.
208. Mughal MM, Gildea TR, Murthy S, et al. Short-term deployment of self-expanding metallic stents
facilitates healing of bronchial dehiscence. Am J Respir Crit Care Med 2005;172:768–771.
209. Thistlethwaite PA, Yung G, Kemp A, et al. Airway stenoses after lung transplantation: incidence,
management, and outcome. J Thorac Cardiovasc Surg 2008;136:1569–1575.
210. Schreinemakers HH, Weder W, Miyoshi S, et al. Direct revascularization of bronchial arteries for
lung transplantation: an anatomical study. Ann Thorac Surg 1990;49:44–53; discussion 53–54.
211. Couraud L, Baudet E, Nashef SA, et al. Lung transplantation with bronchial revascularisation.
975
booksmedicos.org
Surgical anatomy, operative technique and early results. Eur J Cardiothorac Surg 1992;6:490–495.
212. Daly RC, McGregor CG. Routine immediate direct bronchial artery revascularization for single-lung
213. Daly RC, Tadjkarimi S, Khaghani A, et al. Successful double-lung transplantation with direct
bronchial artery revascularization. Ann Thorac Surg 1993;56:885–892.
214. Pettersson G, Arendrup H, Mortensen SA, et al. Early experience of double-lung transplantation
with bronchial artery revascularization using mammary artery. Eur J Cardiothorac Surg 1994;8:520–
524.
215. Burton CM, Milman N, Carlsen J, et al. The Copenhagen National Lung Transplant Group: survival
after single lung, double lung, and heart-lung transplantation. J Heart Lung Transplant
2005;24:1834–1843.
216. Pettersson GB, Karam K, Thuita L, et al. Comparative study of bronchial artery revascularization in
lung transplantation. J Thorac Cardiovasc Surg 2013;146:894–900.e893.
217. Sato M, Keshavjee S. Bronchiolitis obliterans syndrome: alloimmune-dependent and -independent
injury with aberrant tissue remodeling. Semin Thorac Cardiovasc Surg 2008;20:173–182.
218. Chalermskulrat W, Neuringer IP, Schmitz JL, et al. Human leukocyte antigen mismatches
predispose to the severity of bronchiolitis obliterans syndrome after lung transplantation. Chest
2003;123:1825–1831.
219. Keller CA, Cagle PT, Brown RW, et al. Bronchiolitis obliterans in recipients of single, double, and
heart-lung transplantation. Chest 1995;107:973–980.
220. Hartwig MG, Anderson DJ, Onaitis MW, et al. Fundoplication after lung transplantation prevents
the allograft dysfunction associated with reflux. Ann Thorac Sur 2011;92:462–468; discussion 468–
469.
221. Daud SA, Yusen RD, Meyers BF, et al. Impact of immediate primary lung allograft dysfunction on
bronchiolitis obliterans syndrome. Am J Respir Crit Care Med 2007;175:507–513.
222. Todd JL, Jain R, Pavlisko EN, et al. Impact of forced vital capacity loss on survival after the onset
of chronic lung allograft dysfunction. Am J Respir Crit Care Med 2014;189:159–166.
223. Sato M, Waddell TK, Wagnetz U, et al. Restrictive allograft syndrome (RAS): a novel form of
chronic lung allograft dysfunction. J Heart Lung Transplant 2011;30:735–742.
224. Young LR, Hadjiliadis D, Davis RD, et al. Lung transplantation exacerbates gastroesophageal reflux
disease. Chest 2003;124:1689–1693.
225. Davis CS, Shankaran V, Kovacs EJ, et al. Gastroesophageal reflux disease after lung transplantation:
pathophysiology and implications for treatment. Surgery 2010;148:737–744; discussion 744–735.
226. Fisichella PM, Davis CS, Shankaran V, et al. The prevalence and extent of gastroesophageal reflux
disease correlates to the type of lung transplantation. Surg Laparosc Endosc Percutan Tech
2012;22:46–51.
227. Mendez BM, Davis CS, Weber C, et al. Gastroesophageal reflux disease in lung transplant patients
with cystic fibrosis. Am J Surg 2012;204:e21–e26.
228. Gasper WJ, Sweet MP, Golden JA, et al. Lung transplantation in patients with connective tissue
disorders and esophageal dysmotility. Dis Esophagus 2008;21:650–655.
229. Ward C, Forrest IA, Brownlee IA, et al. Pepsin like activity in bronchoalveolar lavage fluid is
suggestive of gastric aspiration in lung allografts. Thorax 2005;60:872–874.
230. Stovold R, Forrest IA, Corris PA, et al. Pepsin, a biomarker of gastric aspiration in lung allografts: a
putative association with rejection. Am J Respir Crit Care Med 2007;175:1298–1303.
231. Shafi MA, Pasricha PJ. Post-surgical and obstructive gastroparesis. Curr Gastroenterol Rep
2007;9:280–285.
232. Berkowitz N, Schulman LL, McGregor C, et al. Gastroparesis after lung transplantation. Potential
role in postoperative respiratory complications. Chest 1995;108:1602–1607.
233. Robertson AG, Krishnan A, Ward C, et al. Anti-reflux surgery in lung transplant recipients:
outcomes and effects on quality of life. Eur Respir J 2012;39:691–697.
234. D’Ovidio F, Mura M, Ridsdale R, et al. The effect of reflux and bile acid aspiration on the lung
allograft and its surfactant and innate immunity molecules SP-A and SP-D. Am J Transplant
2006;6:1930–1938.
976
booksmedicos.org
235. Fisichella PM, Davis CS, Lundberg PW, et al. The protective role of laparoscopic antireflux surgery
against aspiration of pepsin after lung transplantation. Surgery 2011;150:598–606.
236. Hadjiliadis D, Duane Davis R, Steele MP, et al. Gastroesophageal reflux disease in lung transplant
recipients. Clin Transplant 2003;17:363–368.
237. Li B, Hartwig MG, Appel JZ, et al. Chronic aspiration of gastric fluid induces the development of
obliterative bronchiolitis in rat lung transplants. Am J Transplant 2008;8:1614–1621.
238. Meltzer AJ, Weiss MJ, Veillette GR, et al. Repetitive gastric aspiration leads to augmented indirect
allorecognition after lung transplantation in miniature swine. Transplantation 2008;86:1824–1829.
239. D’Ovidio F, Mura M, Tsang M, et al. Bile acid aspiration and the development of bronchiolitis
obliterans after lung transplantation. J Thorac Cardiovasc Surg 2005;129:1144–1152.
240. Neujahr DC, Uppal K, Force SD, et al. Bile acid aspiration associated with lung chemical profile
linked to other biomarkers of injury after lung transplantation. Am J Transplant 2014;14:841–848.
241. Shah N, Force SD, Mitchell PO, et al. Gastroesophageal reflux disease is associated with an
increased rate of acute rejection in lung transplant allografts. Transplant Proc 2010;42:2702–2706.
242. Mason DP, Little SG, Nowicki ER, et al. Temporal pattern of transfusion and its relation to rejection
after lung transplantation. J Heart Lung Transplant 2009;28:558–563.
243. Blondeau K, Mertens V, Vanaudenaerde BA, et al. Gastro-oesophageal reflux and gastric aspiration
in lung transplant patients with or without chronic rejection. Eur Respir J 2008;31:707–713.
244. Reder NP, Davis CS, Kovacs EJ, et al. The diagnostic value of gastroesophageal reflux disease
(GERD) symptoms and detection of pepsin and bile acids in bronchoalveolar lavage fluid and
exhaled breath condensate for identifying lung transplantation patients with GERD-induced
aspiration. Surg Endosc 2014;28:1794–1800.
245. Tang T, Chang JC, Xie A, et al. Aspiration of gastric fluid in pulmonary allografts: effect of pH. J
Surg Res 2013;181:e31–e38.
246. Theisen J, Nehra D, Citron D, et al. Suppression of gastric acid secretion in patients with
gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile
acids. J Gastrointest Surg 2000;4:50–54.
247. Raviv Y, D’Ovidio F, Pierre A, et al. Prevalence of gastroparesis before and after lung
transplantation and its association with lung allograft outcomes. Clin Transplant 2012;26:133–142.
248. Abbassi-Ghadi N, Kumar S, Cheung B, et al. Anti-reflux surgery for lung transplant recipients in the
presence of impedance-detected duodenogastroesophageal reflux and bronchiolitis obliterans
syndrome: a study of efficacy and safety. J Heart Lung Transplant 2013;32:588–595.
249. Fisichella PM, Davis CS, Gagermeier J, et al. Laparoscopic antireflux surgery for gastroesophageal
reflux disease after lung transplantation. J Surg Res 2011;170:e279–e286.
250. Neujahr DC, Mohammed A, Ulukpo O, et al. Surgical correction of gastroesophageal reflux in lung
transplant patients is associated with decreased effector CD8 cells in lung lavages: a case series.
Chest 2010;138:937–943.
251. Fisichella PM, Davis CS, Lowery E, et al. Pulmonary immune changes early after laparoscopic
antireflux surgery in lung transplant patients with gastroesophageal reflux disease. J Surg Res
2012;177:e65–e73.
252. Cantu E, 3rd, Appel JZ, 3rd, Hartwig MG, et al. J. Maxwell Chamberlain Memorial Paper. Early
fundoplication prevents chronic allograft dysfunction in patients with gastroesophageal reflux
disease. Ann Thorac Surg 2004;78:1142–1151; discussion 1142–1151.
253. Ott HC, Clippinger B, Conrad C, et al. Regeneration and orthotopic transplantation of a bioartificial
lung. Nat Med 2010;16:927–933.
254. Petersen TH, Calle EA, Zhao L, et al. Tissue-engineered lungs for in vivo implantation. Science
2010;329:538–541.
977
booksmedicos.org
Chapter 40
Pancreas and Islet Transplantation

Randall S. Sung
Key Points
1 The Diabetes Control and Complications Trial (DCCT) demonstrated that tight control of blood
glucose and minimization of hemoglobin A1C delays the progression of secondary complications of
diabetes.
2 Recipients with functioning pancreas transplants have normal glycemic control without the need for
exogenous insulin, and pancreas transplantation has a beneficial impact on diabetic complications.
3 Pancreas graft survival rates are 90% at 1 year.
4 Most pancreas transplants are performed in patients with end-stage renal disease (ESRD), either
concomitant with or following a kidney transplant.
5 In general, eligibility criteria for pancreas transplantation are more stringent than for kidney
transplantation alone.
6 Pancreas transplant outcome is dependent on the careful selection of donors and on meticulous
pancreas procurement technique.
7 Immunosuppression for pancreas transplantation is similar to that for kidney transplantation.
8 In contrast to kidney transplants, the effect of a pancreas transplant on patient survival is probably
only modest.
9 Islet transplantation does not require an operative procedure.
10 Although early outcomes are excellent at major islet centers, long-term rates of insulin independence
are worse than whole-pancreas transplants, but continue to improve.
Diabetes mellitus is a spectrum of impaired glucose tolerance that ranges from gestational glucose
intolerance to severe hyperglycemia and ketoacidosis. Diabetes, which affects approximately 8% of the
U.S. population, can be divided into two major classifications. Type 1, previously referred to as insulin-
dependent diabetes, is an autoimmune disease characterized by the eventual loss of all pancreatic β-cell
function. Type 2 diabetes, previously referred to as non–insulin-dependent diabetes or adult-onset
diabetes, characteristically presents in obese patients over age 40.1 Many of these individuals eventually
require insulin therapy. The incidence of type 2 diabetes is increasing as the prevalence of obesity
increases, especially in younger age groups. The annual percentage change for age-adjusted prevalence
and incidence of diagnosed diabetes did not change significantly during the 1980s, but increased sharply
each year during 1990 to 2008 before leveling off with no significant change during 2008–2012.2
Analyses of nationally representative data from 1980 to 2012 suggest a doubling of the incidence and
prevalence of diabetes during 1990–2008, and a plateauing between 2008 and 2012. There appear to be
continued increases in the prevalence or incidence of diabetes among subgroups, including non-Hispanic
black and Hispanic subpopulations and those with a high school education or less.
While the mean age of onset is in the early teenage years, the disease may present as early as the first
year of life. Type 1 diabetes afflicts approximately one in every 400 to 500 children and adolescents.3
Patients may present as late as the fourth decade of life, and these patients may be misclassified as type
2 diabetics, despite clearly possessing the physiology of type 1 diabetes. The disease classically presents
in a lean patient with polyuria, polydipsia, and polyphagia. It may present at the time of a concurrent
illness. While there may be a brief “honeymoon” period after presentation where insulin is not required,
exogenous insulin is always required to replace that lost by the complete destruction of β-cell mass.
While hyperglycemic episodes from poorly controlled diabetes, or hypoglycemic events from insulin,
may be life threatening, the major morbidity of type 1 diabetes stems from the myriad long-term
manifestations of the disease, particularly those that are due to accelerated atherosclerosis.
978
booksmedicos.org
PATHOPHYSIOLOGY
The classic pathophysiology of diabetes is that of insulin secretory failure in type 1 diabetes and
peripheral insulin resistance in patients with type 2 diabetes. The etiology, epidemiology, and
pathogenesis of diabetes are much more complex than is reflected in early characterizations of the
disease. Type 1 diabetes is classically described as an autoimmune disorder manifest by destruction of β-
cells, with proinsulin being the most likely primary target.4 Although there are rare monogenic,
immune-mediated forms of type 1 diabetes, the common form is thought to be determined by multiple
genetic and environmental factors. The concordance for type 1 diabetes in monozygotic twins is less
than 100%, and although type 1 diabetes aggregates in some families, it does not segregate with any
clear mode of inheritance.5
There is multigenic susceptibility to type 1 diabetes. Genes within the HLA region, especially those
that encode antigen-presenting molecules, confer the greatest part of the genetic risk of type 1 diabetes.
The likelihood that these many genes may individually only have weak effects make them more difficult
to identify precisely, and may explain the heterogeneity of inheritance of type 1 diabetes. This genetic
susceptibility background is thought to interact with environmental triggers, perhaps infectious, that
lead to autoimmunity and insulitis, the characteristic pathologic lesion of type 1 diabetes, although
definitive proof of these triggers is lacking.
The incidence of type 1 diabetes has been progressively increasing during the past several decades,
particularly among children younger than 5 years. In children at genetic risk, diabetes-related
autoantibodies appear, followed by the evolution of metabolic abnormalities and the eventual clinical
appearance of the disease. If individuals identified by genetic markers subsequently undergo
seroconversion and develop two or more diabetes-related autoantibodies, their risk of progression to
type 1 diabetes is 75% over 10 years and appears to be almost certain over 20 years.6 Attempts at
primary prevention before seroconversion, and secondary prevention in those with diabetes-related
autoantibodies, have not been successful.7 The interventions evaluated to date have been very low risk
since they are designed to be used in at-risk individuals who may or may not progress to type 1
diabetes.
Mucosal tolerance has been exploited in secondary prevention studies using nasal insulin and in
secondary prevention and recent-onset type 1 diabetes studies using oral insulin.8 However, these
studies have not been successful in altering the course of the disease. In the Diabetes Prevention Trial–
Type 1 (DPT-1), a secondary prevention study of oral insulin, those with high levels of insulin
autoantibodies at baseline had a projected 4.5- to 5-year delay in the development of clinical diabetes. A
subsequent analysis showed continued beneficial effects even after oral insulin was discontinued.
In type 2 diabetes, while β-cell hypersecretion initially may exist, ultimately loss of β-cell mass
ensues. β-Cell apoptosis is mediated by glucotoxicity from insulin resistance, and is exacerbated by fatty
acids, lipoproteins, leptins, and cytokines, all of which are elevated in type 2 diabetes and obesity.9
Because of peripheral insulin resistance, many patients require insulin in amounts that exceed one unit
per kilogram, far greater than typically required by type 1 diabetics.
The observation that type 1 and type 2 diabetes frequently cooccur in the same family has raised the
possibility that they are opposite ends of the same disease spectrum, and ample evidence suggests the
two are more similar than initially believed.10,11 Families with mixed diabetes histories tend to have an
intermediate diabetes phenotype: insulin resistance in type 1 and lower BMI and C-peptide
concentrations in type 2 patients. β-Cell destruction is common to both types, and obesity and insulin
resistance have both been shown to be risk factors for childhood type 1 as well as type 2 diabetes. The
“accelerator hypothesis” of diabetes proposes three determinants of disease in all types of diabetes: the
intrinsic rate of β-cell apoptosis, insulin resistance, and autoimmunity (which would apply only to a
subset). Genetic studies suggest there may be a common predisposition. However, the cytokines, signal
transduction pathways, and other soluble mediators of apoptosis are quite different between the insulitis
of type 1 diabetes and the lipotoxic or glucotoxic processes of type 2 diabetes, and thus at minimum
represent distinct mechanisms of β-cell destruction.12
The relatively recent discovery of the replicative potential of a variety of adult tissue types, and their
roles in the pathogenesis of disease, has relevance to the pathogenesis of diabetes. In such a model,
diabetes occurs due to a failure of regeneration of β-cells, and individual variation in the ability to
regenerate β-cells is an important determinant of diabetes development. This hypothesis is partially
supported by the finding of associations of type 2 diabetes with genes having identified roles in cellular
development. While it is broadly agreed that failure of β-cell replication is an important contributor to
diabetes development, increased susceptibility of replicating β-cells to apoptosis in a proapoptotic
979
booksmedicos.org
environment may also lead to loss of β-cell mass. There is also evidence that deficits of β-cell secretion
are as important as those of replication. Furthermore, the range of β-cell mass in adult diabetic and
nondiabetic humans is very wide, and exceeds the apparent capacity for expansion of β-cell mass in
response to regenerative stimuli. Thus it appears more likely that insufficient growth of β-cell mass
during development may be more likely to have a role in the predisposition to diabetes than specific
deficits in regeneration.13
Alternatively, β-cell dedifferentiation, rather than death, may be the mechanism responsible for β-cell
failure in type 2 diabetes.14 When normal β-cells are challenged by mild hyperglycemia or insulin
resistance, they produce and secrete more insulin, thus maintaining euglycemia. Current thinking
suggests that oxidative stress and/or endoplasmic-reticulum stress results in β-cell dysfunction, leading
to increased secretion of incompletely processed proinsulin, which may trigger apoptosis. Stressed β-
cells may undergo dedifferentiation, decreasing expression of β-cell–specific genes, including the
enzyme that processes proinsulin; this may explain increased proinsulin secretion in type 2 diabetes.
Dedifferentiation may also promote expression of embryonic progenitor-cell markers, and these cells
may later secrete non–β-cell hormones such as somatostatin and glucagon.
SECONDARY COMPLICATIONS OF DIABETES

Diabetes mellitus is responsible for tens of thousands of deaths each year in the United States. The high
incidence of cardiovascular complications in diabetics is primarily responsible for the twofold increase
in the risk of death in diabetics compared with those without diabetes.2 Clinical complications of
diabetes include end-stage renal disease (ESRD), retinopathy, peripheral vascular disease, coronary
artery disease, and neuropathy. Diabetic nephropathy is responsible for nearly half of all cases of ESRD;
diabetes is also the leading cause of blindness and amputations in the United States.15 In 2012, 1 in 5
healthcare dollars was spent to support the care of patients with diabetes at a total estimated cost of
$245 billion.16
Improvements in diabetes care have reduced the long-term impact to some extent. Rates of all five
major diabetes complications (acute myocardial infarction, hyperglycemic crisis, stroke, amputations,
and ESRD) declined between 1990 and 2010, with the smallest decline in end-stage renal disease.
However, when expressed as rates for the overall population, in which a change in prevalence also
affects complication rates, there was a decline in rates of acute myocardial infarction and death from
hyperglycemic crisis, but not in rates of amputation, stroke, or ESRD. Thus, while rates of diabetes-
related complications have declined substantially in the past two decades, a large burden of disease
persists because of the continued increase in the prevalence of diabetes.17
While diabetic complications have a multifactorial etiology, they are ultimately secondary to
structural alterations in nerves, blood vessels, and connective tissue. Excess glucose is converted to
sorbitol by aldose reductase, leading to the reduction of cellular content of myoinositol, abnormal
phosphoinositide metabolism, and reduction in Na+-K+-ATPase activity. In experimental animals, aldose
reductase inhibitors prevent diabetic neuropathy, cataracts and retinopathy.18 The accumulation of
advanced glycosylation end products (AGEs), due to abnormal nonenzymatic glycosylation of proteins,
and extensive crosslinking of these proteins, is likely to be pathogenic.19 Ligation of endothelial cell
receptors by AGEs results in the release of proinflammatory cytokines and activation of the coagulation
cascade. Microangiopathy is characterized by thickening of capillary basement membranes, which
increases with the duration of disease, and altered capillary permeability.
1 The Diabetes Control and Complications Trial (DCCT) demonstrated that tight control of blood
glucose prevents and delays the progression of secondary complications of diabetes.20,21 This study, in
which patients with type 1 diabetes were randomized to conventional treatment with one or two doses
of daily insulin versus intensive treatment with three or more injections per day, demonstrated a
dramatic reduction in the risk of progression of retinopathy, microalbuminuria, albuminuria, peripheral
neuropathy, and cardiovascular disease in the subjects randomized to intensive treatment. However, the
major side effect of intensive treatment was a threefold increase in the risk of severe hypoglycemic
episodes; approximately 10% of patients in the intensive insulin therapy cohort experienced five or
more episodes of seizure or coma during the study period. Even in the absence of overt brain injury,
multiple episodes of severe hypoglycemia have been associated with cerebral perfusion abnormalities
and poor neuropsychiatric performance. In addition, there is a significant risk of accident during
hypoglycemic episodes. Frequently, as hypoglycemia becomes more frequent and autonomic neuropathy
980
booksmedicos.org
worsens, patients may develop a syndrome of unawareness to hypoglycemia where the typical
symptoms of tremor and anxiety do not occur. Such patients with hypoglycemic unawareness may
develop profound hypoglycemia, especially if left unsupervised, and risk severe neurologic and
traumatic injury.
In a similar trial, patients randomized to intensive insulin therapy, compared to those randomized to
conventional therapy, had lower all-cause mortality. The most common causes of death were
cardiovascular disease (22%), cancer (20%), and acute complications (18%).22 The long-term risk of an
impaired glomerular filtration rate (GFR) was significantly lower among persons treated early in the
course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional
diabetes therapy.23 Notably, all-cause mortality was significantly higher among those with higher mean
hemoglobin A1C (HbA1C) levels and with renal disease during the 20-year follow-up.22
The overall management of diabetes is focused upon maintaining blood glucose as close to normal
range as possible while attempting to minimize significant hypoglycemic episodes. Although the
frequency and extent of hyperglycemia is important in the assessment of glucose management, long-
term glycemic control is best assessed by evaluation of blood levels of hemoglobin A1C which measures
the extent of glycosylation of hemoglobin. Although the incidence of diabetes is increasing, the overall
treatment efficacy has improved. The use of subcutaneous insulin pumps is being increasingly
employed, inhaled insulin has been used in selected patients, and infusion devices which also assess
serum glucose and automatically adjust insulin dose accordingly are being developed.24,25 Fully
automated artificial-pancreas systems have been developed which link glucose sensors with insulin
pumps through computerized control algorithms, which dictate insulin delivery in response to real-time
sensor data.26 Recent studies that have been carried out in hospitals have shown that such systems can
improve glucose control and reduce the risk of nocturnal hypoglycemia in children, adolescents, and
adults. Although such studies are encouraging, the major challenge ahead is successful implementation
of such systems outside the hospital.
In practice it is the rare diabetic who can maintain tight glucose control without hypoglycemic
complications. In fact, in a study of type 2 diabetics designed to reduce cardiovascular complications
through normalization of glycemic control, intensive therapy was associated with increased early
mortality and no reduction of cardiovascular events.27 Most type 1 diabetics, even if on optimal insulin
therapy, are unable to maintain hemoglobin A1C levels in the normal range, and most will ultimately
develop progressive diabetic complications.
PANCREAS TRANSPLANTATION
Overview
2 Pancreas transplantation, while not technically a cure, represents an important therapeutic insulin
replacement option for many type 1 diabetics. Recipients with functioning pancreas transplants have
normal glycemic control without the need for exogenous insulin. Initial experience with pancreas
transplantation, from the first pancreas transplant performed by Kelly and Lillehei in 1966 until the
1980s, was marked by low success rates and high mortality.28 In 1980 the 1-year graft survival rate for
pancreas transplantation was only 21%, and there was tremendous skepticism about the utility of the
procedure.
3 Advances in surgical technique and immunosuppression have dramatically improved current graft
survival rates to around 90% at 1 year. In addition to the development of cyclosporine, the introduction
of bladder drainage of the donor pancreas, first introduced by Sollinger in 1985 using a button of donor
duodenum, and subsequently modified by Corry in 1986 using an entire segment of duodenum
anastomosed to the urinary bladder, dramatically improved the results of pancreas transplantation (Fig.
40-1).29,30 Graft survival continued to improve throughout the 1980s and 1990s, especially for isolated
pancreas transplantation (pancreas transplant alone [PTA], or pancreas after kidney transplantation
[PAK]), the results of which have been historically inferior to simultaneous kidney–pancreas transplants
(SPK). Both short- and long-term survival of pancreas transplants have slowly improved over the past
decade. Because bladder drainage is associated with significant morbidity, most pancreas transplants are
currently performed with enteric exocrine drainage and venous drainage into the systemic circulation.
However, pancreas transplantation may also be performed by draining pancreatic venous blood into the
recipient portal circulation, usually via the superior mesenteric vein.
981
booksmedicos.org
Figure 40-1. Simultaneous pancreas kidney transplantation performed with drainage of the pancreatic exocrine secretions into the
urinary bladder (bladder drainage). This technique has been predominant until recently. Note that a segment of the second portion
of the duodenum is left attached to the pancreas. Despite its heterotopic location, the transplanted pancreas responds to
gastrointestinal hormones with a marked increase in secretion of pancreatic juice that has very high bicarbonate content. Also note
that the portal vein drains into the iliac vein (i.e., systemic venous drainage). In healthy individuals 50% of the secreted insulin is
extracted from the circulation in the first pass through the liver. Transplant recipients with systemic venous drainage have
peripheral insulin levels two to two and one half times higher than normal.
Patient Selection
Pancreas transplantation is usually performed in patients with type 1 diabetes. The diagnosis of type 1
diabetes is relatively straightforward for most individuals. A history of juvenile or young adult onset,
diabetic ketoacidosis, a lean body habitus, and a low insulin requirement (<0.7 units/kg) all support
the diagnosis of type 1 diabetes. In contrast, older age of onset, obesity, an interval of treatment with
diet or oral agents, or high insulin requirements are all suggestive of type 2 diabetes. A subset of adult-
onset diabetics will display characteristics otherwise associated with type 1 diabetes, including absence
of insulin production. Whether these individuals are properly classified as type 1 or type 2 diabetics
may be subject to debate, but these individuals may certainly benefit from pancreas transplantation.
Individuals with type 1 physiology but adult age of onset and low but detectable C-peptide secretion
may also be considered for pancreas transplantation. Approximately 5% of pancreas transplant
recipients are classified as having type 2 diabetes, and outcomes for these recipients are similar to those
with type 1 diabetes.31 As these are typically highly selected individuals without significant insulin
resistance, most type 2 diabetics would not be considered candidates. Some type 1 diabetics may
develop insulin resistance as a result of years of insulin therapy; this is frequently accompanied by
increased body weight and insulin requirements. While insulin resistance may improve after
transplantation in such patients, or may be managed with additional oral hypoglycemic agents, these
patients are at higher risk for remaining on insulin after pancreas transplantation.32 While provocative
tests for insulin resistance exist, they are not commonly employed.
A small percentage of pancreas transplant recipients do not have type 1 diabetes, but have diabetes
from other causes. Several have undergone pancreatectomy for chronic pancreatitis or other
conditions.33 Some pancreas transplants (<1%) are performed as part of a multivisceral transplant that
includes liver and small intestine in patients who do not have diabetes; in these transplants, the
pancreas is included in the graft to facilitate the technical conduct of the operation and to reduce
complications.34
4 Most individuals evaluated for pancreas transplantation have chronic renal disease. These patients
may present prior to onset of dialysis, while currently receiving dialysis, or following kidney
transplantation. For individuals without a functioning kidney transplant, potential options include
simultaneous deceased donor kidney/pancreas transplantation (SPK), living donor kidney
transplantation followed by PAK, simultaneous living donor kidney–deceased donor pancreas
transplantation (SPLK), or simultaneous living donor kidney–pancreas transplantation. Of these options
982
booksmedicos.org
the former two are by far the most common.
Simultaneous Kidney–Pancreas Transplantation

SPK from a deceased donor is the most commonly performed pancreas transplant option, with the
number exceeding all other types combined. An SPK transplant has the advantage of requiring only one
operation for both transplants. Since alloreactivity against the transplanted pancreas tends to be
concordant with activity against the kidney, pancreas rejection may be heralded by signs of kidney
rejection, which are more sensitive and present earlier. Consequently, SPK pancreas outcomes have
been historically superior to those of solitary pancreas transplants.
Pancreas After Kidney Transplantation

If a living kidney donor is available, candidates have the option of receiving a living donor transplant,
followed by a deceased donor pancreas transplant. This approach has the disadvantage of requiring two
separate operations, but the recipient enjoys the benefit of a living donor kidney transplant that in
many circumstances occurs sooner than would an SPK from a deceased donor. Since the primary
survival benefit of the kidney–pancreas transplant comes from the restoration of renal function, this is a
significant advantage. However, since a PAK is essentially a solitary pancreas transplant
immunologically distinct from the kidney transplant, pancreas outcomes are worse than for SPK.
Simultaneous Living Donor Kidney–Deceased Donor Pancreas Transplantation

SPLK is another option performed at a few centers.35 Candidates with identified living donors are listed
for deceased donor pancreas transplantation. When a deceased donor pancreas becomes available, the
living kidney donor transplant is performed at the same time as the pancreas transplant. This approach
has the advantages of sequential living donor kidney followed by PAK transplants while requiring only
one operation. It does require that the potential living donor be available to donate at any time, a
requirement that excludes some donors from this approach. It also has the disadvantage of potentially
delaying a kidney transplant for the recipient if the waiting time for a deceased donor pancreas is long.
However, since waiting times for solitary pancreas in some areas of the country can be quite short, the
advantages may be substantial.
Living Donor Kidney–Pancreas Transplantation

A few centers perform living donor kidney–pancreas transplantation, with a single living donor
donating the tail of the pancreas as well as the kidney (Fig. 40-2). This approach has all the advantages
of a single operation, a single donor, and no waiting time. Results have been comparable to deceased
donor SPK transplants.36,37 Widespread adoption of this approach has been limited by concerns about
donor morbidity from the pancreatectomy. Serious complications such as pancreatitis, fistula, abscess,
or pseudocyst can occur. Glucose intolerance and frank diabetes have occurred, although this problem
has been nearly eliminated with more stringent donor selection criteria.37,38
Pancreas transplant candidates with renal failure may be counseled in a variety of ways depending on
the availability of a living donor. How individuals are counseled depends in part on factors particular to
the potential living donor and recipient, and also on the expected waiting time for SPK and PAK
transplantation, which vary greatly by geographic region. Since the mortality benefit of a kidney–
pancreas transplant derives primarily from the kidney transplant, priority is generally given to
achieving kidney transplantation expeditiously. In geographic regions where the waiting time for SPK is
long (5 years is not unusual), living donor kidney transplantation is advised. Recipients of living donor
kidney transplant can then be listed for PAK which can be performed following recovery from the living
donor kidney transplant. Individuals without living donors or those with borderline living donors in
areas with short waiting times can be listed for SPK. Interestingly, there does not appear to be the same
adverse impact in outcome with a limited interval of pretransplant dialysis (less than 2 years) in SPK
recipients that is observed in kidney-alone recipients, whether deceased or living donor.39 Therefore,
even candidates with living donors may reasonably opt for SPK if anticipated waiting times are short.
Pancreas-Alone Transplantation
A small number of type 1 diabetics are evaluated for PTA. These individuals are generally extremely
labile diabetics who have progressive complications but do not have nephropathy. In these individuals
the risk–benefit equation is quite different than those uremic diabetics evaluated for kidney–pancreas
983
booksmedicos.org
transplantation. For nonuremic diabetics evaluated for pancreas transplantation the risk of
immunosuppression in addition to the surgical procedure must be weighed against the potential benefits
from transplantation. This contrasts to uremic diabetics, where the risk of immunosuppression is already
assumed by virtue of the need for a kidney transplant. This risk includes renal failure due to chronic
calcineurin inhibitor use. This is commonly cited as justification to not perform PTA, and recent
evidence suggests the 10-year risk is at least 20% and is related to pretransplant GFR.40 Whether PTA
for type 1 diabetes results in a significant survival benefit is controversial. PTA in most centers is
generally offered only in the most exceptional cases, the most common indication being frequent life-
threatening hypoglycemic events. However, several transplant programs exist that have a different
philosophical outlook on the risks and benefits of PTA, and these referral centers generally perform
large numbers of PTA. Most PTAs are from deceased donors, with a small number of centers offering
living donor PTA. Living donor pancreas transplants carry a higher rate of technical failure but a lower
rate of immunologic failure.41,42
Figure 40-2. Live donor pancreas and kidney transplantation. A: Provided that the donor has a normal glucose tolerance test, a
living donor may donate the segment of the pancreas that is to the left of the superior mesenteric vessels. B: Transplantation of tail
of the pancreas is based on the splenic artery and vein.
Evaluation and Screening

5 In general, eligibility criteria for pancreas transplantation are more stringent than for kidney
transplantation alone, since the operation and recovery are more rigorous, the potential complications
more serious, and the benefits less pronounced compared with kidney transplantation. Candidates
984
booksmedicos.org
should have excellent functional status in anticipation of the more extensive surgery and more frequent
complications. Age is not tightly related to outcome, but patients over the age of 60 are carefully
scrutinized.43 A detailed history of the patient’s diabetes and treatment is obtained, including current
glycemic control, hypoglycemic events, secondary complications, insulin requirements, and overall
quality of life. Obesity in and of itself is not a contraindication, as outcomes for carefully selected obese
(BMI >30) recipients are similar to nonobese recipients, although surgical complications and the
likelihood of remaining insulin dependent may be slightly higher.44 Selection practices vary widely—for
some centers, pancreas transplantation is reserved for those with significant complications and poor
glycemic control who have failed alternative treatments, while for others the presence of type 1
diabetes and a full understanding of the risks and benefits are sufficient, with patient preferences
playing a significant role. In general, because of the added need for immunosuppression in PTA, these
diabetes-related criteria are much more stringent than for SPK or PTA, where the risk of
immunosuppression is already assumed by virtue of the kidney transplant.
All candidates, in addition to assessment of the potential benefit of pancreas transplantation, should
have at the least noninvasive cardiac stress testing such as dobutamine stress echocardiography or
adenosine thallium stress scintigraphy. Potential candidates with reversible myocardial defects undergo
coronary angiography, and many centers perform angiography on all candidates. The decision to
perform pretransplantation coronary revascularization must be made with consideration of both
peritransplant mortality and long-term survival. Although survival outcomes are diminished in
recipients with coronary artery disease,45 a history of coronary revascularization is not necessarily a
contraindication; individuals with extensive myocardium at risk and without revascularization options
are frequently excluded.
Screening for peripheral vascular occlusive disease is often performed. Although distal peripheral
vascular occlusive disease is characteristic of longstanding diabetes, aortoiliac disease and femoral
popliteal vascular disease may also be present. Femoral popliteal disease is generally not a
contraindication to transplantation, unless there are clinical signs of arterial insufficiency such as severe
claudication or nonhealing ulcers. The presence of iliac disease is more problematic, as it can
compromise inflow to the transplanted organs or increase the risk for postoperative arterial
complications. In addition, diabetics may have significant vascular calcification which could preclude
transplantation even in the absence of flow abnormalities. Screening for peripheral vascular occlusive
disease, in addition to a thorough physical examination, may include noninvasive flow studies and/or
CT scanning to evaluate vascular calcification. Candidates with a history or examination findings
suggestive of cerebrovascular disease should be screened for hemodynamically significant carotid
occlusive disease.
Other evaluations, as with other types of organ transplants, are tailored to the individual medical
history, and differ among centers. Screening for malignancy commonly includes mammography and pap
smears for women, prostate-specific antigen levels in men, and colonoscopy. Individuals with a prior
history of treated cancer and who are judged to be at low risk for recurrence are usually candidates
following an appropriate disease-free interval. This interval is decreasing as greater experience with
transplantation in individuals with a history of cancer has accumulated, and can be as little as 2 years
for many solid epithelial tumors to none for carcinoma in situ or early prostate cancer.46 Screening for
chronic viral infections such as hepatitis B, hepatitis C, and HIV is commonly performed, and pancreas
transplants in selected individuals with chronic hepatitis are being performed with increasing
frequency.47,48 As with liver and kidney transplantation, early experience with pancreas transplantation
in carefully selected individuals with HIV infection has been encouraging.49 Social work and/or
psychiatric evaluation is performed to rule out psychiatric disease, inadequate social environments, and
other issues that may impact the recipient’s ability to participate in posttransplantation management.
985
booksmedicos.org
Figure 40-3. Number of U.S. simultaneous pancreas–kidney (SPK), pancreas after kidney transplantation (PAK), and pancreas
transplantation alone (PTA) pancreas transplants performed by year. (Data from Scientific Registry of Transplant Recipients. 2013
Annual Report. Rockville, MD: Health Resources and Services Administration, Department of Health and Human Services; 2015).
The Kidney–Pancreas Waiting List and Recipients

The number of patients on the waiting list for a simultaneous kidney–pancreas transplant has decreased
from a peak of 2,396 in 2005 to 2,076 in 2012.50 The majority of patients are white (60%), though the
percentages of white candidates is decreasing, while the percentage of African-American (24%) and
Hispanic/Latino patients (13%) continues to increase. The number of patients on the waiting list has
decreased since 2000 for all adult age groups except those in 50 to 64, and the age distribution has
shifted upward. While the majority are ages 35 to 49 (57% in 2012), the percentage who are ages 50 to
64 is increasing (23% in 2012) and the percentage who are ages 18 to 34 (19% in 2012) is decreasing.
The annual death rate on the SPK waiting list was 69 per 1,000 patient years in 2012, compared with 96
in 2006.
The number of SPK transplants performed has declined from 924 in 2006 to 801 in 2012 (Fig. 40-3).
Median times to SPK have increased from 14.8 months for those registered in 2006–2007 to 16.2
months for those registered in 2010–2011. Time to transplant is longer for African-American and
Hispanic/Latino recipients. While the majority of SPK recipients are white (65%) and males (64%), the
percentage of SPK recipients who are African American (20% in 2012) and Hispanic (12% in 2010) in
increasing. The age distribution of recipients parallels that of the waiting list.
The Pancreas Transplant Waiting List and Recipients

The number of patients awaiting isolated pancreas transplants in 2012 is also decreasing, with 413
patients awaiting PTA versus 528 in 2006 and 583 awaiting PAK versus 986 in 2006.50 The increase in
the number of patients waiting for isolated pancreas transplant in the last 5 years is largely due to a
sharp decrease in the numbers of new registrations rather than an increase in transplants performed.
The great majority of patients awaiting isolated pancreas transplants are white (80% for PTA, 75%
for PAK); there have been significant increases in the percentage of African Americans on the PAK and
PTA lists over the last several years. Although women continue to constitute 54% of the PTA waiting
list in 2012, they are only 46% of the PAK waiting list. The majority of patients awaiting both PTA and
PAK are between 35 and 49 years old, but as with SPK candidates, the percentage of older patients
listed for PAK and PTA has increased, with 36% and 30%, respectively, of the waiting list in 2012 being
between the age of 50 and 64 years.
The median time to transplant for PAK has increased over the last 5 years, with the mean waiting
time for candidates registered in 2008–2009 now being 36.9 months. This is greater than the median
time to transplant for SPK registrants. Wait times for PTAs have also increased, nearly doubling since
2007–2011 to 19.1 months for those registered in 2010–2011.
The age and race of recipients of solitary pancreas transplants reflect the waiting list. In 2012, 88% of
PTA and 72% of PAK and recipients were white. More PAK recipients (64%) were male, but more PTA
recipients (63%) were women, and this gender gap has widened in the past 5 years.
Deceased Donor Pancreas Allocation

As with many organs, deceased donor pancreas allocation is determined primarily by geography, with
most organs offered to centers in the Donation Service Area (DSA) of donor origin. The base organ
986
booksmedicos.org
allocation unit is the organ procurement organization (OPO) which serves the population within the
DSA. The 58 DSAs are organized into 11 regions, which serve as the second-tier of organ allocation. As
with other organs, pancreata are allocated according to nationally determined policies.51 There is
mandatory sharing of pancreata to highly sensitized candidates that are completely matched to the
donor; beyond this, pancreata are allocated to these pancreas candidates first locally, then regionally,
then nationally based primarily on waiting time.
If the pancreas candidate is an SPK candidate, then a kidney from the same donor is usually also
allocated to the SPK candidate, regardless of the candidate’s place on the kidney waiting list. While such
a policy promotes pancreas utilization, it has been somewhat controversial, since preferential allocation
of kidneys to simultaneous kidney–pancreas (SPK) candidates prevents allocation to kidney-alone
candidates who have generally been waiting longer. Solitary pancreata are more difficult to place
compared with SPK because their outcomes are slightly worse, but are more easily shared voluntarily
since OPOs have no obligation to share kidneys along with pancreas for outside SPK candidates; since
pancreas donors are carefully selected, the kidneys from these donors are usually able to be
transplanted into a local kidney candidate. Thus, shared pancreata are generally restricted to PTA or
PAK candidates.52
Pancreas allocation is also complicated by the fact that the pancreas donor selection criteria for islet
transplant and whole-organ transplant overlap, leading to competition among certain types of organs. In
determining whether a given pancreas will be allocated to a solid organ or islet transplant candidate,
donor age and BMI are considered. Donors under age 50 and with BMI <30 are allocated for whole-
organ pancreas transplant locally. If there is no local acceptance, the pancreas is offered regionally and
then nationally. If there is no candidate for whole pancreas, the pancreas is then allocated for islets. For
donors older than age 50 or with BMI >30, whose pancreata are rarely used for whole-organ
transplant, the organ is first offered for pancreas transplant locally; if there are no local candidates, the
pancreas is then offered for islets.51
Pancreata are significantly underutilized compared to other solid organs such as liver and kidney. As
discussed below, donor selection criteria are more rigorous. Restrictions on cold ischemia time for
whole-pancreas transplantation and particularly for islet transplantation make the placement of
pancreata that are not used by the recovering center difficult. There is significant geographic variation
in pancreas use, which correlates with activity by local transplant centers.53
Donor Evaluation
6 The selection of appropriate pancreas donors is perhaps the most important determinant of successful
pancreas transplantation. Many of the early complications of pancreas transplantation are thought to be
secondary to processes related to organ quality and preservation, rather than the technical conduct of
the recipient operation. While the ideal donor is young, nonalcoholic and nonobese, very few donors
meet this description, and the surgeon frequently needs to consider pancreata from imperfect donors.
Donor selection criteria may vary among surgeons and transplant centers, and may depend upon past
experience, waiting time, and recent outcomes. Primary criteria are the age of the donor, donor BMI,
donor cause of death, and the gross appearance of the organ at the time of recovery. Additional
information that may influence the decision include aspects of the medical and social history, donor
hemodynamics, laboratory values, HLA matching, and anticipated preservation time. As with donor
selection with other organs, the decision-making process often involves consideration of multiple factors
in aggregate.
The importance of donor age on graft outcomes has been confirmed by multiple studies, and the
maximum age threshold is significantly lower than for liver and kidney transplantation.54,55 Many
centers use an age threshold, which may range from 40 to 50, above which donors are selected very
carefully. The mechanism by which age affects outcomes is not firmly established: age appears to
influence both early technical and late graft loss.55,56
Donor BMI has been found to be a determinant of graft failure by single-center and transplant registry
analyses.57,58 Very few pancreata from donors with BMI greater than 30 are used for solid-organ
transplant, and are more likely to be recovered for islet transplant.52 Interestingly, for overweight but
not obese donors (BMI 25 to 30), a large single-center study found a higher rate of technical failure for
donors who also had a cerebrovascular attack as cause of death.57 It is not known whether associations
with BMI relate to fatty infiltration of the pancreas or by a separate mechanism.
The circumstances of death and the condition of the donor influence donor selection. Pancreata from
donors with stroke as a cause of death have reduced graft survival. Although experience from donors
987
booksmedicos.org
after cardiac death (DCD) remains relatively limited (only 1.5% of all pancreas transplants in 2011),
outcomes have been good with careful donor selection.50,59,60 Laboratory values, including serum
amylase and lipase, play a relatively minor role in donor selection. Insulin administration is generally
not considered a contraindication to pancreas donation. While the presence of donor hyperglycemia may
raise concerns about latent diabetes, in most donors this reflects the rapid administration of dextrose-
containing solutions, corticosteroids for cerebral edema, and high-dose catecholamines for blood
pressure support rather than latent pancreatic endocrine insufficiency. Abnormal HbA1C has been
utilized as a relative contraindication, but is not well studied and is not uniformly available for use.
Evidence of injury to other organs such as liver and kidneys, as a marker of abdominal ischemia, while
not ordinarily a contraindication, may be considered in marginal cases.
Donors with a history of type 2 diabetes, excessive alcohol use or pancreatitis may be used. A history
of cardiovascular disease or cardiac risk factors are also not contraindications but may influence
decision making or be associated with mesenteric atherosclerotic disease. A social history which
suggests an increased risk of transmission of hepatitis or HIV should be evaluated, as with other organs,
in the context of the degree of perceived risk relative to the benefit of the transplant.
Intraoperative evaluation of the donor organ is said to be the most important determinant of donor
selection. Evidence of inflammation or fibrosis, which may manifest as focal or diffuse firmness to
palpation, is considered to be a contraindication. Fatty infiltration of the pancreas, trauma and
pancreatic edema are also adverse findings, although the latter may be correctable with donor
management. Traumatic injury to the pancreas or hematoma within the substance of the pancreas would
preclude transplantation. However, a prior splenectomy is not a contraindication, provided that the tail
can be dissected atraumatically.
Factors not intrinsic to the donor may bear on the decision to perform a transplant. The higher risk of
graft failure associated with solitary pancreas transplants leads some centers to have more stringent
selection criteria for PTA and PAK. While cold ischemia is a risk factor for graft survival, pancreata
from selected donors can be transplanted with cold ischemic times approaching 24 hours with good
outcomes. Attention to HLA matching varies widely by center; the many analyses performed suggest
that any relationships between matching and graft outcome that may exist are not likely to be very
significant.56,58,61
As for deceased donor livers and kidneys, a Donor Risk Index for pancreas has been described.53 The
pancreas DRI (PDRI) is based on 10 factors demonstrated to have significant impact on pancreas
transplant outcomes. These include age, gender, race (black or Asian), BMI, height, CVA as cause of
death, cold ischemia time, DCD, and terminal creatinine greater than 2.5 (Table 40-1). There is great
variation in outcome by PDRI: the difference in graft survival at 1 year between the lowest 20% of
PDRI (best outcomes) and the highest 20% is about 11% for SPK transplants and 16% to 17% for
solitary transplants (Table 40-2). In addition to predicting outcomes for individual patients, indices like
the PDRI are useful in assessing trends in pancreas utilization, which is quite variable by geography and
by transplant center.53
Procurement Technique
The importance of the pancreatic procurement cannot be overstated. It is thought by many pancreas
transplant surgeons to be more critical to the success of the transplant than the recipient procedure.
Because the pancreas is susceptible to traumatic injury, it must be carefully dissected and manipulated
to avoid injury to the pancreatic parenchyma. Typically the pancreas is procured along with the liver
and kidneys. This is performed in standard fashion through a midline incision which extends from the
sternal notch to the pubic symphysis. After a generous Kocher maneuver, mobilization of the right
colon, and isolation of the distal and supraceliac aorta to prepare these vessels for clamping, the
pancreas is mobilized. This is most commonly achieved by entering the lesser sac, dividing the
gastrocolic omentum. This dissection continues with division of the short gastric vessels and the
avascular gastrosplenic ligament. The pancreas is dissected from the pancreatic bed using the spleen as a
handle. The tail is lifted from the pancreatic bed using blunt dissection and the occasional use of
electrocautery. The proximal jejunum is dissected at the ligament of Treitz. An antibiotic and/or
betadine containing solution are frequently instilled into the duodenum through a nasogastric tube for
decontamination. The duodenum is divided both at the ligament of Treitz and at the pylorus using a
stapler. Division of the middle colic vessels permits exposure of the proximal small bowel mesentery,
which is divided distal to the pancreas with a vascular stapler. The mobilization of the pancreas may be
performed either prior to or following the aortic perfusion procedure described below.
988
booksmedicos.org
Perfusion of the pancreas is generally achieved through an intra-arterial cannula placed in the distal
aorta following clamping of the supraceliac aorta and the aortic bifurcation. This is typically achieved
with approximately 3 L of University of Wisconsin or HTK (histidine–tryptophan–ketoglutarate)
solution while the entire abdominal organs are packed in saline slush. Preservation solutions are
generally regarded to be equivalent, although a few studies suggest slightly worse outcomes with
HTK.58,62,63 Some centers will also perfuse the abdominal viscera with a portal perfusion cannula,
typically through the inferior mesenteric vein, although some surgeons maintain that overperfusion of
either the arterial or the venous circulation may result in pancreatic edema and an increased risk of
complications.
Table 40-1 Summary of Pancreas DRI
Table 40-2 Results: Unadjusted 1-year Pancreas Allograft Survival by DRI and
Transplant Type
The pancreas can be removed either en bloc with the liver and kidneys, en bloc with the liver, or
separately, following removal of the liver. Whatever the technique, the portal triad is dissected out in
cooperation with the liver procurement team. Typically the portal vein is shared by dividing it at the
level of the coronary vein. Only in the rarest of circumstances should there be any difficulty using both
the liver and the pancreas from the same donor even in the presence of hepatic arterial anomalies. In
the presence of a replaced right hepatic artery, the superior mesenteric artery (SMA) can be divided just
distal to the replaced right hepatic artery, leaving a very short cuff of SMA on the pancreas.
Alternatively, the replaced right hepatic artery, if large enough to be safely reconstructed by the liver
transplant team without a cuff of SMA, can be transected as it exists superiorly from behind the head of
the pancreas. This is also true in the rare case where a completely replaced hepatic artery emerges from
the superior aspect of the head of the pancreas; usually the artery in this case is long enough and large
enough to be used for liver transplant without a celiac axis or aortic cuff. The bile duct and
gastroduodenal artery are ligated on the pancreas side and divided on the liver side. Dissection then
proceeds along the superior aspect of the pancreas along the proper hepatic artery. The splenic artery,
which constitutes the other arterial blood supply to the pancreas, is divided a few millimeters from its
origin to allow for adequate length on the pancreas while allowing the stump to be oversewn without
compromising flow to the liver. Once the pancreas is removed or split from the liver, the pancreas is
packed in preservation solution; the entire common iliac artery and its two main branches, the internal
and external iliac arteries, are packaged along with the pancreas for back-table reconstruction. A graft
989
booksmedicos.org
of donor iliac vein is also included in case the portal vein needs to be extended, which is done by some
surgeons. Although most centers transplant the pancreas as soon as possible, up to 24 hours of cold
ischemia time (time between perfusate infusion and organ reperfusion) has not been associated with
reduced graft survival in carefully selected donors.53,56
Back-Table Preparation of the Pancreas

The pancreas is placed on ice and remains cold at all times on the back table. The spleen is removed by
dividing all vessels near the spleen, either by ligature or stapling, taking care to avoid injury to the tail
of the pancreas which should be clearly identified. Some surgeons elect to wait until reperfusion of the
pancreas in the recipient to remove the spleen. Significant peripancreatic fat, if left on at the time of
procurement, should be trimmed. Both ends of the distal duodenum are shortened to the point where
they are immediately adjacent to the head of the pancreas. Both stapled ends of the duodenum may be
oversewn with silk or polypropylene sutures. Some surgeons elect to reinforce the mesenteric staple line
by oversewing with polypropylene suture. The iliac artery Y-graft is typically attached by anastomosis
of the internal iliac artery to the splenic artery and anastomosis of the externally iliac artery to the SMA
(Fig. 40-4). In the absence of a Y-graft, the splenic artery may be implanted in end-to-side fashion to the
SMA. The portal vein is mobilized by freeing from surrounding adventitial tissue to the confluence of
the splenic vein and superior mesenteric vein. This should allow an adequate length of portal vein for
anastomosis, as only 1 to 2 cm of portal vein length is generally needed.
Figure 40-4. Simultaneous pancreas–kidney transplantation performed with drainage of the pancreatic exocrine secretions into the
proximal jejunum (enteric drainage). This technique has been adopted by most transplant centers in the United States for
simultaneous pancreas–kidney transplants. For solitary pancreas transplantation, some centers still utilize bladder drainage to
allow monitoring of the urinary amylase. Note that the donor portal vein drains into the recipient superior mesenteric vein (portal
venous drainage), preventing peripheral hyperinsulinemia. Many centers continue to place the pancreas in the pelvis, combining
enteric drainage and systemic venous drainage. This placement requires enteric anastomosis to a more distal segment of jejunum
or ileum.
Recipient Operation
The pancreas transplant is typically performed through a midline incision, although a lower quadrant
incision similar to a kidney transplant incision may be used. The recipient should receive broad
spectrum antibiotics preoperatively. The pancreas transplant, for systemic venous drainage, is placed in
the iliac fossa, preferably on the right side. After dissection of the recipient artery and vein, the portal
vein is anastomosed in end-to-side fashion to the systemic vein. The distal inferior vena cava, common
iliac vein, or external iliac vein may be used; the recipient vein segment should be mobile enough for
990
booksmedicos.org
the portal vein to reach without tension. The common iliac artery component of the donor Y-graft is
then anastomosed in end-to-side fashion to either the recipient external iliac artery or common iliac
artery; the distal aorta can also serve as the site of anastomosis. A pancreas placed on the left side in the
recipient may be placed either medial or lateral to the sigmoid colon. Multiple variations have been
described.
Because of concerns about the systemic hyperinsulinemia that invariably develops with systemically
drained pancreas transplants, portal venous drainage is also utilized (Fig. 40-5). As 50% of insulin is
removed with the first pass through the liver, systemic drainage leads to elevated peripheral insulin
levels, which is not observed following portal venous drainage. Since hyperinsulinemia has been
associated with dyslipidemia and accelerated atherosclerosis, portal venous drainage theoretically ought
to decrease cardiovascular risk compared with systemic drainage.64 Portal drainage is associated with
stimulation of the IGF-I/GH axis, contributing to glucose control despite lower insulin levels.65
However, despite a nearly 10-year experience with the procedure, no effect on cardiac morbidity or
mortality has been shown, and graft and patient survival are essentially equivalent.66–68
Although the type of venous drainage typically depends on the preferences of individual surgeons or
transplant centers, the decision to perform portal or systemic drainage may also depend upon the
anatomy of an individual patient. Patients with multiple previous abdominal operations or who have a
thickened mesentery may be more suited for systemic venous drainage. Alternatively, patients who
have had multiple transplants or other operations on the iliac vessels may be candidates for portal
venous drainage.
For portal venous drainage the superior mesenteric vein is dissected out just below the transverse
mesocolon.69 The right common iliac artery is almost completely dissected. An end-to-side anastomosis
of the donor portal vein to the recipient superior mesenteric vein is performed with the duodenum
oriented superiorly and the tail pointed inferiorly. The iliac artery graft of the donor is then passed
through a hole created in the small bowel mesentery, and anastomosed to the recipient common iliac
artery.
Most centers currently use enteric exocrine drainage for simultaneous kidney/pancreas transplant and
some centers use enteric drainage for all transplants including solitary pancreas transplantation. This
shift to enteric drainage occurred as a result of the significant morbidity associated with bladder-drained
pancreas transplants. Morbidity includes recurrent urinary tract infections, hematuria, chemical
urethritis, severe bicarbonate wasting, and dehydration. Historically, approximately 25% of individuals
who receive a bladder-drained pancreas transplants require enteric conversion because of persistent
complications,70 but an additional percentage endure significant morbidity early after transplant. The
major advantage of bladder drainage is the ability to monitor urinary amylase, a decrease in which can
be associated with rejection. This can be helpful in solitary pancreas transplants, but is not as important
for simultaneous pancreas/kidney transplants where graft function may be monitored by serum
creatinine. Improved immunosuppression and an increased utilization of biopsy to diagnose rejection
have led to a decreased reliance on urinary amylase.71
Enteric drainage is achieved by creating a side-to-side or end-to-side anastomosis of donor duodenum
to recipient jejunum. This may be a loop of jejunum, or a Roux-en-Y configuration may be created. For
bladder drainage a side-to-side anastomosis between the donor duodenum and the bladder is performed.
Enteric drainage is always used for pancreas transplants with portal venous drainage because the
orientation of the pancreas precludes anastomosis of the duodenum to the bladder.
If a simultaneous kidney–pancreas transplant is performed, the kidney transplant is usually placed in
the left iliac fossa. The anastomoses, as with a kidney transplant via a retroperitoneal incision, are
typically to the external iliac artery and external iliac vein. The kidney is typically placed in an
intraperitoneal location, which increases the potential for torsion of the kidney on its vascular pedicle
compared with kidney-alone transplants which are usually placed in a retroperitoneal location. Some
surgeons prefer to raise a retroperitoneal flap to place the kidney retroperitoneally after implantation.
Advantages to this approach include improved percutaneous access should biopsy be required, and a
decreased risk of postbiopsy hemorrhage.
Following revascularization of the pancreas, attention is paid to bleeding from the pancreas which can
be quite brisk. This is controlled with ties or suture ligatures. Since thrombosis is a common
complication of pancreas transplantation, anticoagulation in the perioperative period is frequently
employed, particularly for solitary pancreas transplantation. Thrombosis is less frequent in simultaneous
pancreas–kidney transplantation, where uremic platelet dysfunction is protective. The extent of
anticoagulation may range from the intraoperative administration of heparin prior to clamping of
991
booksmedicos.org
vessels, followed up by low-dose heparin infusion and warfarin anticoagulation, to more conservative
approaches such as the use of low-dose heparin for a limited interval postoperatively, or the use of
aspirin or other antiplatelet agents. Hypercoagulability states may predispose to graft thrombosis in a
significant number of individuals, although definitive data are lacking; anticoagulation is individualized
based on risk.72 Whatever the approach, patients should be monitored for bleeding, since as many as
10% of patients experience postoperative hemorrhage requiring reoperation.73
Figure 40-5. Back-table preparation of the pancreas. Before transplantation, the pancreas must be prepared in a slush-filled basin
to maintain cold preservation. Preparation includes unifying the arterial blood supply of the pancreas by anastomosis of the donor
external iliac artery to the superior mesenteric artery and the donor internal iliac artery to the splenic artery. The donor common
iliac artery is used for anastomosis to the recipient iliac artery. During back-table preparation, donor splenectomy is performed.
Following revascularization serum glucose levels are obtained hourly. It is common for the blood
glucose to decline significantly following revascularization, and it is not uncommon for it to fall to
normal levels soon after the patient’s arrival in the recovery room. At some point intravenous fluids
should be converted to dextrose-containing solution in order to prevent hypoglycemia. Pancreas
transplant recipients with enteric drainage require only maintenance fluid with consideration of third-
space losses. Simultaneous kidney–pancreas transplant recipients may require the additional fluid
replacement that would be administered following kidney transplantation alone. Individuals who
receive bladder-drained pancreas transplants require replacement of pancreatic exocrine losses, which
can be quite profound in the early postoperative period.
Immunosuppression
7 Immunosuppression for pancreas transplantation is similar to that for kidney transplantation. The
immunogenicity of a pancreas transplant is considered to be greater than the majority of solid-organ
transplants because of the extensive lymphoid component of the gland. In addition, the difficulty in
diagnosing rejection compared to other solid-organ transplants makes the choice of immunosuppression
more significant for pancreas transplants. Most centers use some forms of triple maintenance therapy
utilizing a calcineurin inhibitor, an antiproliferative agent, and steroids, although steroid-free regimens
are becoming more common. According to data from the Scientific Registry of Transplant Recipients,
92% of kidney–pancreas recipients in 2012 received tacrolimus as maintenance therapy, compared to
only 3.5% who received cyclosporine.50 Mycophenolate mofetil is the antiproliferative agent of choice
in pancreas transplantation; the use of sirolimus declined from a peak of 19% in 2001 to 7% in 2012.
The use of steroids for pancreas transplantation, while still much lower than prior to 2000, increased
from 61% in 2007 to 68% in 2012.
The use of induction therapy to inhibit lymphocyte function is common. Several large randomized
multicenter trials utilizing either T-cell–depleting antibody induction (OKT3, ATGAM, and
thymoglobulin) or interleukin-2 (IL-2) receptor antibody inhibition (daclizumab and basiliximab)
showed a reduction in the incidence of acute rejection but failed to demonstrate a significant effect on
patient or graft survival.74,75 Despite this modest impact on overall graft outcome, 89% of kidney–
pancreas transplant recipients received induction therapy in 2012, 79% T-cell–depleting agents, and
12% IL-2 receptor antibody.50 The International Pancreas Transplant Registry (IPTR) has demonstrated
a lower risk of pancreas graft loss in all categories of pancreas transplantation with the use of
tacrolimus, and also demonstrated similar associations with the use of mycophenolate mofetil.56
Consistent with the multicenter trials, IPTR analyses also fail to demonstrate a beneficial effect of
induction therapy on patient and graft survival.
992
booksmedicos.org
Several groups have reported excellent intermediate-term patient and graft outcomes utilizing steroid
minimization protocols.76–78 These protocols generally employ an induction agent (usually a depleting
T-cell antibody), tacrolimus, and either MMF or sirolimus. Steroids are given for a maximum of 3 days.
These steroid minimization protocols, as in kidney transplantation, aim to avoid the significant short-
and long-term side effects associated with corticosteroids. Regimens employing maintenance
monotherapy have also been successfully employed, although based on registry data, these appear to be
falling into disfavor.50,79
Complications
Thrombosis of the pancreas transplant is the most common cause of graft loss in the early postoperative
period, occurring in 5% to 10% of transplants. Why pancreas transplants are more prone to thrombosis
than other solid-organ transplants is uncertain. The most likely mechanism is that ischemia reperfusion
injury in the pancreas, characterized by the release of cytokines and activation of pancreatic enzymes,
leads to accelerated injury and a procoagulant state. Diabetic patients have impaired fibrinolysis and
are, therefore, relatively hypercoagulable. The relatively low venous flow through the portal vein,
which leads to diminished flow velocity, may be contributory. Thrombosis is slightly more common in
solitary pancreas transplantation than in SPK, probably due to the absence of uremic platelet
dysfunction present in SPK recipients. The risk of thrombosis has been associated with donor factors
such as older patient age, renal dysfunction, cold ischemic time, body mass index, DCD status, and
cerebrovascular cause of death.55,80,81
Pancreas transplant thrombosis is usually heralded by a sudden rise in blood glucose in a pancreas
that was previously functioning. Confirmation of the diagnosis is usually obtained with duplex
ultrasound. Although anecdotal reports have described successful surgical and angiographic
thrombectomy or thrombolysis in restoring flow to the pancreas,82,83 the usual treatment is removal of
the infarcted pancreas. While this usually occurs immediately after diagnosis, some centers opt to relist
the patient urgently and wait until another pancreas transplant becomes available. Depending on the
waiting time for another pancreas, the added morbidity of delaying the graft pancreatectomy is usually
not significant. In contrast, asymptomatic thrombosis, whether partial or even complete, has been
successfully managed with anticoagulation, especially if late in onset.84,85 Because of the high risk of
thrombosis, some degree of anticoagulation is frequently employed after pancreas transplantation.86 It
is likely due to these efforts and improvements in immunosuppression that the thrombosis rate for
simultaneous pancreas–kidney transplants has decreased to less than 5% for simultaneous pancreas–
kidney transplant and to less than 10% for isolated pancreas transplants (Fig. 40-6).
Bleeding is another frequent cause for reoperation in the early postoperative period. Because of the
large number of vessels that enter and exit the pancreas, bleeding following reperfusion is not unusual.
While readily controllable, it is not uncommon for bleeding points to emerge later in the procedure, and
postoperatively. This can be minimized by meticulous attention to ligating vascular structures during
pancreas procurement. The use of anticoagulation in the perioperative period, as described above, adds
to the bleeding risk. Pancreas transplant recipients are monitored carefully in the early postoperative
period for signs and symptoms of intra-abdominal hemorrhage.
The other major early complication is leak from the donor duodenum. Duodenal leaks occur in
approximately 5% to 10% of cases, usually 1 to 2 weeks after the transplant.87 A leak may present as
fever, abdominal pain, leukocytosis, lower abdominal tenderness, and persistent ileus. The diagnosis
may be supported by the finding of a focal fluid collection near the head of the pancreas on CT scanning
or ultrasound. Alternatively, diffuse peritonitis may reflect disseminated contamination. For bladder-
drained pancreas transplants, the diagnosis may be made by cystography.
993
booksmedicos.org
Figure 40-6. Technical graft failure rates for U.S. pancreas transplant recipients by year. (Data from Scientific Registry of Transplant
Recipients. 2013 Annual Report. Rockville, MD: Health Resources and Services Administration, Department of Health and Human
Services; 2015).
The management of a suspected duodenal leak is operative. Peripancreatic sepsis or abscess can occur
in the absence of a frank duodenal leak. This is caused by the growth of organisms transmitted into the
peritoneal cavity during performance of the duodenal anastomosis. The peritoneum should be lavaged
and all necrotic debris removed. If a leak is present it is usually at the stapled end of the duodenum
rather than at the anastomosis. The likelihood of success for repair of a duodenal leak depends on the
viability of the duodenum at the point of the leak, the patient’s overall hemodynamic stability, and the
degree of surrounding inflammation. Usually one attempt at repair is made, but failure may necessitate
removal of the pancreas in order to control life-threatening sepsis. Some surgeons have adopted a
practice of managing leaks from duodenal enteric anastomoses by conversion to bladder drainage. This
minimizes the risk of recurrent contamination of the peritoneal cavity with enteric contents and allows
for Foley catheter decompression of the duodenum, but has the morbidity associated with bladder
drainage. Occasionally a fluid collection or leak which presents late and without systemic sepsis can be
treated with percutaneous CT-guided drainage.88 In addition, drainage of infection without primary
repair of the duodenal leak has been successfully employed in situations where inflammation is so
profound that the leak could not be primarily repaired. However, the morbidity associated with these
duodenal fistulas dictates that these options be employed only when definitive repair is not possible.
In contrast to renal transplantation, the complications of pancreas transplantation can be severe and
life threatening if not properly managed. Even in the most experienced centers, occasional patients who
suffer extended intensive care unit stays and even death are not unusual. This is a consequence of both
the tenuous medical status of longstanding diabetics and the substantial morbidity of pancreas
transplant complications. Therefore, given the limited survival benefit of pancreas transplantation,
particularly compared with kidney transplantation, patients should be counseled frankly about the
potential magnitude of these complications so that they have a realistic expectation of outcomes. Even
with honest discussion and informed consent, most individuals will elect pancreas transplantation, and
many will pursue multiple pancreas transplants even with a history of significant complications from
previous pancreas transplants.
Diagnosis and Treatment of Rejection

The timely and accurate diagnosis of pancreas transplant rejection is one of the most important and
challenging aspects of posttransplant management. As with kidney transplant rejection, pancreas
rejection, whether acute cellular rejection or antibody-mediated rejection, is associated with inferior
graft survival.89 Furthermore, both pre- and posttransplant donor-specific antibody (DSA) are associated
with antibody-mediated rejection and reduced pancreas and kidney graft survival.89,90 The incidence of
pancreas rejection is about 20% to 25% in the first 2 years.50 Therefore, the implications of delayed or
missed antirejection treatment can be profound.
There is no single laboratory abnormality capable of diagnosing rejection. Amylase and lipase serum
levels are commonly elevated, and can arouse suspicion, but are not specific. Hyperglycemia is also
nonspecific, and if due to rejection occurs late, signifies significant pancreatic endocrine injury and has a
dismal prognosis. While imaging modalities including ultrasound may identify abnormalities in
parenchyma or perfusion, they are neither sensitive nor specific.91 Hence, the diagnosis of rejection is
best made with histologic examination of a pancreatic biopsy specimen.92 The pancreas graft in SPK
994
booksmedicos.org
transplants may be monitored by following the serum creatinine, as the concordance rate for rejection
between kidney and pancreas grafts is believed to be high, although isolated pancreas rejection clearly
occurs.93,94 Improvements in the outcome of solitary pancreas transplants are attributable to
improvements in overall quality of immunosuppression, and to more accurate diagnosis and treatment
of pancreas rejection.
The technique of pancreas transplant biopsy has evolved over the years. In the era of bladder-drained
pancreas transplants, cystoscopic biopsy of both the pancreas and transplant duodenum was common.95
As more enteric-drained pancreas transplants have been performed, a greater reliance on percutaneous
biopsy has developed, using either ultrasound or CT-guided techniques.96 Laparoscopic-assisted or open
pancreas biopsy may be utilized for patients whose pancreas transplant is not accessible to percutaneous
approaches, although the need for operative biopsy is decreasing as the percutaneous procedure has
become more routine.97 Enteroscopic biopsy has been described, and a high jejunal anastomosis can
facilitate utilization of this method.98 The indications for pancreatic biopsy include hyperamylasemia,
hyperlipasemia, hyperglycemia, or unexplained pain in the vicinity of the pancreas transplant. The
differential diagnosis includes pancreatitis, cytomegalovirus (CMV) infection, and toxicity from
calcineurin inhibitors and, in the early postoperative period, peripancreatic infection. The histologic
grading system developed at the University of Maryland for determining rejection grade in pancreas
biopsies is generally used (Table 40-3).99 Indeterminate rejection may be treated with increases in
calcineurin inhibitor dose or pulse corticosteroids. More substantial rejection is generally treated with
depleting antilymphocyte antibody therapy, either OKT3 or Thymoglobulin.
As long-term survival of pancreas transplants becomes more commonplace, chronic rejection is
emerging as an important problem.100 Unfortunately, as with kidney transplantation, while newer
agents have improved short-term survival by preventing acute rejection, improvement of short-term
survival has not translated into improved long-term graft survival.101 Chronic rejection is histologically
characterized as expansion of fibrous septa within the pancreatic parenchyma. This may progress to
lobular atrophy or loss of both acini and β-cells. Although there are parallels to chronic allograft
nephropathy, whether chronic calcineurin inhibitor toxicity contributes to chronic pancreas rejection is
unknown.
Table 40-3 Diagnosis: Revised Banff Classification for Diagnosis and Grading
Pancreas Allograft Rejection86
995
booksmedicos.org
Recurrent Autoimmunity
Selective β-cell destruction in pancreas transplants may occur in a pattern similar to the insulitis seen in
type 1 diabetes. This pattern is histologically distinct from cellular rejection. Although recurrent
autoimmunity has been documented in both immunosuppressed pancreas transplant recipients and
nonimmunosuppressed living donor recipients from identical twin siblings, well-documented case series
have been infrequent. A variety of associations have been suggested with autoantibodies to glutamic
acid decarboxylase (GAD-65) and islet cells (IA-2), but patterns of autoantibody expression have not
proven reliable enough to establish their etiologic relevance or prognostic value.102,103
Posttransplant Viral Infections

The higher level of immunosuppression given to pancreas transplant recipients compared with kidney
transplant recipients, particularly with respect to lymphocyte-depleting induction therapy, places
pancreas transplant recipients at risk for conditions known to be influenced by overall
immunosuppressive exposure. While rates of CMV infection are generally higher than for kidney
recipients, especially when the donor is known to carry the virus, the use of intravenous and oral
ganciclovir has reduced the incidence of significant CMV-associated disease.104,105 The incidence of CMV
disease may also be lower in those recipients receiving steroid-free immunosuppression.105 Data are
mixed with respect to the incidence of polyoma-associated, or BK, nephropathy, with some analyses
suggesting a higher rate and other an equivalent incidence in SPK recipients compared with kidney-
alone recipients.106,107 As with kidney-alone recipients, those SPK recipients with BK nephropathy have
inferior kidney graft survival. Posttransplant lymphoproliferative disorder (PTLD), often associated
with Epstein–Barr virus (EBV) infection, has a 5-year incidence of approximately 2%, which is similar to
or higher than kidney recipients.108,109 Pancreas recipients with PTLD have a worse prognosis than
other abdominal organ transplants recipients with PTLD.
996
booksmedicos.org
Figure 40-7. Pancreas graft survival among adult pancreas transplant recipients, 2008. (Data from Scientific Registry of Transplant
Recipients. 2013 Annual Report. Rockville, MD: Health Resources and Services Administration, Department of Health and Human
Services; 2015).
Results of Kidney–Pancreas Transplantation

Current kidney graft survival at 1 and 5 years following SPK transplantation is 96% and 80%,
respectively.50 African Americans have historically had somewhat poorer 5-year graft survival than
whites. Kidneys from older donors have the poorest graft survival; 5-year graft survival from donors
older than 50 is 68% compared with approximately 80% from donors aged 11 to 34. As opposed to
previous decades, 5-year kidney graft survival is not associated with HLA matching.
Pancreas graft survival at 1 and 5 years following SPK transplantation is 86% and 73%, respectively
(Fig. 40-7). Worse 5-year graft survival is seen in African-American recipients compared with whites.
Recipients with a previous transplant (kidney, pancreas, or both) have worse pancreas graft survival. As
with kidney survival, there is no difference in 5-year pancreas graft survival with increasing levels of
HLA mismatch.
Registry analyses demonstrate a mortality benefit of SPK transplantation compared with dialysis110 or
deceased donor kidney transplantation alone.111 These benefits diminish with higher-risk donors,
particularly older donors.112 Patient survival at 1 year and 5 years following SPK transplantation is 98%
and 92%, respectively. Race, ethnicity, gender, and transplant center volume are not associated with
decreased patient survival at 5 years, and patient survival has improved since 1995 but not appreciably
in the past 10 years.50
Results of Solitary Pancreas Transplantation

The 1-year pancreas graft survival for recipients of a PAK transplant has improved in the last 5 years,
from 78% for PAK transplants performed in 2005 to 88% for transplants performed in 2011.50 Graft
survival for PAK at 5 years is currently 53%. One-year pancreas graft survival for PTA has improved in
the last 5 years to 80%. The unadjusted graft survival for PTA at 5 years is 53%. Graft survival rates for
PTA are better than PAK early, but the rate of graft failure in the long term is greater for PTA than for
PAK. Patient survival for both SPK and PAK recipients is excellent, >90% at 1 year and >80% at 5
years.
8 Whether pancreas transplantation positively impacts patient mortality is controversial. One study
reported that registrants on the waiting lists for PAK and PTA had better survival rates than recipients
who underwent these procedures.110 Subsequently, another group, using a similar cohort but different
analytical methods, reported better survival rates for recipients of solitary pancreas transplantation than
registrants on the waiting list.113 These discrepancies are in part related to the differing methodologies
used in the two studies with respect to deaths among those removed from the waitlist and also to
variability in the year-to-year death rates on the waiting list. In contrast, both studies demonstrated a
conclusive benefit for SPK recipients compared with remaining on the waiting list, which illustrates the
importance of restoration of kidney function in this population, as with kidney-alone transplant. While
opinions on the specific benefit of the pancreas transplant differ in light of the differing conclusions of
these two studies, together the studies indicate any survival benefit conferred by the pancreas transplant
is likely to be modest. In fact, most studies do not demonstrate a graft or patient survival advantage of
SPK over living donor kidney transplant.111,114 The survival benefit of SPK over deceased donor kidney
997
booksmedicos.org
transplant alone has been recently further quantified, and while statistically significant, the survival
benefit was not considered clinically meaningful.115
Effect of Pancreas Transplantation on Secondary Complications of Diabetes Mellitus

There are data that clearly demonstrate the impact of pancreas transplantation on the course of
secondary complications of diabetes. This could be predicted from the results of the DCCT, in that
pancreas transplantation leads to a complete normalization of blood glucose and glycosylated
hemoglobin levels that are vastly superior to those achievable by intensive insulin therapy. Therefore, it
should not be surprising that pancreas transplantation has an impact on diabetic complications.
For example, while type 1 diabetic recipients of kidney transplants alone show typical findings of
diabetic nephropathy following transplantation, SPK transplantation prevents the development of
recurrent diabetic nephropathy.116 In addition, native diabetic nephropathy, including microvascular
structural abnormalities has been demonstrated to reverse 10 years following successful isolated
pancreas transplantation.117,118 These reports demonstrate convincingly that pancreas transplantation
has a significant impact on diabetic nephropathy.
Effects on diabetic neuropathy have also been documented using nerve conduction studies, which are
significantly improved following pancreas transplantation and SPK.119 Small corneal nerve fiber
regeneration can be detected.120,121 Furthermore, clinical progression of diabetic neuropathy is
significantly diminished compared to nontransplanted controls. However, no study has been able to
demonstrate clinical improvement in existing diabetic neuropathy following transplantation. There is
also an impact on autonomic neuropathy, with clinical improvement in epinephrine responses to
hypoglycemia.122
While the DCCT demonstrated a relationship between glycemic exposure and retinopathy, the effect
of pancreas transplantation on retinopathy is only modest. While stabilization of moderate retinopathy
has been demonstrated, long-term graft function (>3 years) is required.123,124 Many pancreas transplant
candidates have advanced retinopathy, and an effect has not been demonstrated in these individuals.
Early acceleration of retinopathy, a phenomenon that has been noted with other methods of improving
glycemic control, can occur in the first 6 to 12 months following transplant.
Pancreas transplantation also appears to have a modest impact of cardiovascular disease parameters.
Despite the findings of the DCCT trial, assessment of the clinical impact of pancreas transplantation on
the progression of cardiovascular disease lacks a definitive large scale study. Positive effects on lipid
profiles, blood pressures and left ventricular ejection fraction have been demonstrated.125 Some centers
have demonstrated a positive impact on peripheral vascular occlusive disease, with others
demonstrating a worsening of disease.126,127
Regardless of the magnitude of objectively demonstrable benefits of pancreas transplantation, most
recipients enjoy a dramatic improvement in quality of life.94,128,129 While many diabetics can adapt
quite well to the dramatic glucose fluctuations and the associated morbidity of diabetes, the freedom
from insulin and the avoidance of hyper- and hypoglycemia offered by a functioning pancreas transplant
is a primary motivator for many recipients. The fervor with which many candidates pursue pancreas
transplantation, especially retransplantation is an indication of the enormous benefit on quality of life
for these individuals.
ISLET TRANSPLANTATION
Overview
9 The notion that insulin-producing β-cells could be physically separated from the pancreas and
transplanted for the treatment of diabetes has long been recognized. Islet transplantation, as a cellular
transplant, has significant potential advantages over whole-organ pancreas transplantation. Islet
transplantation does not require an operative procedure.130 In addition, the potential ability to preserve
islets opens up possibilities with regard to distribution, allocation, transportation, and preparation of the
islet recipient. Pretreatment of the graft to reduce immunogenicity or enhance survival and function is
also possible.131 Recipients of successful islet transplants can have glucose metabolism and insulin
secretion profiles that are close to normal, and maintain metabolic control in a manner equivalent to
whole-pancreas transplantation.132 Although effects on long-term mortality and progression of diabetic
complications are unproven, these benefits are also anticipated. From a long-range perspective, the
development of islet transplantation sets some of the procedural, technical, and regulatory groundwork
998
booksmedicos.org
for the eventual establishment of stem-cell derived β-cell transplantation. Furthermore, technologic
advances in islet isolation for allotransplantation have been very successfully utilized in
autotransplantation following pancreatic resection.
History
The development of islet transplantation was historically limited by poor graft survival. The first human
islet allograft in a type 1 diabetic was performed in 1974 by the University of Minnesota.133 The first
islet autograft for the treatment of chronic pancreatitis was performed at Minnesota in 1977. Despite
intense research in islet transplantation over three decades, until 2000 clinical islet transplantation met
with minimal success.134 While transplanted islets were capable of physiologic function, as evidenced by
the 66% rate of insulin independence at 1 year in the 163 recipients of islet autografts from 1974 to
1995, even these recipients had significantly reduced functional β-secretory reserve.135
Allotransplantation presented an even greater hurdle; in the 96 islet allograft recipients with type 1
diabetes from 1990 to 1994, C-peptide production and insulin independence at 1 year were 25% and
7%, respectively.134 Of the 270 recipients until 1999, only six had achieved insulin independence for
greater than 2 years.
The dramatic improvement in islet transplant outcome reported by the Edmonton Group in 2000
stimulated an increase in islet transplant activity.136 Several important refinements in islet isolation and
immunosuppression have been credited for the improvement in outcomes, including careful attention to
pancreas procurement; minimization of cold ischemia time of the pancreas prior to isolation; avoidance
of xenoproteins in the islet isolation process; and avoidance of steroids in the immunosuppressive
regimen. The use of sequential infusions to achieve insulin independence has been critical to success for
many centers. Subsequently, the enthusiasm that accompanied this success was tempered by the
inability for many new centers to replicate the success of more established centers,137 the disappointing
long-term survival of the transplants,138 and the costs associated with islet transplants, which are still
not reimbursed by third-party payers and Medicare.139 As a result, the volume of islet transplants has
contracted in the past decade, as have the number of centers performing transplants.140 Nevertheless,
incremental improvement in efficacy and long-term outcomes in selected centers has resulted in
sustained optimism that this procedure will ultimately be regarded as an alternative to pancreas
transplantation.141,142
Islet Isolation
The precise separation of the islets from the other tissues of the pancreas (exocrine cells, lymphatics,
and vascular structures), is the most important determinant of successful islet transplantation. One of
the limitations of islet isolation is the difficulty in getting a large number of high-quality islets, and
consistent success in islet isolation is a combination of science, art, and experience. Although a variety
of methods have been utilized, most currently employ some modification of the semiautomated method
described by Ricordi in 1988.143 This method combines mechanical distension with enzymatic digestion
of the pancreas. After cleaning the pancreas of surrounding fat, the pancreatic duct is cannulated with
an angiocatheter and the pancreas is distended and loaded with warm collagenase solution, which
digests the pancreas.144 The pancreas is then placed into a sterile chamber, which also contains a
number of stainless steel or glass spheres. Additional collagenase solution is added, and the chamber is
attached to a shaking apparatus or agitated by hand. The collagenase solution is recirculated and kept at
37°C as the chamber is agitated. Agitation of the chamber allows the spheres to continue to disrupt the
structural integrity of the pancreas as it digests. Following digestion, the separation of islets from
nonislet tissue is performed via density gradient centrifugation. After suspension in culture media, islets
are counted and assessed for sterility, purity, viability, and functional capacity. As islet isolation in the
United States is regulated by the U.S. Food and Drug Administration, stringent product release criteria
are in place to ensure the quality of the transplanted islets.
The percentage of islet isolations that result in a transplantable preparation varies widely among
centers, between 25% and 70%, and depends both on donor selection practices and the experience and
expertise of the particular center. Many elements of the process, such as collagenase batch or type,
gradient preparation, the use of culture and culture conditions, and additives to prevent islet loss, are
not standardized. This variability reflects both the need for improvements in isolation efficiency and the
art/science currently inherent in the process. The ultimate goal is to develop a reproducible process
with enough fidelity to allow islet preparations to be biologically licensed, which appears to be a major
barrier to federal funding for the procedure, which will be necessary for broader application.
999
booksmedicos.org
Patient Selection
Candidates for islet transplantation are selected in a similar manner as for whole-organ pancreas
transplantation. Islet transplantation is currently limited to adult type 1 diabetics with progressive
diabetic complications who have failed intensive insulin therapy. Because islet transplantation remains
experimental therapy with limited availability, the procedure is generally offered only to ideal
candidates with minimal medical conditions other than diabetes. Most centers require evaluation and/or
a period of treatment by an experienced endocrinologist specializing in diabetes. Candidates with
coronary artery disease, chronic infections, including hepatitis B and C, or a prior solid-organ transplant
are excluded. Nonuremic candidates must be free of renal insufficiency, due to concerns about
aggravation of nephropathy by calcineurin inhibitors. Since efficacy of the islet transplant appears to be
related to the number of islets transplanted per kilogram of recipient body weight, only lean (<70 kg
or BMI <28) recipients are selected. Although most islet transplants are currently performed in
nonuremic diabetics, islet transplants either concurrent with or following kidney transplantation are
also performed.145,146
Donor Selection/Procurement/Preservation
Donor selection for islet isolation differs from that for whole-pancreas transplantation in several
respects. While the ideal donor for islet isolation is still young and healthy, the age and weight criteria
are less stringent than for whole-pancreas transplantation. Donors greater than age 50, donors on
vasopressors, and especially obese donors are all perfectly suitable for islet isolation. Since the ideal
pancreas is easily distensible and digestible, fatty pancreata are felt to be especially suitable, whereas
fibrotic pancreata are not. As previously mentioned, pancreata from older and obese donors (which are
infrequently used for whole pancreas) are preferentially allocated for islet transplantation rather than
for regional and national sharing for whole-pancreas transplantation.52
The pancreas is procured in a manner similar to whole-pancreas transplantation. However, less
attention to preservation of vascular structures is required. Attention is paid to surface cooling
following flushing of preservation solution, and avoidance of pancreatic injury. A number of reports
have highlighted the importance of a dedicated team trained in pancreas procurement in the success of
islet isolation.147,148 Expanded use of the two-layer technique of pancreas preservation, using both
standard preservation solution (UW solution or HTK) and oxygenated perfluorocarbon solution, has
resulted in increased islet yields.149–152 The two-layer technique also permits the successful use for islet
transplantation of pancreata subjected to prolonged cold ischemia as long as 18 hours. Success with
pancreata from DCD has been reported.153
Transplant Techniques
The portal circulation of the liver is currently the preferred site for islet transplantation (Fig. 40-8).154
This can be performed by a minilaparotomy, with infusion of the islets into a peripheral mesenteric
vein. However, most centers utilize interventional radiology techniques, avoiding both a surgical
incision and general anesthesia. Percutaneous transhepatic portal vein catheterization is done under
ultrasound and fluoroscopic guidance, with usually a small gauge (4-French) catheter. The islets are
infused into the portal vein through the catheter by either gravity from an infusion bag or by hand
injection, and the islets lodge in the hepatic parenchyma. Portal vein pressure is monitored
intermittently throughout the procedure. Following infusion of the islets, hemostasis is usually achieved
using a combination of coils and gelfoam. Recipients receive heparin in the islet preparation,
systemically during the procedure, and in the perioperative period as prophylaxis against portal vein
thrombosis, a now rare but serious complication.
Perioperative Care
Although islet transplantation is in theory an outpatient procedure, it is not uncommon for recipients to
receive a few days of inpatient care for monitoring purposes. Immediately following the islet transplant,
patients are maintained on bed rest for a short interval and monitored for bleeding. Liver function tests
are monitored, and a liver ultrasound is frequently done to assess portal venous flow and to check for
hematoma. It has been demonstrated that intensive glycemic control with insulin in the immediate
posttransplant period is beneficial for islet function.155 Hence, many centers will give insulin
postoperatively to keep the serum glucose tightly controlled, in order to “rest” the islets. Additional
adjuncts to prevent the instant blood-mediated inflammatory reaction (IBMIR), which results in early
1000
booksmedicos.org
islet loss and reduced β-cell mass in the recipient, may include antioxidants such as Vitamin E,
etanercept (anti-TNFα antibody), anakinra (IL-1β antagonist), reparixin (CXCR1/2 inhibitor),
pentoxifylline, and others.156
Figure 40-8. Islet transplantation. The pancreas is procured as a whole organ from the donor. The islets are isolated from the
pancreas and are purified and infused into a cannula placed in a branch of the recipient’s portal vein.
Immunosuppression
Current thinking focuses on the importance of the elimination of steroids from the immunosuppressive
regimen, which typically uses basiliximab induction, and maintenance therapy with low-dose tacrolimus
and sirolimus. Regimens employing mycophenolate mofetil and cyclosporine are also used, and
thymoglobulin is an alternative induction agent. The best results for islet–kidney transplantation are
cases where steroids are avoided or eliminated at the time of islet transplantation. While long-term
effects of either the islet transplant or steroid elimination on kidney function are not known, steroid
avoidance in kidney transplant recipients is now routine.50 Regimens that avoid both steroid and
calcineurin inhibitors have been successfully used.157
Metabolic Control
Islet recipients show significant improvement in metabolic function and glycemic reserve, although
hormonal counter regulation to hypoglycemia is diminished, actual hypoglycemic events are rare.158
Data from the Collaborative Islet Transplant Registry show that at 1 year, approximately 59% of all
transplant recipients were free of severe hypoglycemic events and maintained hemoglobin A1C
(HbA1C) level of <6.5%. Of these 1-year responders, 69%, 54%, and 44% maintained this composite
endpoint at 2, 3, and 4 years, respectively. Ninety-one percent of all recipients were free of severe
hypoglycemic episodes at 1 year, and 80% at 4 years.141 Islet recipients also demonstrate a reduction in
behaviors adopted in avoiding hypoglycemia and attenuation in concerns about hypoglycemic
episodes.159 Islet transplantation also results in improved insulin sensitivity mediated by effects at both
the liver and skeletal muscle.160 However, islet recipients have significantly diminished β-cell reserve
than do recipients of whole-pancreas transplants, which may account for their reduced long-term
survival.161 Acute insulin response to intravenous glucose is commonly used to determine islet
engraftment, and is a robust early metabolic marker to predict return to insulin therapy.162 Analyses of
the impact on diabetic complications and mortality await further experience.
Complications
Morbidity from islet transplantation is substantial but much less than for whole-pancreas
transplantation. The most common serious complication is bleeding (1% to 5%). Most cases of bleeding
can be managed nonoperatively with adjustments in anticoagulation, though occasionally laparotomy is
1001
booksmedicos.org
required. The side effects of immunosuppression, such as hyperlipidemia and mouth ulcers in sirolimus-
containing regimens, are much more common and can significantly affect quality of life.163 Renal
insufficiency is an uncommon but serious consequence.138 Transient elevations of portal venous pressure
during islet infusion and elevations of liver function tests following infusion are common and usually
well tolerated.164,165 However, reduction in liver perfusion during the islet infusion has been linked to
premature graft failure.166 The demonstration of late steatosis has raised concerns about chronic liver
disease; to date this has not been reported.167 CMV infection is rare. Mortality is virtually nil.
Sensitization and the development of posttransplant DSA, which was originally thought not to occur
following allogenic islet transplantation, are now recognized as a significant challenge. Recent
experience has shown that most recipients showed DSA or autoantibody increases (de novo expression
or titer increase) after islet transplantation. Recipients who have a posttransplant antibody increase
have similar initial performance but significantly lower graft survival than patients without an
increase.168 Patients with complete graft loss who discontinue immunosuppression had significantly
higher levels of anti-HLA antibodies than those with functioning grafts still on immunosuppression.169
Ways to minimize sensitization in these recipients includes minimizing the number of islet donors used
per recipient, and in the absence of donor-specific anti-HLA antibodies, repeating HLA mismatches with
subsequent islet infusions.
Results
10 The short-term results of islet transplantation at high-volume centers are approaching that of whole-
pancreas transplantation. The most successful centers achieve insulin independence rates of 80% to 90%
at 1 year.136,170–171 In the Immune Tolerance Network multicenter trial of the Edmonton Protocol,
success rates at the most successful centers (Edmonton, Minnesota, and Miami) were significantly
higher than at the other centers.137 However, long-term rates of insulin independence are worse than
whole-pancreas transplants, but continue to improve. Overall, insulin independence at 3 years after
transplant improved from 37% in the years 2003–2006 to 44% in the years 2007–2010, and the islet
reinfusion rate was lower: 48% by 1 year in 2007–2010 versus 60% to 65% in 1999–2006. While in
most centers less than 50% of recipients are insulin-free at 3 years, in experienced centers the 5-year
insulin independence rate approaches 50% which approaches the graft survival of PTA.138,141,142
One of the shortcomings of islet transplantation compared with whole-pancreas transplantation is the
inability to reverse diabetes with the islets from one pancreas. Most of the recipients in the modern era
have required two or more islet infusions to achieve insulin independence. However, some centers have
successfully employed single-donor islet transplantation by utilizing careful donor and recipient
selection, usually by transplanting islets from pancreata from large donors into small
recipients.170,172–173 As long-term outcome appears to be related to β-cell mass, which is likely to be
lower for single-donor infusions, these recipients may return to insulin or require retransplants
earlier.174 At the recipient level, administration of anti-inflammatory agents, whether nonspecific or
directed at specific molecular targets, has become the mainstay of perioperative treatment. The ability
to maximize the use of islets and minimize islet requirements and pancreas utilization for an individual
recipient is critical if islet transplantation is to compare favorably with whole-pancreas transplantation.
Graft Failure
Graft failure appears to occur earlier than for whole-pancreas transplants. This may be related to a
lower initial islet mass or the inability to histologically diagnose and treat islet rejection, since the islets
are scattered about the liver parenchyma. As with pancreas graft failure, there is no true agreement on
what constitutes graft failure, since recipients may require insulin yet make C-peptide and have superior
metabolic control compared with pretransplant. Most outcome measures focus on insulin independence
as the most stringent, and C-peptide production as the least stringent. Recent findings indicate that
immunologic markers of rejection or recurrent autoimmunity, and metabolic indicators may identify
recipients at risk for inferior outcomes and impending graft failure, although treatment algorithms
based on these predictors are not standardized.162,168,175–176 A number of investigators have
demonstrated the ability to label and identify islets in vivo in recipients in order to monitor functional
islet mass—an example of this is ferucarbotran-labelling of islets, which enables their long-term
noninvasive visualization by MRI and correlates with sustained C-peptide production.177
Recipients with prior graft function who have returned to insulin are candidates for retransplantation.
In fact, some centers have used transplanted islets from isolations where yields are insufficient for a
primary transplant as retransplants, where the islet requirement may be less if there is still sufficient
1002
booksmedicos.org
residual graft function.
Alternative Methods
As the current method of islet allotransplantation has made great progress toward clinical application
over a long period of time, other alternative methods have also advanced. There continues to be a great
deal of interest in the use of encapsulated islets. These capsules can be made from a variety of materials
designed to be permeable enough to permit the passage of insulin and glucose, but to isolate the islet
from the immune system. Several pilot clinical trials in humans, with transplantation into the peritoneal
cavity without immunosuppression have been reported, which confirms the safety of the procedure and
the demonstration of graft function, if not insulin independence.178,179 No allo- or autoantibody has been
detected in this small number of recipients. Human islets can also be shipped safely for long distances
after encapsulation and culture without compromising viability and function.180 The major barriers to
graft function and longevity have been the tendency of the capsules to cluster and fibrose, which limits
their efficacy.
Animal studies suggest that bone marrow precultured with human islets may enhance the survival and
function of transplanted islets, thus significantly improving the therapeutic efficacy of islet
transplantation.181 Other work has cotransplanted mesenchymal stem cells with islets, which may be
beneficial for islet engraftment by promoting cell survival/angiogenesis and reducing
inflammation.182,183
THE FUTURE OF PANCREAS AND ISLET TRANSPLANTATION

Many challenges remain in determining the ideal insulin replacement therapy for type 1 diabetics.
While the current allocation system designed to maximize whole-pancreas transplantation ensures the
most efficient use of donor pancreata, improvements in the efficiency of islet isolation may require that
further refinements be made to allocation policy. Current outcomes support the prioritization of whole-
pancreas transplantation over islet transplantation, and sufficient long-term survival reproducible
among a larger number of centers may be required before islet transplantation can move further into
the mainstream. If this occurs, the reduced morbidity of islet transplantation may mean that a large
number of candidates who are not surgical candidates for pancreas transplantation may be islet
candidates in the future. Many centers have taken the philosophical step to offer islet transplantation
primarily to diabetics who would not otherwise receive immunosuppression, that is, nonuremic
diabetics. This is somewhat in contrast to PTA transplantation, which is offered to only the most
exceptional candidates. Taken further, islet transplantation could theoretically be open to a large
number of type 1 diabetics that would surely exhaust the limited supply of human donor pancreata.
However, the experience gained by the development of islet transplantation would surely apply to
technologies not affected by donor supply, such as islet xenografts or engineered β-cells, which could
have a profound impact on the devastating effects of diabetes on the public health worldwide.
References
1. American Diabetes Association. National Diabetes Statistics. Accessed December 1, 2008.
http://www.diabetes.org/diabetes-statistics.jsp
2. Geiss LS, Wang J, Cheng YJ, et al. Prevalence and incidence trends for diagnosed diabetes among
adults aged 20 to 79 years, United States, 1980–2012. JAMA 2014;312(12):1218–1226.
3. Engelgau MM, Geiss LS, Saaddine JB, et al. The evolving diabetes burden in the United States. Ann
Intern Med 2004;140:945–950.
4. Faideau B, Larger E, Lepault F, et al. Role of beta-cells in type 1 diabetes pathogenesis. Diabetes
2005;54(suppl 2):S87–S96.
5. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009;360:1646–1654.
6. Ziegler AG, Rewers M, Simell O, et al. Seroconversion to multiple islet autoantibodies and risk of
progression to diabetes in children. JAMA 2013;309(23):2473–2479.
7. Skyler JS. Primary and secondary prevention of type 1 diabetes. Diabet Med 2013;30(2):161–169.
8. Skyler JS, Krischer JP, Wolfsdorf J, et al; Diabetes Prevention Trial–Type 1 Diabetes Study Group.
Effects of oral insulin in relatives of patients with type 1 diabetes mellitus. Diabetes Care
1003
booksmedicos.org
2005;28:1068–1076.
9. Donath MY, Ehses JA, Maedler K, et al. Mechanisms of β-cell death in type 2 diabetes. Diabetes
2005;54(suppl 2):S108–S113.
10. Tuomi T. Type 1 and type 2 diabetes. What do they have in common? Diabetes 2005;54(suppl
2):S40–S45.
11. Boitard C, Efendic S, Ferrannini E, et al. A tale of two cousins: type 1 and type 2 diabetes. Diabetes
2005;54(suppl 2):S1–S3.
12. Cnop M, Welsh N, Jonas J-C, et al. Mechanisms of pancreatic b-cell death in type 1 and type 2
diabetes. Diabetes 2005;54(suppl 2):S97–S107.
13. Butler PC, Meier JJ, Butler AE, et al. The replication of beta-cells in normal physiology, in disease
and for therapy. Nat Clin Pract End Metab 2007;3(11):758–768.
14. Dor Y, Glaser B. Beta-cell dedifferentiation and type 2 diabetes. N Engl J Med 2013;368:572–573.
15. Rubin RJ, Altman WM, Mendelson DN. Health care expenditures for people with diabetes mellitus,
1992. J Clin Endocrinol Metab 1994;78:809A–809F.
16. American Diabetes Association. Economic costs of diabetes in the US in 2012. Diabetes Care
2013;36(4):1033–1046.
17. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States,
1990–2010. N Engl J Med 2014;370:1514–1523.
18. Greene DA, Lattimer S, Ulbrecht J, et al. Glucose-induced alterations in nerve metabolism: current
perspective on the pathogenesis of diabetic neuropathy and future directions for research and
therapy. Diabetes Care 1985;8:290–299.
19. Sheetz MJ, King GL. Molecular understanding of hyperglycemia’s adverse effects for diabetic
complications. JAMA 2002;288:2579–2588.
20. DCCT Research Group. The effect of intensive treatment of diabetes on the development and
progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med
1993;329:977–986.
21. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology
of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive
diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med
2005;353(25):2643–2653.
22. Livingstone SJ, Levin D, Looker HC, et al. Estimated life expectancy in a Scottish cohort with type
1 diabetes, 2008–2010. JAMA 2015;313(1):37–44.
23. The DCCT/EDIC Research Group. Intensive diabetes therapy and glomerular filtration rate in type
1 diabetes. N Engl J Med 2011;365:2366–2376.
24. Garg S, Zisser H, Schwartz S, et al. Improvement in glycemic excursions with a transcutaneous,
real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care 2006;29(1):44–50.
25. Ceglia L, Lau J, Pittas AG. Meta-analysis: efficacy and safety of inhaled insulin therapy in adults
with diabetes mellitus. Ann Int Med 2006;145(9):665–675.
26. Phillip M, Battelino T, Atlas E, et al. Nocturnal glucose control with an artificial pancreas at a
diabetes camp. N Engl J Med 2013;368:824–833.
27. Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington
RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med
2008;358(24):2545–2559.
28. Kelly WD, Lillehei R, Merkel F, et al. Allotransplantation of the pancreas and duodenum along with
the kidney in diabetic nephropathy. Surgery 1967;61:827–837.
29. Sollinger HW, Cook K, Kamps D, et al. Clinical and experimental experience with
pancreaticocystostomy for exocrine pancreatic drainage in pancreas transplantation. Transplant Proc.
1984;16:749–751.
30. Nghiem DD, Corry RJ. Technique of simultaneous renal pancreatoduodenal transplantation with
urinary drainage of pancreatic secretion. Am J Surg 1987;153:405–406.
31. Nath DS, Gruessner AC, Kandaswamy R, et al. Outcomes of pancreas transplants for patients with
type 2 diabetes mellitus. Clin Transplant 2005:19:792–797.
32. Dean PG, Kudva YC, Larson TS, et al. Posttransplant diabetes mellitus after pancreas
1004
booksmedicos.org
transplantation. Am J Transplant 2008;8(1):175–182.
33. Gruessner RW, Sutherland DE, Drangstveit MB, et al. Pancreas allotransplants in patients with a
previous total pancreatectomy for chronic pancreatitis. J Am Coll Surg 2008;206:458–465
34. Scientific Registry of Transplant Recipients, special analysis for the Organ Procurement and
Transplantation Network Pancreas Committee, 2008.
35. Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas living-donor kidney
transplantation: a new approach for the type 1 diabetic uremic patient. Ann Surg 2000;232:696–
703.
36. Gruessner RW, Kendall DM, Drangstveit MB, et al. Simultaneous pancreas-kidney transplantation
from live donors. Ann Surg 1997;226:471–482.
37. Gruessner RW. Living donor pancreas transplantation. In: Gruessner RW, Sutherland DE, eds.
Transplantation of the Pancreas. New York, NY: Springer; 2004:429.
38. Gruessner RW, Pugliese A, Reijonen HK, et al. Development of diabetes mellitus in living pancreas
donors and recipients. Expert Rev Clin Immunol 2011;7(4):543–551.
39. Wiseman AC, Huang E, Kamgar M, et al. The impact of pre-transplant dialysis on simultaneous
pancreas-kidney versus living donor kidney transplant outcomes. Nephrol Dial Transplant
2013;28(4):1047–1058.
40. Kim SJ, Smail N, Paraskevas S, et al. Kidney function before pancreas transplant alone predicts
subsequent risk of end-stage renal disease. Transplantation 2014;97(6):675–680.
41. Boggi U, Amorese G, Marchetti P, et al. Segmental live donor pancreas transplantation: review and
critique of rationale, outcomes, and current recommendations. Clin Transplant 2011;25(1):4–12.
42. Sutherland DE, Radosevich D, Gruessner R, et al. Pushing the envelope: living donor pancreas
transplantation. Curr Opin Organ Transplant 2012;17(1):106–115.
43. Shah AP, Mangus RS, Powelson JA, et al. Impact of recipient age on whole organ pancreas
transplantation. Clin Transplant 2013;27(1):E49–E55.
44. Afaneh C, Rich B, Aull MJ, et al. Pancreas transplantation considering the spectrum of body mass
indices. Clin Transplant 2011;25(5):E520–E529.
45. Mangus RS, Powelson J, Kinsella SB, et al. Pretransplant coronary artery disease associated with
worse clinical outcomes in pancreas transplantation. Clin Transplant 2013;27(4):E442–E447.
46. Morath C, Mueller M, Goldschmidt H, et al. Malignancy in renal transplantation. J Am Soc Nephrol
2004;15:1582–1588.
47. Stehman-Breen CO, Psaty BM, Emerson S, et al. Association of hepatitis C virus infection with
mortality and graft survival in kidney–pancreas transplant recipients. Transplantation 1997;64:281–
286.
48. Honaker MR, Stratta RJ, Lo A, et al. Impact of hepatitis C virus status in pancreas transplantation: a
case controlled study. Clin Transplant 2002; 16:243–251.
49. Stock P, Roland M, Carlson L, et al. Solid organ transplantation in HIV-positive patients. Transplant
Proc 2001;33:3646–3648.
50. Scientific Registry of Transplant Recipients. In: Rockville MD, eds. 2012 Annual Report. Health
Resources and Services Administration, Department of Health and Human Services; 2004.
51. Organ Procurement and Transplantation Network. Organ distribution: pancreas allocation. Policy
11.
52. Stegall MD, Dean PG, Sung RS, et al. The rationale for the new deceased donor pancreas allocation
schema. Transplantation 2007;83:1156–1162.
53. Axelrod DA, Sung RS, Meyer K, et al. Systematic evaluation of pancreas allograft quality, outcomes,
and geographic variation in utilization. Am J Transplant 2010;10:837–845.
54. Douzdjian V, Gugliuzza KG, Fish JC. Multivariate analysis of donor risk factors for pancreas
allograft failure after simultaneous pancreas-kidney transplantation. Surgery 1995;118:73–81.
55. Humar A, Ramcharan T, Kandaswamy R, et al. Technical failures after pancreas transplants: why
grafts fail and the risk factors–a multivariate analysis. Transplantation 2004;78:1188–1192.
56. Gruessner AC, Gruessner RW. Pancreas transplant outcomes for United States (US) and non-US
cases as reported to the United Network for Organ Sharing (UNOS) and the International Pancreas
Transplant Registry (IPTR) as of June 2004. Clin Transplant 2005;19:433–455.
1005
booksmedicos.org
57. Humar A, Ramcharan T, Kandaswamy R, et al. The impact of donor obesity on outcomes after
cadaver pancreas transplants. Am J Transplant 2004;4:605–610.
58. Scientific Registry of Transplant Recipients. Final Analysis for Data request for the Outcomes Model
Review Sub-Committee of the OPTN Pancreas Transplantation Committee Meeting of March 5, 2008.
59. Salvalaggio PR, Davies DB, Fernandez LA, et al. Outcomes of pancreas transplantation in the United
States using cardiac-death donors. Am J Transplant 2006;6:1059–1065.
60. Fernandez LA, Di Carlo A, Odorico JS, et al. Simultaneous pancreas-kidney transplantation from
donation after cardiac death: successful long-term outcomes. Ann Surg 2005;242(5):716–723.
61. Berney T, Malaise J, Morel P, et al; The Euro SPK Study Group. Impact of HLA matching on the
outcome of simultaneous pancreas–kidney transplantation. Nephrol Dial, Transplant 2005;20:ii48-
ii53.
62. Fridell JA, Agarwal A, Milgrom ML, et al. Comparison of histidine-tryptophan-ketoglutarate
solution and University of Wisconsin solution for organ preservation in clinical pancreas
transplantation. Transplantation 2004;77:1304–1306.
63. Stewart ZA, Cameron AM, Singer AL, et al. Histidine-Tryptophan-Ketoglutarate (HTK) is associated
with reduced graft survival in pancreas transplantation. Am J Transplant 2009;9:217–221
64. Rosenlof LK, Earnhardt RC, Pruett TL, et al. Pancreas transplantation. An initial experience with
systemic and portal drainage of pancreatic allografts. Ann Surg 1992;215:586–597.
65. Frystyk J, Ritzel RA, Maubach J, et al. Comparison of pancreas-transplanted type 1 diabetic
patients with portal-venous versus systemic-venous graft drainage: impact on glucose regulatory
hormones and the growth hormone/insulin–like growth factor-I axis. J Clin Endocrinol Metab
2008;93:1758–1766.
66. Petruzzo P, Lefrancois N, Berthillot C, et al. Impact of pancreatic venous drainage site on long-term
patient and graft outcome in simultaneous pancreas-kidney transplantation. Clin Transplant
2008:22:107–112.
67. Stratta RJ, Shokouh-Amiri MH, Egidi MF, et al. A prospective comparison of simultaneous kidney-
pancreas transplantation with systemic-enteric versus portal-enteric drainage. Ann Surg
2001;233:740–751.
68. Bazerbachi F, Selzner M, Marquez MA, et al. Portal venous versus systemic venous drainage of
pancreas grafts: impact on long-term results. Am J Transplant 2012;12(1):226–232..
69. Gaber AO, Shokouh-Amiri H, Grewal HP, et al. A technique for portal pancreatic transplantation
with enteric drainage. Surg Gynecol Obstet 1993;177:417–419.
70. Sollinger HW, Sasaki TM, D’Alessandro AM, et al. Indications for enteric conversion after pancreas
transplantation with bladder drainage. Surgery 1992;112:842–846.
71. Benedetti E, Najarian JS, Gruessner AC, et al. Correlation between cystoscopic biopsy results and
hypoamylasuria in bladder-drained pancreas transplants. Surgery 1995;118:864–872.
72. Adrogue HE, Matas AJ, McGlennon RC, et al. Do inherited hypercoagulable states play a role in
thrombotic events affecting kidney/pancreas transplant recipients? Clin Transplant 2007:21:32–37.
73. Troppmann C, Gruessner AC, Dunn DL, et al. Surgical complications requiring early relaparotomy
after pancreas transplantation: a multivariate risk factor and economic impact analysis of the
cyclosporine era. Ann Surg 1998;227:255–268.
74. Stratta RJ, Alloway RR, Lo A, et al. Two-dose daclizumab regimen in simultaneous kidney-pancreas
transplant recipients: primary endpoint analysis of a multicenter, randomized study. Transplantation
2003;75:1260–1266.
75. Kaufman DB, Iii GW, Bruce DS, et al. Prospective, randomized, multi-center trial of antibody
induction therapy in simultaneous pancreas-kidney transplantation. Am J Transplant 2003;3:855–
864.
76. Freise CE, Kang SM, Feng S, et al. Excellent short-term results with steroid-free maintenance
immunosuppression in low-risk simultaneous pancreas-kidney transplantation. Arch Surg
2003;138:1121–1126.
77. Kaufman DB, Leventhal JR, Koffron AJ, et al. A prospective study of rapid corticosteroid
elimination in simultaneous pancreas-kidney transplantation: comparison of two maintenance
immunosuppression protocols: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus.
1006
booksmedicos.org
78. Kaufman DB, Leventhal JR, Gallon LG, et al. Alemtuzumab induction and prednisone-free
maintenance immunotherapy in simultaneous pancreas-kidney transplantation comparison with
rabbit antithymocyte globulin induction – long-term results. Am J Transplant 2006;6:331–339.
79. Thai NL, Khan A, Tom K, et al. Alemtuzumab induction and tacrolimus monotherapy in pancreas
transplantation: one- and two-year outcomes. Transplantation 2006;82:1621–1624.
80. Troppmann C, Gruessner AC, Benedetti E, et al. Vascular graft thrombosis after pancreatic
transplantation: univariate and multivariate operative and nonoperative risk factor analysis. J Am
Coll Surg 1996;182:285–316.
81. Finger EB, Radosevich DM, Dunn TB, et al. A composite risk model for predicting technical failure
in pancreas transplantation. Am J Transplant 2013;13(7):1840–9.
82. Gilabert R, Fernandez-Cruz L, Real MI, et al. Treatment and outcome of pancreatic venous graft
thrombosis after kidney-pancreas transplantation. Br J Surg 2002;89:355–360.
83. Ciancio G, Julian JF, Fernandez L, et al. Successful surgical salvage of pancreas allografts after
complete venous thrombosis. Transplantation 2000;70:126–131.
84. Kim YH, Park JB, Lee SS, et al. How to avoid graft thrombosis requiring graftectomy: immediate
posttransplant CT angiography in pancreas transplantation. Transplantation 2012;94(9):925–930.
85. Garcia-Roca R, Samame J, Garcia-Criado MA. et al. Preservation of pancreas graft function after
complete venous thrombosis: report of four cases treated conservatively. Transplantation
2012;93(2):214–218.
86. Scheffert JL, Taber DJ, Pilch NA, et al. Clinical outcomes associated with the early postoperative
use of heparin in pancreas transplantation. Transplantation 2014;97(6):681–685.
87. Sollinger HW, Odorico JS, Knechtle SJ, et al. Experience with 500 simultaneous pancreas-kidney
transplants. Ann Surg 1998;228:284–296.
88. Nath DS, Gruessner A, Kandaswamy R, et al. Late anastomotic leaks in pancreas transplant
recipients – clinical characteristics and predisposing factors. Clin Transplant 2005:19:220–224.
89. Niederhaus SV, Leverson GE, Lorentzen DF, et al. Acute cellular and antibody-mediated rejection of
the pancreas allograft: incidence, risk factors and outcomes. Am J Transplant 2013;13(11):2945–
2955.
90. Cantarovich D, De Amicis S, Akl A, et al. Posttransplant donor-specific anti-HLA antibodies
negatively impact pancreas transplantation outcome. Am J Transplant 2011;11(12):2737–2746.
91. Kersting S, Ludwig S, Ehehalt F, et al. Contrast-enhanced ultrasonography in pancreas
transplantation. Transplantation 2013;95(1):209–214.
92. Kuo PC, Johnson LB, Schweitzer EJ, et al. Solitary pancreas allografts. The role of percutaneous
biopsy and standardized histologic grading of rejection. Arch Surg 1997;132(1):52–57.
93. Bartlett ST, Schweitzer EJ, Johnson LB, et al. Equivalent success of simultaneous pancreas kidney
and solitary pancreas transplantation. A prospective trial of tacrolimus immunosuppression with
percutaneous biopsy. Ann Surg 1996;224:440–452.
94. Sutherland DER, Gruessner RWG, Dunn DL, et al. Lessons learned from more than 1,000 pancreas
transplants at a single institution. Ann Surg 2001;233(4):463–501.
95. Carpenter HA, Engen DE, Munn SR, et al. Histologic diagnosis of rejection by using cystoscopically
directed needle biopsy specimens from dysfunctional pancreatoduodenal allografts with exocrine
drainage into the bladder. Am J Surg Pathol 1990;14:837–846.
96. Atwell TD, Gorman B, Larson TS, et al. Pancreas transplants: experience with 232 percutaneous US-
guided biopsy procedures in 88 patients. Radiology 2004;231:845–849.
97. Kayler LK, Merion RM, Rudich SM, et al. Evaluation of pancreatic allograft dysfunction by
laparoscopic biopsy. Transplantation 2002;74:1287–1289.
98. Margreiter C, Aigner F, Resch T, et al. Enteroscopic biopsies in the management of pancreas
transplants: a proof of concept study for a novel monitoring tool. Transplantation 2012;93(2):207–
213.
99. Drachenberg CB, Torrealba JR, Nankivell BJ, et al. Guidelines for the diagnosis of antibody-
mediated rejection in pancreas allografts-updated Banff grading schema. Am J Transplant
2011;11(9):1792–1802.
100. Humar A, Khwaja K, Ramcharan T, et al. Chronic rejection: the next major challenge for pancreas
transplant recipients. Transplantation 2003;76:918–923.
1007
booksmedicos.org
101. Waki K, Sugawara Y, Tamura S, et al. Simultaneous pancreas-kidney transplantation in the United
States: an analysis of the UNOS registry. Clin Transpl 2010;20:35–44.
102. Ringers J, van der Torren CR, van de Linde P, et al. Pretransplantation GAD-autoantibody status to
guide prophylactic antibody induction therapy in simultaneous pancreas and kidney transplantation.
103. Assalino M, Genevay M, Morel P, et al. Recurrence of type 1 diabetes after simultaneous pancreas-
kidney transplantation in the absence of GAD and IA-2 autoantibodies. Am J Transplant
2012;12(2):492–495.
104. Ricart MJ, Malaise J, Moreno AN, et al; Fernandez-Cruz L the Euro-SPK Study Group.
Cytomegalovirus: occurrence, severity, and effect on graft survival in simultaneous pancreas–
kidney transplantation. Nephrol Dial Transplant 2005;20(suppl 2):ii25–ii32.
105. Axelrod D, Leventhal JR, Gallon LG, et al. Reduction of CMV disease with steroid-free
immunosuppresssion in simultaneous pancreas–kidney transplant recipients. Am J Transplant
2005;5:1423–1429.
106. Gupta G, Shapiro R, Thai N, et al. Low Incidence of BK virus nephropathy after simultaneous
kidney pancreas transplantation. Transplantation 2006;82:382–388.
107. Lipshutz GS, Mahanty H, Feng S, et al. BKV in simultaneous pancreas-kidney transplant recipients: a
leading cause of renal graft loss in first 2 years posttransplant. Am J Transplant 2005;5:366–373.
108. Paraskevas S, Coad JE, Gruessner A, et al. Posttransplant lymphoproliferative disorder in pancreas
transplantation: a single-center experience. Transplantation 2005;80:613–622.
109. Caillard S, Lamy FX, Quelen C, et al. French transplant centers. Epidemiology of posttransplant
lymphoproliferative disorders in adult kidney and kidney pancreas recipients: report of the French
registry and analysis of subgroups of lymphomas. Am J Transplant 2012;12(3):682–93.
110. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients
with diabetes and preserved kidney function. JAMA 2003;290:2817–2823.
111. Reddy KS, Stablein D, Taranto S, et al. Long-term survival following simultaneous kidney-pancreas
transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and
renal failure. Am J Kidney Dis 2003;41:464–470.
112. Kayler LK, Wen X, Zachariah M, et al. Outcomes and survival analysis of old-to-old simultaneous
pancreas and kidney transplantation. Transpl Int 2013;26(10):963–972.
113. Gruessner RWG, Sutherland DER, Gruessner AG. Mortality assessment for pancreas transplants. Am
J Transplant 2006;4(12):2018–2026.
114. Ojo AO, Meier-Kriesche HU, Hanson JA et al. The impact of simultaneous pancreas-kidney
transplantation on long-term patient survival. Transplantation 2001;71:82–90.
115. Sung RS, Zhang M, Schaubel DE, et al. A reassessment of the survival advantage of simultaneous
kidney-pancreas versus kidney-alone transplantation. Transplantation 2015;99(9):1900.
116. Bilous RW, Mauer SM, Sutherland DE, et al. The effects of pancreas transplantation on the
glomerular structure of renal allografts in patients with insulin-dependent diabetes. N Engl J Med
1989;321:80–85.
117. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after
pancreas transplantation. N Engl J Med 1998;339:69–75.
118. Khairoun M, de Koning EJ, van den Berg BM, et al. Microvascular damage in type 1 diabetic
patients is reversed in the first year after simultaneous pancreas-kidney transplantation. Am J
Transplant 2013;13(5):1272–1281.
119. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic
neuropathy. N Engl J Med 1990;322:1031–1037.
120. Tavakoli M, Mitu-Pretorian M, Petropoulos IN, et al. Corneal confocal microscopy detects early
nerve regeneration in diabetic neuropathy after simultaneous pancreas and kidney transplantation.
Diabetes 2013;62(1):254–260.
121. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal conforcal microsopy detects early nerve
regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care
2007;30:2608–2612.
122. Kendall DM, Rooney DP, Smets YF, et al. Pancreas transplantation restores epinephrine response
and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and
1008
booksmedicos.org
autonomic neuropathy. Diabetes 1997;46:249–257.
123. Walsh AW. Effects of pancreas transplantation on secondary complications of diabetes: retinopathy.
In: Gruessner RWG, Sutherland DER, eds. Transplantation of the Pancreas. New York, NY:Springer;
2004:462–470.
124. Giannarelli R, Coppelli A, Sartini MS, et al. Pancreas transplant alone has beneficial effects on
retinopathy in type 1 diabetic patients. Diabetologia 2006;49:2977–2982.
125. Boggi U, Vistoli F, Amorese G, et al. Long-term (5 years) efficacy and safety of pancreas
transplantation alone in type 1 diabetic patients. Transplantation 2012;93(8):842–846.
126. Morrissey PE, Shaffer D, Monaco AP, et al. Peripheral vascular disease after kidney-pancreas
transplantation in diabetic patients with end-stage renal disease. Arch Surg 1997;132:358–362.
127. Knight RJ, Schanzer H, Guy S, et al. Impact of kidney-pancreas transplantation on the progression
of peripheral vascular disease in diabetic patients with end-stage renal disease. Transplant Proc
1998;30:1947–1949.
128. Nakache R, Tyden G, Groth CG. Quality of life in diabetic patients after combined pancreas-kidney
or kidney transplantation. Diabetes 1989;38(suppl 1):40–42.
129. Gross CR, Limwattananon C, Matthees BJ. Quality of life after pancreas transplantation: a review.
Clin Transplant 1998;12:351–361.
130. Owen RJ, Ryan EA, O’Kelly K, et al. Percutaneous transhepatic pancreatic islet cell transplantation
in type 1 diabetes mellitus: radiologic aspects. Radiology 2003;229:165–170.
131. Lau H, Reemtsma K, Hardy MA. Prolongation of rat islet allograft survival by direct ultraviolet
irradiation of the graft. Science 1984;223:607–609.
132. Ryan EA, Lakey JR, Paty BW, et al. Successful islet transplantation: continued insulin reserve
provides long-term glycemic control. Diabetes 2002;51:2148–2157.
133. Sutherland DE, Matas AJ, Goetz FC, et al. Transplantation of dispersed pancreatic islet tissue in
humans: autografts and allografts. Diabetes 1980;29(suppl 1):31–44.
134. Brendel MD, Hering BJ, Schultz AO, et al, eds. International Islet Transplant Registry 2001. 2001;8:1.
135. Teuscher AU, Kendall DM, Smets YF, et al. Successful islet autotransplantation in humans:
functional insulin secretory reserve as an estimate of surviving islet cell mass. Diabetes
1998;47:324–340.
136. Shapiro AM, Lakey JR, Ryan EA, et al. Islet transplantation in seven patients with type 1 diabetes
mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000;343:230–238.
137. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet
transplantation. N Engl J Med 2006;355(13):1318–1330.
138. Ryan EA, Paty BW, Senior PA, et al. Five year follow-up after clinical islet transplantation. Diabetes
2005;54:2060–2069.
139. Markmann JF, Kaufman DB, Ricordi C, et al. Financial issues constraining the use of pancreata
recovered for islet transplantation: a white paper. Am J Transplant 2008;8(8):1588–1592.
140. Close N, Alejandro R, Hering B, et al. Second annual analysis of the collaborative islet transplant
registry. Transplant Proc 2007;39:179–182.
141. Tiwari JL, Schneider B, Barton F, et al. Islet cell transplantation in type 1 diabetes: an analysis of
efficacy outcomes and considerations for trial designs. Am J Transplant 2012;12:1898–1907.
142. Shapiro AM. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and
long-term outcome. Rev Diabet Stud 2012;9:385–406.
143. Ricordi C, Lacy PE, Firike EH, et al. Automated method for isolation of human pancreatic islets.
Diabetes 1988;37:413–420.
144. Linetsky E, Bottino R, Lehmann R, et al. Improved human islet isolation using a new enzyme blend,
LiberaseTM. Diabetes 1997;46:1120–1123.
145. Gerber PA, Pavlicek V, Demartines N, et al. Simultaneous islet-kidney versus pancreas–kidney
transplantation in type 1 diabetes mellitus: a 5 year single centre follow-up. Diabetologia
2008;51(1):110–119.
146. Kaufman DB, Baker MS, Chen X, et al. Sequential kidney/islet transplantation using prednisone-free
immunosuppression. Am J Transplant 2002;2:674–677.
147. Lakey JR, Warnock GL, Rajotte RV, et al. Variables in organ donors that affect the recovery of
1009
booksmedicos.org
human islets of langerhans. Transplantation 1996;61:1047–1053.
148. Kneteman NM, Lakey JR, Kizilisik TA, et al. Cadaver pancreas recovery technique. Impact on islet
recovery and in vitro function. Transplantation 1994;58:1114–1119.
149. Lakey JR, Tsujimura T, Shapiro AM, et al. Preservation of the human pancreas before islet isolation
using a two-layer (UW solution-perfluorochemical) cold storage method. Transplantation
2002;74:1809–1811.
150. Ricordi C, Fraker C, Szust J, et al. Improved human islet isolation outcome from marginal donors
following addition of oxygenated perfluorocarbon to the cold-storage solution. Transplantation
2003;75:1524–1527.
151. Hering BJ, Matsumoto I, Sawada T, et al. Impact of two-layer pancreas preservation on islet
isolation and transplantation. Transplantation 2002;74:1813–1816.
152. Paushter DH, Qi M, Danielson KK, et al. Histidine-tryptophan-ketoglutarate and University of
Wisconsin solution demonstrate equal effectiveness in the preservation of human pancreata
intended for islet isolation: a large-scale, single-center experience. Cell Transplant 2013; 22:1113–
1121.
153. Markmann JF, Deng S, Desai NM, et al. The use of non-heart-beating donors for isolated pancreatic
islet transplantation. Transplantation 2003;75:1423–1429.
154. Weimar B, Rauber K, Brendel MD, et al. Percutaneous transhepatic catheterization of the portal
vein: a combined CT- and fluoroscopy-guided technique. Cardiovasc Intervent Radiol 1999;22:342–
344.
155. Bretzel RG, Brandhorst D, Brandhorst H, et al. Improved survival of intraportal pancreatic islet cell
allografts in patients with type-1 diabetes mellitus by refined peritransplant management. J Mol
Med 1999;77:140–143.
156. Citro A, Cantarelli E, Maffi P, et al. CXCR1/2 inhibition enhances pancreatic islet survival after
transplantation. J Clin Invest 2012;122:3647–3651.
157. Posselt AM, Szot GL, Frassetto LA, et al. Clinical islet transplantation at the University of
California, San Francisco. Clin Transpl 2010;235–243.
158. Paty BW, Ryan EA, Shapiro AM, et al. Intrahepatic islet transplantation in type 1 diabetic patients
does not restore hypoglycemic hormonal counterregulation or symptom recognition after insulin
independence. Diabetes 2002;51:3428–3434.
159. Radosevich DM, Jevne R, Bellin M, et al. Comprehensive health assessment and five-yr follow-up of
allogeneic islet transplant recipients. Clin Transplant 2013;27:E715–E724.
160. Rickels MR, Kong SM, Fuller C, et al. Improvement in insulin sensitivity after human islet
transplantation for type 1 diabetes. J Clin Endocrinol Metab 2013;98:E1780–E1785.
161. Frank A, Deng S, Huang X, et al. Transplantation for type I diabetes: comparison of vascularized
whole-organ pancreas with isolated pancreatic islets. Ann Surg 2004;240(4):631–640.
162. Hirsch D, Odorico J, Danobeitia JS, et al. Early metabolic markers that anticipate loss of insulin
independence in type 1 diabetic islet allograft recipients. Am J Transplant 2012;12(5):1275–1289.
163. Hirshberg B, Rother KI, Digon BJ 3rd, et al. Benefits and risks of solitary islet transplantation for
type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health
experience. Diabetes Care 2003;26:3288–3295.
164. Casey JJ, Lakey JR, Ryan EA, et al. Portal venous pressure changes after sequential clinical islet
transplantation. Transplantation 2002;74:913–915.
165. Rafael E, Ryan EA, Paty BW, et al. Changes in liver enzymes after clinical islet transplantation.
166. Esposito A, Palmisano A, Maffi P, et al. Liver perfusion changes occurring during pancreatic islet
engraftment: a dynamic contrast-enhanced magnetic resonance study. Am J Transplant 2014;14:202–
209.
167. Markmann JF, Rosen M, Siegelman ES, et al. Magnetic resonance-defined periportal steatosis
following intraportal islet transplantation: a functional footprint of islet graft survival? Diabetes
2003;52:1591–1594.
168. Piemonti L, Everly MJ, Maffi P, et al. Alloantibody and autoantibody monitoring predicts islet
transplantation outcome in human type 1 diabetes. Diabetes 2013;62:1656–1664.
169. Naziruddin B, Wease S, Stablein D, et al. HLA class I sensitization in islet transplant recipients:
1010
booksmedicos.org
report from the collaborative islet transplant registry. Cell Transplant 2012;21:901–908.
170. Hering BJ, Kandaswamy R, Harmon JV, et al. Transplantation of cultured islets from two-layer
preserved pancreases in type 1 diabetes with anti-CD3 antibody. Am J Transplant. 2004;4:390–401.
171. Froud T, Ricordi C, Baidal DA, et al. Islet transplantation in type 1 diabetes mellitus using cultured
islets and steroid-free immunosuppression: Miami experience. Am J Transplant 2005;5(8):2037–
2046.
172. Gangemi A, Salehi P, Hatipoglu B, et al. Islet transplantation for brittle type 1 diabetes: the UIC
protocol. Am J Transplant 2008;8:1250–1261.
173. Markmann JF, Deng S, Huang X, et al. Insulin independence following isolated islet transplantation
and single islet infusions. Ann Surg 2003; 237:741–750.
174. Keymeulen B, Gillard P, Mathieu C, et al. Correlation between b-cell mass and glycemic control in
type 1 diabetic recipients of islet cell graft. PNAS 2006;103(46):17444–17449.
175. Han D, Xu X, Pastori RL, et al. Elevation of cytotoxic lymphocyte gene expression is predictive of
islet allograft rejection in nonhuman primates. Diabetes 2002;51:562–566.
176. Shapiro AM, Hao EG, Lakey JR, et al. Novel approaches toward early diagnosis of islet allograft
rejection. Transplantation 2001;71:1709–1718.
177. Saudek F, Jirak D, Girman P, et al. Magnetic resonance imaging of pancreatic islets transplanted
into the liver in humans. Transplantation 2010;90:1602–1606.
178. Jacobs-Tulleneers-Thevissen D, Chintinne M, Ling Z, et al. Beta Cell Therapy Consortium EU-FP7.
Sustained function of alginate-encapsulated human islet cell implants in the peritoneal cavity of
mice leading to a pilot study in a type 1 diabetic patient. Diabetologia 2013;56:1605–1614.
179. Basta G, Montanucci P, Luca G, et al. Long-term metabolic and immunological follow-up of
nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts:
four cases. Diabetes Care 2011;34:2406–2409.
180. Vaithilingam V, Barbaro B, Oberholzer J, et al. Functional capacity of human islets after long-
distance shipment and encapsulation. Pancreas 2011;40:247–252.
181. Luo JZ, Xiong F, Al-Homsi AS, et al. Allogeneic bone marrow cocultured with human islets
significantly improves islet survival and function in vivo. Transplantation 2013;95:801–809.
182. Yeung TY, Seeberger KL, Kin T, et al. Human mesenchymal stem cells protect human islets from
pro-inflammatory cytokines. PLoS ONE 2012;7:e38189.
183. Ding Y, Bushell A, Wood KJ. Mesenchymal stem-cell immunosuppressive capabilities: therapeutic
implications in islet transplantation. Transplantation 2010;89:270–273.
1011
booksmedicos.org
SECTION C: HEAD AND NECK
1012
booksmedicos.org
Chapter 41
Head and Neck

J. Kenneth Byrd and Robert L. Ferris
Key Points
1 Squamous cell carcinoma (SCC) is the most common malignancy of the head and neck region.
Tobacco, alcohol, and human papillomavirus are the major risk factors.
2 A cystic neck mass in an adult represents a neck metastasis until proven otherwise, and should not be
incised and drained.
3 A multidisciplinary team should evaluate patients with a suspected head and neck tumor for
treatment options.
4 Functional reconstruction is equally important as oncologic resection in head and neck surgery.
5 Patients with new hoarseness for more than 2 weeks should be evaluated by a physician capable of
performing flexible fiberoptic laryngoscopy.
INTRODUCTION
The head and neck is a complex anatomical subsite, containing the major structures responsible for
sight, hearing, smell, speech, and swallowing. Disorders of the head and neck can therefore cause
detriment to quality of life by interfering with these functions. Knowledge of the anatomy of the region
is crucial to treat patients who present with complaints involving the head and neck, whether benign or
malignant. The following chapter will provide an overview of common presentations of head and neck
disorders, including head and neck cancer, which accounts for over 50,000 cases per year.
PATIENT EVALUATION
1 As in any clinical evaluation, a careful patient history should be taken, paying particular attention to
the timing of onset, severity, progression, and associated symptoms. Table 41-1 lists some of the more
common presenting signs and symptoms of head and neck cancer. Social history is of particular
importance in head and neck patients, as tobacco and alcohol use synergistically increase the risk of
head and neck squamous cell carcinoma (SCC).1 The clinician should document type, frequency, and
duration of use on any patient suspected to have a head and neck disorder. Sexual history may also be
of some interest, as the number of oral sexual partners has been associated with an increased risk of
HPV-related oropharyngeal cancer.2
On physical examination, the physician should proceed systematically through each area of the head
and neck. Gross deformity, skin lesions, previous incisions or scars, and radiation sequelae should be
noted. The physician should pay attention to any breathing difficulty, including stridor, stertor, and
nasal obstruction.
Each mucosal subsite of the head and neck region should be thoroughly inspected (Table 41-2). A
headlight or headlamp should be used to inspect the oral cavity, oropharynx, and larynx/hypopharynx
(if indirect mirror laryngoscopy is performed). Dentures should be removed prior to bimanual
examination of the oral cavity and oropharynx using tongue blades to check all mucosal surfaces.
Although some otolaryngologists prefer indirect laryngoscopy to visualize the larynx and
hypopharynx, patients with large tongues and/or hyperactive gag reflexes may be difficult to examine.
In the setting of possible malignancy, we recommend that all patients undergo flexible fiberoptic
laryngoscopy, which provides excellent dynamic visualization and the ability to record images and
video when coupled with appropriate equipment. Additionally, flexible or rigid endoscopy provides a
more detailed view of the nasal cavity than anterior rhinoscopy. Figure 41-1 demonstrates the view of
the larynx provided by in-office stroboscopy.
1013
booksmedicos.org
The cervical lymph nodes should be palpated carefully, taking note of the location in levels I to V of
the neck, as described by Robbins et al. (Fig. 41-2),3 as well as lateral and superior–inferior mobility.
Pulsatility of the mass may suggest a vascular pathology, and should not be biopsied prior to imaging.
The laryngeal and tracheal framework should be examined to determine any disruption to the normal
architecture, as well as the position relative to the sternum. The thyroid gland should also be palpated
as part of every head and neck examination, although this is addressed in a separate chapter.
In the neurologic examination, particular attention should be paid to the cranial nerves. In sinonasal
pathology, hyposmia may be due to nasal obstruction, or alternatively due to direct involvement of the
olfactory nerve. Extraocular movement abnormalities can result from orbital or skull base pathology.
Temporal wasting or facial numbness may be a sign of perineural spread in the trigeminal nerve, and
facial weakness or twitching in the setting of a parotid mass suggests malignancy. Ipsilateral vocal
paralysis or impaired palatal elevation may suggest involvement of the vagus nerve, important to note
in skull base paragangliomas. Preoperative shoulder weakness in the setting of lymphadenopathy may
prompt the surgeon to counsel the patient about the need for radical neck dissection, as the spinal
accessory nerve may be involved by tumor.
WORKUP
In the setting of an accessible tumor (e.g., oral tongue, tonsil) biopsy may be performed in the office
under local anesthesia. In more distal subsites, operative direct laryngoscopy is required. For palpable
salivary or cervical masses, fine-needle aspiration is easily performed without image guidance. In most
patients with head and neck pathology, CT with contrast is the preferred imaging modality. MRI can be
of value in some cases, such as when perineural spread is a concern, to evaluate for invasion of intrinsic
tongue musculature in oral or oropharyngeal cancer, and for orbital and dural assessment. When
malignancy is diagnosed, metastatic workup with PET/CT or chest CT should be performed in stage
III/IV pathology.
Table 41-1 Differential Diagnosis of the Neck Mass
Table 41-2 Subsites of Head and Neck
1014
booksmedicos.org
AIRWAY MANAGEMENT
Although the anesthesia team is primarily responsible for evaluating the airway, the surgeon should
share some responsibility in patients with head and neck disorders. A number of patient factors have
been described in the anesthesia literature as predictors of difficult laryngoscopy, including
sternomental distance, Mallampati score, thyromental distance, and mouth opening.4 However, the head
and neck surgeon will be more aware of the endoscopic airway anatomy as a result of preoperative
imaging and laryngoscopy. Bulky supraglottic and oropharyngeal masses may lead to failure of mask
ventilation and difficulty passing an orotracheal tube; lesions prone to bleeding may cause similar
problems. Patients with fibrosis from prior radiation or chemoradiation may have impaired laryngeal
excursion, in addition to trismus. In a prospective study of intubation in patients with head and neck
pathology, one group found that prior radiotherapy, a diagnosis of cancer, and supraglottic or glottic
subsite were predictive of airway difficulty.5 Indeed, it is imperative that the surgeon and
anesthesiologist communicate about the airway plan prior to induction.
Figure 41-1. In-office stroboscopy demonstrates a normal larynx with glottis open. Stroboscopy allows for dynamic visualization of
the mucosal wave and arytenoid movement.
1015
booksmedicos.org
Figure 41-2. The cervical lymph nodes are divided into six groups, or levels.
Figure 41-3. Tracheostomy. A: The incision for an elective tracheostomy is typically placed on a horizontal axis, approximately
two finger breadths above the sternal notch. A vertical incision allows for less bleeding when the procedure must be performed
emergently. B: The strap muscles are separated in the midline. The thyroid isthmus may bulge into the wound (C), necessitating
inferior retraction or division (D). E: After the second tracheal ring is cleaned off, an inferiorly based flap (i.e., Bjork flap) is
developed in the tracheal wall and sutured to the skin. This allows for easy access to the trachea while the tract is maturing.
In patients for whom difficulty is predicted, fiberoptic nasotracheal or orotracheal intubation may be
safely performed with the patient spontaneously breathing with topical anesthesia and sedation.
Alternatively, planned awake tracheotomy is an option in patients with severe obstruction and abnormal
anatomy. Additionally, a tracheotomy kit should always be nearby for emergent cricothyrotomy or
tracheotomy, should it be necessary. Figure 41-3 demonstrates the typical sequence of steps in a
tracheotomy.
INFECTIOUS
1016
booksmedicos.org
Pharyngitis and Abscesses
Acute pharyngitis is a common presentation in outpatient offices and the emergency department.
Although group A streptococcus is a concern due to its potential complications, it accounts for only 10%
to 15% of pharyngeal infections in adults; the majority are viral. Patients with fever, tonsillar exudates,
absence of cough, and cervical lymphadenopathy are more likely to have bacterial pharyngitis, and
should be tested for streptococcus and subsequently treated with amoxicillin, clindamycin, or a
macrolide.6 Those without streptococcal pharyngitis may generally be treated with hydration and
analgesics, although antibiotics may be indicated if atypical bacteria are suspected or if symptoms fail to
improve.
The most common head and neck abscess is the peritonsillar abscess, which typically arises from
untreated bacterial pharyngitis that leads to bacterial invasion of the parapharyngeal space if not
drained. Patients typically present with throat pain, trismus, dysphagia and odynophagia, and a muffled
voice. Physical examination reveals palatal and tonsillar bulging and uvular deviation toward the
unaffected side. Imaging is often unnecessary but may be useful in equivocal cases. Drainage is
performed at bedside after topical anesthetic spray and injected lidocaine or bupivacaine are used to
anesthetize the area; trismus is often greatly improved after local is administered, facilitating drainage.
An 18-gauge needle can be of use to localize the pus collection and plan the incision. An 11 or 15 blade
is then used to make an incision, which is enlarged with a hemostat when the abscess is localized.
Palpation of the tonsil with the hemostat or a cotton swab will express the remaining fluid (Fig. 41-4).
Antibiotics with broad coverage (e.g., amoxicillin-clavulanate or clindamycin) should be prescribed for
10 to 14 days.7 Patients with a history of multiple peritonsillar abscesses should be considered for
tonsillectomy.
Figure 41-4. Schematic representation of a peritonsillar abscess. Purulence develops between the tonsillar capsule and the superior
pharyngeal constrictor muscle. As a result, the palate bulges and the tonsil is deviated medially. Inflammation in the region of the
pterygoid muscles results in pain and trismus which may be significant.
In evaluating the patient with pharyngitis or a peritonsillar abscess, it is important to differentiate

from epiglottitis. Patients may present similarly, with odynophagia, a muffled voice, and drooling.
However, patients with acute bacterial epiglottitis are more toxic in appearance and have impending
airway compromise. Plain film radiographs of the neck will display the “thumbprint” sign, or an
edematous epiglottis. If the patient is tolerant, transnasal flexible laryngoscopy can be used to confirm
the diagnosis, but early securing of the airway in the operating room with tracheotomy or fiberoptic
intubation is paramount.
Progression of odontogenic or pharyngeal infections can lead to deep neck space infections, as well.
Early evaluation of the patient’s airway is paramount in deep neck infections, as they may rapidly
progress, particularly in the immunocompromised (e.g., diabetics). Elective intubation is often required,
and tracheotomy may be necessary in the setting of prolonged airway edema. Of particular concern are
infections involving the floor of mouth, or Ludwig angina, which can quickly progress bilaterally, and
cause airway compromise via posterior displacement of the base of tongue and trismus. In this setting,
awake fiberoptic transnasal intubation may be attempted, but the surgeon should be prepared for awake
tracheotomy. Infections in other neck spaces, including the Danger Space and Prevertebral Space, may
spread quickly through the entire neck and cause rapid decompensation. Figure 41-5 lists the relevant
deep neck spaces and paths of spread.
Operative intervention is usually required for deep neck infections, involving incision and drainage of
the affected spaces. Copious irrigation with placement of suction drains is recommended to decrease the
likelihood of reaccumulation, and reexploration is occasionally needed. Additionally, the odontogenic
source of the infection should be addressed, ideally at the same time as the incision and drainage.
1017
booksmedicos.org
SINUSITIS
In the clinical setting, patients and caregivers often lump upper respiratory infection (URI) and
“sinusitis” together. Indeed, the common cold virus is the most common infection associated with URI,
which concomitantly involves the nasal mucosa and paranasal sinuses. Rhinosinusitis is therefore a
better term than “sinusitis.” Rhinosinusitis is classified as acute, subacute, and chronic based on length
of duration: less than 4 weeks, 4 to 12 weeks, and greater than 12 weeks, respectively.8
Figure 41-5. The deep spaces of the neck are distinct but interconnected compartments. Infections in any one of these may spread
to involve other potential spaces and critical structures contained therein.
In the acute setting, it is important to differentiate between viral and bacterial rhinosinusitis, as both
will present with fever, facial pressure and/or pain, nasal obstruction, and purulent or discolored nasal
discharge. The American Academy of Otolaryngology-Head and Neck Surgery Clinical Practice
Guideline for adult sinusitis notes that the vast majority of URIs are viral, and that bacterial
rhinosinusitis should be suspected when symptoms persist after 10 days or worsen after a period of
improvement.8
In the setting of presumed viral rhinosinusitis, patients should be treated with antipyretics and
analgesics, and decongestants may be considered. For acute bacterial rhinosinusitis, amoxicillin was
recommended as the first-line antibiotic in the 2007 guidelines; however, some now recommend
amoxicillin-clavulanate for 5 to 7 days due to the increasing prevalence of resistance. A fluoroquinolone
or doxycycline may be used as first-line treatment in patients with penicillin allergy.9
Surgery is not indicated for patients with acute sinusitis, unless orbital or intracranial involvement
occurs, or in the setting of an immunocompromised patient who fails to respond to medical treatment.
Similarly, imaging is recommended against, except in the aforementioned situations.8 However,
complicated acute bacterial rhinosinusitis (Table 41-3) should be suspected when visual, mental status, or
neurologic changes are present. Proptosis, chemosis, and periorbital edema may signify extension of
infection into the orbit (Fig. 41-6). Contrasted CT is useful to determine the extent of disease, and may
be complemented by MRI. Prompt consultation with ophthalmology and/or neurosurgery is warranted
for these cases.
Acute, severe, evolving sinonasal complaints in the immunocompromised should raise concern for
acute invasive fungal sinusitis, which is rapidly progressive and fatal if untreated. Patients with HIV,
organ transplant, chemotherapy-induced neutropenia, and even uncontrolled diabetes mellitus may be
susceptible. The organisms most commonly associated are from the Aspergillus, Rhizopus, Mucor,
Rhizomucor, and Absidia genera.10 Nasal endoscopy should be performed at the bedside, and which will
demonstrate pale or black, necrotic mucosa, typically involving the turbinates or septum. Frozen section
biopsy is performed, rather than fungal cultures, as immediate diagnosis is imperative. The patient
should be emergently and aggressively debrided to bleeding, vascularized tissue in the operating room,
and concomitant consultation of an Infectious Disease specialist with initiation of antifungal drugs is
advised. Reversal of the underlying immunocompromised state will improve prognosis, as well.
COMPLICATIONS
Table 41-3 Complications of Sinusitis
1018
booksmedicos.org
SIALADENITIS
Patients with sialadenitis present with acute onset pain in the parotid or submandibular areas. Patients
who are debilitated, dehydrated, or have decreased salivary flow due to medications or other factors
(e.g., previous radiation) are predisposed to salivary gland infection. Sialadenitis is a clinical diagnosis,
based on reproducible pain with palpation of the affected gland(s), temporal course, and presence of
purulence in Warthin or Stensen duct. Sialadenitis may be viral or bacterial, viral infections (mumps,
HIV, etc.) having a tendency to affect multiple glands bilaterally. In acute bacterial sialadenitis,
symptoms tend to present quickly, with purulent salivary secretions, tense, erythematous skin, fever,
and leukocytosis. Most infections are caused by Staphylococcus aureus, although a variety of anaerobes
and other oral pathogens may be cultured.11
Figure 41-6. Contrasted coronal CT demonstrates a right-sided periorbital abscess (asterisk) arising in a child with acute bacterial
ethmoid sinusitis. Urgent ophthalmologic consultation was obtained, which revealed increased intraocular pressure. The child was
taken for endoscopic ethmoidectomy and orbital decompression.
Patients with uncomplicated sialadenitis should be treated with hydration, sialogogues, gland
massage, and broad spectrum antibiotics if bacterial pathogens are suspected. If purulent saliva is noted,
cultures may be sent. Worsening of symptoms after initiation of therapy should prompt consideration of
abscess development, and imaging with ultrasound or CT should be performed. Recurrent or chronic
salivary infections less often result from chronic infection, but rather structural or inflammatory
disorders are more common. Connective tissue disorders, such as Sjogren syndrome, rheumatoid
arthritis, and sarcoidosis may present with or develop salivary gland involvement, and should prompt
consultation with a rheumatologist if suspected. Alternatively, a history of repeated episodes of
sialadenitis or gland fullness can be due to sialolithiasis. Physical examination with palpation of the
1019
booksmedicos.org
submandibular and parotid ducts will reveal a palpable mass in cases with large, distal stones. These are
best approached via intraoral cutdown on a lacrimal probe. However, smaller stones in the hilum or
gland parenchyma may require imaging for diagnosis.
Although parotidectomy or submandibular gland excision has long been the treatment for such stones
and strictures, improvements in fiberoptic technology have led to increasing adoption of sialendoscopy
to implement gland-sparing interventions. A recent meta-analysis demonstrated a high proportion of
success and low incidence in complications for patients undergoing sialendoscopy for obstructive
disease.12
Finally, it is important to rule out neoplasia in patients with repeated salivary complaints, as tumors
can cause transient obstruction, as well.
CYSTIC NECK INFECTIONS

2 A variety of head and neck infections may present atypically. While it is true that adult patients may
rarely manifest infectious, cystic neck lesions, they should be presumed malignant until proven
otherwise because of the high prevalence cystic lymph node metastasis in SCC, particularly the HPV-
related disease (Fig. 41-7). Large, necrotic lymph nodes may become painful and swollen if hemorrhage
or superinfection occurs, mimicking benign disease. It is important to note that incision and drainage of
cancerous lymph nodes can hinder cure due to widespread tumor seeding.
Figure 41-7. Contrasted axial CT demonstrates a large, rim-enhancing mass involving the right level III and IV neck. Image-guided
FNA was required to confirm HPV-related squamous cell carcinoma due to its cystic nature.
1020
booksmedicos.org
Algorithm 41-1. Workup of a Neck Mass in an Adult Patient.
With the previous caveats, the infrequent adult patient may present with atypical suppurative
lymphadenitis or an infected, previously unrecognized branchial cleft cyst. If history and physical
examination are suspicious for this, a limited trial of antibiotics may be initiated for 1 to 2 weeks to
monitor for improvement. However, further workup, including complete physical examination,
imaging, and fine-needle aspiration should be simultaneously undertaken to prevent delays in diagnosis.
If a cystic neck mass is to be removed for diagnosis, a frozen section should be sent at the time of
surgery, with completion neck dissection planned if SCC is present. Algorithm 41-1 is a suggested
approach to the adult with a lateral neck mass.
HEAD AND NECK NEOPLASMS

3 Patients with diagnosed head and neck tumor should be referred to a center with a multidisciplinary
care team, including head and neck surgeons, radiation oncologists, medical oncologists, dentists,
pathologists, radiologists, speech therapy, and social work. Treatment of head and neck neoplasms,
whether surgical or nonsurgical, is likely to have an impact on speech, swallowing, and overall quality
1021
booksmedicos.org
of life, and anticipation and aggressive treatments of these aspects are crucial.
Table 41-4 Salivary Tumors
SALIVARY
Salivary tumors, although rare, encompass a large number of benign and malignant pathologies (Table
41-4). The parotid is the most commonly involved gland, followed by minor salivary glands, the
submandibular gland, and the sublingual gland. The majority of parotid tumors (∼75%) are benign, the
most common type being pleomorphic adenoma.13,14 However, there is an inverse relationship between
frequency of gland involvement and rate of malignancy, with approximately 50% malignant pathology
in the submandibular gland and up to 86% in the sublingual gland. The most common malignant tumor
is mucoepidermoid carcinoma, followed by adenoid cystic carcinoma (ACC) and adenocarcinoma.13
Table 41-5 lists the T-staging for parotid malignancies according to the American Joint Committee on
Cancer.15 Additionally, the parotid gland contains lymph nodes that receive lymphatic drainage from
the scalp and face.
Salivary tumors commonly present with painless swelling, and the most typical location is in the
parotid tail. However, tumors that arise in the deep lobe of the parotid (deep to the plane of the facial
nerve) may extend into the parapharyngeal space and grow quite large before they are noticed, and
may cause trismus or a pharyngeal bulge. Warthin tumors are associated with male gender and
smoking, and may be bilateral or multifocal.16 Although most salivary tumors are benign, the presence
of pain, trismus, or facial weakness should raise the clinician’s suspicion of malignancy.
In the setting of a small tumor without atypical symptoms, routine imaging is not necessarily
required, as it is unlikely to change the surgical plan. When imaging is desired, CT is the mainstay of
imaging due to its widespread availability and ease to obtain, although MRI can be useful to further
delineate the extent of a mass and perineural invasion.17 Figure 41-8A,B demonstrates MRI
characteristics of a pleomorphic adenoma on contrasted MRI.
Table 41-5 Staging of Major Salivary Gland Tumors
Fine-needle aspiration may be performed prior to surgery, based on surgeon preference. In practice,
FNA may be useful for counseling patients in whom malignancy is found that a more aggressive surgery
will be performed, or to avoid surgery in patients with inflammatory disease or lymphoid malignancies.
However, the surgeon should be aware that the specificity for neoplasia and malignancy is high,
however the sensitivity is lower and more variable for both.18
For benign lesions, partial superficial parotidectomy, taking just the tissue immediately around the
tumor, is sufficient. Additionally, there is some evidence that, in experienced hands, extracapsular
dissection without facial nerve identification may be equally effective and less morbid than superficial
parotidectomy.19,20 Figure 41-9 demonstrates the steps performed in superficial parotidectomy with
1022
booksmedicos.org
facial nerve dissection.
Although “total parotidectomy” is typically recommended for malignancy, tumors may not be found
to be malignant until final pathology.21 Furthermore, a total parotidectomy is very difficult to perform
en bloc with preservation of the facial nerve, which should always be attempted if it is functional. In
small tumors localized to the superficial lobe, a superficial parotidectomy with an ample cuff of normal
gland is adequate. Tumors in the deep lobe require superficial parotidectomy for nerve identification
and mobilization, which may cause a temporary paresis due to retraction. If tumor involvement
necessitates nerve sacrifice, it should be reconstructed with a nerve graft.
PATHOLOGY-SPECIFIC CONCERNS
Pleomorphic adenoma is typically a well-encapsulated, enhancing, round lesion with a tendency to recur
if incompletely excised or if there is tumor spillage. Malignant transformation occurs in approximately
6%, and increases with the length of observation.22 Although benign, up to 40% may have extension
beyond the capsule (“tumor pseudopodia”), and incomplete capsules have also been described.23
Therefore, it is generally recommended to take a cuff of parotid with the tumor, although the surgeon
frequently finds that it is necessary to dissect the tumor capsule directly off the facial nerve. In cases
that recur, surgical salvage is recommended, but radiation may aid in local control for patients who are
not surgical candidates.
The prognosis and treatment of mucoepidermoid carcinoma and ACC are largely affected by
histologic grade. Mucoepidermoid carcinoma is classified as low grade or high grade, and sometimes as
intermediate grade depending on the grading system used. High-grade tumors tend to be more
aggressive, recurring locally and metastasizing frequently. Similarly, ACC can be subdivided by
histologic type, tubular being the most indolent and solid being the least. ACCs have a great propensity
for perineural invasion, and therefore MRI should be performed to evaluate for nerve involvement, and
frozen sections should be taken to clear nerves when they are involved.
Figure 41-8. Precontrast (A) and postcontrast (B) T1 MRI demonstrate a lobulated, heterogeneous mass within the right parotid
gland just posterior to the retromandibular vein, consistent with a pleomorphic adenoma.
1023
booksmedicos.org
Figure 41-9. Superficial parotidectomy. A: The standard Blair incision or the cosmetically superior rhytidectomy incision may be
employed. B: Branches of the facial nerve course between the superficial and deep lobes of the parotid. C: The main trunk of the
facial nerve is identified 8 mm deep to the tympanomastoid suture line and at the same level as the digastric muscle. D: The nerve
is then dissected distally, separating it from the substance of the parotid. E: Schematic representation of the relationship between
the parotid and surrounding structures.
1024
booksmedicos.org
In general, ipsilateral neck dissection should be performed when lymphadenopathy is present, and in
the N0 neck when there is high-grade pathology (salivary duct carcinoma, high-grade MEC, SCC,
adenocarcinoma except for polymorphous low-grade adenocarcinoma, carcinoma ex-pleomorphic
adenoma). Postoperative radiation should be used for stage III/IV disease, high-grade pathology, and
perineural or extensive tissue invasion.
SINONASAL
Sinonasal tumors may present with vague symptoms, including nasal obstruction, epistaxis, decreased
smell, or nasal discharge. Sinonasal tumors are rare, the most common being the benign inverted
papilloma, with a yearly incidence between 0.2 and 0.6 per 100,000. However, there are over 70
pathologies that may involve the paranasal sinuses, over half of which are malignant.24 The maxillary
sinus is most commonly affected, followed by the ethmoid, sphenoid, and frontal sinuses.25
Rigid endoscopy is required to evaluate the patient with a possible sinonasal tumor. Imaging of the
sinuses and skull base with fine-cut CT is advisable prior to biopsy to evaluate for the integrity of the
orbits, vasculature, and skull base, and to rule out odontogenic origin for maxillary sinus pathology.
MRI is also valuable to assess for dural, intraorbital, and neural integrity. Figure 41-10 is a contrasted
T1 image of a sinonasal mucosal melanoma; MRI provides evidence that both the dura and the
periorbita are intact, allowing for an endoscopic resection without craniotomy or orbital exenteration.
When possible, inverted papilloma should be resected in its entirety with drilling of its site of
attachment to prevent recurrence, which may be as high as 70% without complete resection. The
specimen should be sent for pathologic evaluation due approximately 10% risk of concurrent or delayed
malignancy.26 However, when tumor involves critical structures (optic nerve, carotid artery, etc.), they
should be preserved and the patient followed closely.
For sinonasal malignancies, surgery is the mainstay for most lesions. SCC is the most common (40%
to 50%), followed by adenocarcinoma and ACC.27 “Round blue cell” tumors are less common, but
represent several different pathologies, including esthesioneuroblastoma, sinonasal undifferentiated
carcinoma (SNUC), neuroendocrine carcinoma, small cell carcinoma, mucosal melanoma, lymphoma,
and various sarcomas. Rhabdomyosarcoma is most common in the pediatric population, and should be
treated nonsurgically as primary therapy. Consultation with a head and neck pathologist is particularly
important in patients with small blue cell tumors because high-grade pathologies (SNUC, small cell)
tend to metastasize early and are also often treated with induction chemotherapy and radiation, or
concurrent chemoradiation.
Figure 41-10. Postcontrast T1 coronal image of a sinonasal mucosal melanoma. MRI allows for the distinction between the
vascular tumor and trapped secretions in the maxillary sinus (asterisk), and provides evidence that the periorbita is intact (arrow).
The widespread adoption of endoscopic sinus surgery in the 1990s has led to increasing comfort with
minimally invasive techniques for sinonasal tumors. For inverted papilloma, the endoscopic approach is
associated with a decrease in both recurrence rate and morbidity for inverted papilloma compared to
open approaches.26,28 Similarly, evidence is building that T1 and T2 sinonasal tumors may be safely and
effectively removed with the endoscopic approach, and that endoscopic resection may complement open
surgery in combined cases.29,30
1025
booksmedicos.org
HEAD AND NECK SQUAMOUS CELL CARCINOMA
SCC is the most common malignancy of the upper aerodigestive tract, and is associated with
approximately 50% overall survival due to its aggressive nature and the tendency for patients to present
with advanced stage. The staging criteria for the common head and neck tumor subsites are available in
the American Joint Commission on Cancer or the National Cancer Comprehensive Network.15,31 Staging
is based on the size and invasiveness of the primary tumor site, the number, size, and location of
metastatic lymph nodes, and the presence or absence of distant metastases. Tables 41-6 to 41-9 list the
TNM staging for the oral cavity, oropharynx, and larynx, which are grouped into an overall stage of I to
IV (Table 41-10). Patients with AJCC stage I/II tumors may be treated with single modality therapy,
radiation, or surgery. Those with stage III/IV will require multimodality treatment. It is of particular
importance that higher-stage patients undergo multidisciplinary evaluation due to combination therapy
and the need for aggressive functional rehabilitation after treatment.
Table 41-6 Oral Cavity Staging
Table 41-7 Oropharynx Staging
ORAL CAVITY
4 The subsites of the oral cavity include the lip, oral tongue, floor of mouth, hard palate, gingival
mucosa and retromolar trigone, and buccal mucosa. Although patients are given the choice between
surgical and nonsurgical treatment in most head and neck cancers, surgery is considered the primary
treatment for oral cancer because of its ease of access and because of the risk of osteoradionecrosis of
the mandible when high-dose radiation or chemoradiation is used in the region. Microvascular
reconstruction is very important to restore the structure and function of the structures of the oral cavity
to preserve speech and swallowing and minimize cosmetic deformity for larger tumors, and may require
bone, soft tissue, or a combination of both.
Table 41-8 Larynx Staging
1026
booksmedicos.org
Table 41-9 Nodal Staging for Salivary Cancers and Squamous Cell Carcinoma of
Oral Cavity, Oropharynx, Larynx
Site-specific considerations are important oncologically and functionally for oral cavity cancer. Lower
lip carcinoma, which is most common and often due to sun exposure, has a very low incidence of occult
cervical metastases (<15%), and may be observed in stage I/II with clinically negative nodes.31 In
contrast, the upper lip has unilateral drainage, but a higher incidence of nodal involvement.
Reconstruction of the lip may involve primary closure or local advancement for small lesions (<1/3 of
length), and local or free flap reconstruction for larger tumors.32
In oral tongue cancer, depth of invasion is clinically important. Very thin tumors (<2 mm) have a
low likelihood to spread to regional lymphatics, in contrast to thick tumors (>8 to 9 mm). Although a
definitive consensus has not been reached, many surgeons advocate elective neck dissection for patients
with T1 tumors and depth of invasion >4 mm.33 T1–T2 tongue tumors may be resected and closed
primarily or with a skin or acellular dermis graft; larger lesions require microvascular reconstruction
with enough bulk to allow for speech and deglutition. Similarly, small floor of mouth resections may be
closed primarily, and grafts may be used when the floor of mouth musculature is preserved, but
additional tissue is needed for larger tumors to prevent orocutaneous fistula when simultaneous neck
dissection is performed.
STAGING
Table 41-10 AJCC Stage Grouping for Cancers of the Head and Neck (Excluding
Thyroid and Nasopharynx)
1027
booksmedicos.org
Lesions of the retromolar trigone and buccal mucosa/space present a challenge due to early
involvement of the muscles of mastication. Pterygoid and/or masseter may cause severe trismus,
making preoperative examination and intraoperative exposure difficult. Marginal mandibulectomy
(removal of the inner cortex) may be necessary when the tumor is attached to mandibular periosteum.
Composite resection of a segment of mandible is required when the integrity of the bone is
compromised on preoperative imaging, or when tumor has infiltrated via a tooth root or neural
foramen. Microvascular osteocutaneous reconstruction has become the standard of care for most
segmental defects due to the cosmetic and functional deformity of nonreconstruction (“mandibular
swing”), and because of delayed hardware extrusion that occurs after several years with plating and soft
tissue coverage alone.
NASOPHARYNX
Nasopharyngeal carcinoma (NPC) is an uncommon entity in most of the world, but is endemic to certain
parts of Asia, most notably southern China. Although environmental and dietary factors play a role in
the development of NPC, the most important causal factor is Epstein–Barr virus.34–36 The World Health
Organization subclassifies NPC into three types: keratinizing SCC (I), nonkeratinizing SCC (II), and
undifferentiated carcinoma (III).24 Endemic NPC is 95% type III, which is associated with the best
prognosis, and types I and II are more common in nonendemic areas.
Because the nasopharynx is not easily visualized, and because tumors tend to metastasize early, the
most common presenting symptom is bulky lymphadenopathy. Of note, large lymphadenopathy is less
prognostic in NPC than involvement of the supraclavicular fossa, which is reflected in a different nodal
staging than for other head and neck subsites.15 Other possible complaints at presentation include nasal
obstruction, speech changes, and hearing loss due to involvement of the eustachian tube. Cranial nerve
palsies signify extension into the skull base, suggesting advanced disease.
Biopsy of the nasopharynx or lymph nodes to confirm NPC should be accompanied by imaging with
CT and MRI to evaluate the skull base and infratemporal fossa. The primary treatment for NPC is
nonsurgical, and concurrent chemoradiation has been shown to be superior to radiation alone in
advanced disease.37,38 Surgery is reserved for failure of chemoradiation, and can be successful in
patients with localized disease. In a large series of 312 patients undergoing salvage nasopharyngectomy,
the 5-year overall survival was 62%,39 although the majority of patients required a transfacial approach
with maxillary disarticulation. With the advent of endoscopic techniques, some recurrences may be
salvaged without traditional open approaches via the transnasal or transpterygoid approach, although
control of the internal carotid artery is a concern.40 Similarly, transoral robotic surgery has been
reported for recurrences limited to soft tissue, although division of the soft palate is necessary, and
there are no currently available robotic instruments that are suited to remove bone.41
OROPHARYNX
The oropharynx is comprised of the palatine tonsillar fossae and tonsils, base of tongue, soft palate, and
posterior pharyngeal wall. While the incidence of head and neck SCC of other subsites has decreased
with the prevalence of smokers in the United States, oropharyngeal cancer incidence has risen over the
past two decades. This correlates with our understanding that the human papillomavirus, particularly
subtypes 16 and 18, play a pathogenic role in squamous carcinoma of the oropharynx, and it is now
1028
booksmedicos.org
believed that HPV is responsible for approximately 80% of oropharyngeal cancer.42 In contrast to the
poor prognosis of HPV-negative carcinoma of the oropharynx, HPV-associated cancer is associated with
a favorable prognosis.43,44
Figure 41-11. Transoral robotic surgery for a tongue base tumor. The retractor (green arrow) retracts the oral tongue. The lateral
cut has been made 1 cm away from the tumor (yellow asterisk); the epiglottis (black arrow) is retracted to visualize the vallecula.
Although small T1–T2 tumors of the tonsils are often amenable to transoral excision,45 radiation and
concurrent chemoradiation have been used since the 1990s to treat less accessible and larger tumors due
to equivalent effectiveness and decreased morbidity and mortality compared to the traditional open
approaches, which involved transcervical, transpharyngeal, or transmandibular resection.46 However,
the rising prevalence of younger HPV-positive patients with favorable prognosis and the advent of
minimally invasive approaches have led to increased interest in surgery as primary treatment, due to
the long-term sequelae of radiation and chemotherapy.
Transoral laser microsurgery (TLM) and transoral robotic surgery have emerged in the past 10 years
as techniques to treat T1–T3 tumors transorally with acceptable oncologic and functional outcomes.47,48
Advanced optics and instrumentation allow for complete tumor resection without requiring morbid open
approaches (Figs. 41-11 and 41-12). Currently two prospective NCI funded trials, ECOG 3311(HPV+ n
= 377) and RTOG 1221 (HPV– n = 144), are underway to determine the role of surgical treatment for
HPV positive and negative oropharyngeal cancer.49
HYPOPHARYNX
The hypopharynx, comprised of the pyriform sinuses, postcricoid mucosa, and posterior pharyngeal wall
below the level of the hyoid, is the area between the oropharynx and cervical esophagus. For the
purposes of this chapter, cervical esophageal cancer will not be discussed. Cancer of the hypopharynx
may present insidiously, with gradually increasing dysphagia, hoarseness due to laryngeal involvement,
or ear pain referred through cranial nerves IX and X via Jacobson and Arnold nerves.
Compared to other subsites, the hypopharynx has a poorer prognosis, with an overall survival of only
30% to 35% in early stage cancer,50 and a rate of distant metastases of up to 60%.51 Because of its
proximity to laryngeal structures, hypopharyngeal cancer is typically treated nonoperatively, as most
tumors would require removal of the larynx. Although induction chemotherapy followed by definitive
radiation may be used in these patients, many institutions prefer concurrent chemoradiation,
extrapolating the improved outcomes of concurrent CRT over sequential treatment in trials of other
subsites. Small hypopharyngeal tumors of the posterior wall or pyriform sinus may be treated with
transoral laser or robotic techniques,52,53 although bilateral neck dissection is required for regional
control. Recurrent hypopharyngeal cancer may require total laryngectomy with partial pharyngectomy,
or laryngopharyngectomy with microvascular reconstruction of the neopharynx.
1029
booksmedicos.org
Figure 41-12. Resultant defect from TORS resection, demonstrating the lingual artery in situ, which was coagulated later with
bipolar cautery to prevent bleeding.
LARYNX
Tobacco and alcohol have a dose-dependent, synergistic carcinogenic effect on the epithelium of the
larynx. The glottis, or true vocal cords, is the most common subsite involved, followed by the
supraglottis (tip of the epiglottis to the laryngeal ventricle), and subglottis (1 cm below ventricle to the
inferior border of the cricoid cartilage). In contrast to the respiratory epithelium of the rest of the upper
aerodigestive tract, the glottis is comprised of stratified squamous nonkeratinizing epithelium overlying
a complex lamina propria over the thyroarytenoid ligament and muscle. Due to the fibroelastic support
of the conus elasticus and quadrangular membrane, early glottic tumors have a very low propensity for
spread to regional lymph nodes, in contrast to the supraglottis and subglottis.
5 Early-stage carcinoma of the glottis (T1–T2) can be treated with single modality radiation or
surgery, with approximately 90% cure for T1 and 75% for T2; early recognition and diagnosis at this
stage therefore is key. Surgical treatment is performed via transoral resection, often using the CO2
laser, which has no statistically significant difference in overall or disease-free survival or local control
compared to radiation, although laryngeal preservation rates appear to be higher in the surgical group
based on retrospective studies.54–56 Transoral resection of early glottic and supraglottic cancer has the
advantage of requiring only one treatment, compared to the 6 to 7 weeks of radiation needed.
However, supraglottic carcinoma has a high incidence of occult nodal metastasis, as well as bilateral
drainage, and therefore planned bilateral level 2–4 neck dissection is recommended for patients who
undergo surgery for the primary tumor.
For advanced laryngeal cancer (T3–T4), either surgery followed by radiation or concurrent
chemoradiation may be offered, based on two randomized clinical trials. The so-called “VA Trial”
demonstrated equivalent survival between surgery and radiation versus induction chemotherapy
followed by radiation, with 64% laryngeal preservation in the nonsurgical arm.57 This was followed by
the RTOG 91–11 trial, which demonstrated the superiority of concurrent chemoradiation compared to
radiation alone or after induction chemotherapy for laryngectomy-free survival and local control.58
However, the 10-year follow-up to this study did not demonstrate an advantage of concurrent CRT
versus induction chemotherapy and radiation in overall survival, local control, or overall laryngeal
preservation.59
For advanced stage laryngeal cancer, surgery generally involves total laryngectomy with bilateral
lymphadenectomy, with local tissue or free tissue transfer as needed for pharyngeal reconstruction. This
procedure functionally separates the airway from the digestive tract, but allows for effective verbal
communication via esophageal speech, tracheoesophageal puncture with prosthesis, or electrolarynx.
Open partial laryngeal surgeries, including supraglottic or supracricoid partial laryngectomy, may be
used in selected cases, but have prolonged recovery of swallowing and airway protection.
Additional factors must be considered in choosing a treatment modality for patients with advanced
stage laryngeal cancer. Radiation is less effective in cartilage and bone, and therefore thought to be
inferior to surgery in T4 laryngeal cancer.60 Additionally, patients who present with extensive
paraglottic spread and vocal cord fixation will not regain function of the larynx with treatment, and are
likely to remain tracheostomy-dependent if tracheotomy is performed prior to nonsurgical treatment.61
Similarly, patients with poor pretreatment swallowing are likely to worsen, and may become
1030
booksmedicos.org
permanently gastrostomy-dependent.
NECK DISSECTION
Head and neck SCC has a propensity to travel to the cervical lymphatics, the risk of which increases
with T-stage. Pharyngeal tumors, especially those of the nasopharynx and hypopharynx, may present
with a cervical neck mass. In cases when a patient presents with a neck mass for more than 2 weeks, the
clinician should have a high suspicion for metastatic SCC, rather than an infectious or congenital
etiology, and workup should entail imaging, fine-needle aspiration, and endoscopy.
In any patient presenting with SCC, consideration of therapeutic or elective treatment of the neck is
imperative. In general, the cervical lymph nodes are treated with the same modality as the primary
tumor; if surgery is undertaken for an oral cavity primary, for example, simultaneous neck dissection is
performed. Similarly, the radiation oncologist will contour the treatment field to incorporate the
relevant nodal basins in patients treated nonsurgically. Elective neck dissection or elective neck
irradiation in the absence of clinically positive nodes is performed when the risk of occult nodal
metastasis is greater than 15% (Table 41-11).
MANAGEMENT
Table 41-11 Indications for Elective Treatment of the Neck Based on Anatomic
Locale and T Stage
The techniques for neck dissections have evolved with time, initially being developed in the late 19th
century as an en bloc procedure for removal of cervical lymphatics. Crile and Martin subsequently
popularized the radical neck dissection, removal of the cervical lymphatics with sacrifice of the
sternocleidomastoid muscle, internal jugular vein, and spinal accessory nerve. The modified radical neck
dissection, removal of levels I to V with preservation of one or more of the three structures, then gave
way to the idea of oncologic lymphadenectomy with decreased morbidity.62 Currently, selective neck
dissection, the removal of the at-risk nodal basins with preservation of the SCM, internal jugular, and
accessory nerve, is most commonly as the standard of care, as it preserves oncologic principles and
minimizes morbidity.63 The patterns of lymphatic drainage from each subsite are well described based
on the publications of Lindberg and Shah.64,65 In general, dissection of levels II to IV is performed for
cancers of the larynx, oropharynx, and hypopharynx, while levels I to III and possibly IV are addressed
for oral cavity cancer (Fig. 41-13). Level V is rarely involved except in NPC and skin cancer.
1031
booksmedicos.org
Figure 41-13. Intraoperative photograph demonstrating the left neck after performance of a selective (supraomohyoid) neck
dissection. Selective neck dissection is generally a low morbidity procedure. Vital structures such as the internal jugular vein (IJV),
common carotid artery (CCA), and spinal accessory nerve (large arrow) are carefully preserved. In the context of an N0 neck, other
nonvital structures such as the sternocleidomastoid muscle (SCM), external jugular vein (EJV) greater auricular nerve (GAN),
cervical sensory rootlets (small arrows) and ansa cervicalis (asterisks) may also be spared.
Table 41-12 Complications of Common Head and Neck Surgeries
As in central neck dissection for thyroid cancer, a systematic, comprehensive approach should be used
to perform neck dissection, rather than “node-plucking.” The boundaries for the common “lateral neck
dissection,” encompassing levels II to IV, should extend from the digastric muscle’s insertion on the
mastoid with the SCM superiorly to the plane of the clavicle inferiorly, and from the posterior edge of
the SCM to the strap muscles anteriorly. The floor of dissection is the cervical sensory rootlets in level
III and the fascia overlying the deep musculature in level II (levator scapulae) and in level IV (anterior
1032
booksmedicos.org
and middle scalenes). Care should be taken in level IV to avoid the phrenic nerve and brachial plexus, as
well as the thoracic duct and right lymphatic duct. When level IB is included in the specimen, the
marginal mandibular nerve must be elevated off the submandibular gland and protected to allow for
safe resection of the gland and nodes along the facial vessels. Level V dissection requires identification
of the spinal accessory nerve just below Erb point; it is then traced to its entry into the trapezius to
protect it along its course.
COMPLICATIONS OF HEAD AND NECK SURGERY

Due to the intricate, complex anatomy of the region, surgery of the head and neck may be fraught with
complications and morbidity. Although better understanding of anatomy and refined surgical techniques
have fostered “functional” and “minimally invasive” approaches, complications occur, even in
experienced hands. Salvage surgery after radiation or chemoradiation may be particularly difficult due
to the extensive fibrosis that occurs. Table 41-12 lists common and serious, rare complications of
common head and neck procedures. When performing these procedures, the surgeon should be aware of
critical structures in the area, and thorough discussion with the patient should be a part of the informed
consent process.
References
1. Sankaranarayanan R, Masuyer E, Swaminathan R, et al. Head and neck cancer: a global perspective
on epidemiology and prognosis. Anticancer Res 1998;18(6B):4779–4786.
2. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and
oropharyngeal cancer. N Engl J Med 2007;356(19):1944–1956.
3. Robbins KT, Medina JE, Wolfe GT, et al. Standardizing neck dissection terminology. Official report
of the Academy’s Committee for Head and Neck Surgery and Oncology. Arch Otolaryngol Head Neck
Surg 1991;117(6):601–605.
4. Crosby ET, Cooper RM, Douglas MJ, et al. The unanticipated difficult airway with
recommendations for management. Can J Anaesth 1998;45(8):757–776.
5. Iseli TA, Iseli CE, Golden JB, et al. Outcomes of intubation in difficult airways due to head and neck
pathology. Ear Nose Throat J 2012;91(3):E1–E5.
6. Snow V, Mottur-Pilson C, Cooper RJ, et al. Principles of appropriate antibiotic use for acute
pharyngitis in adults. Ann Intern Med 2001;134(6):506–508.
7. Apostolopoulos NJ, Nikolopoulos TP, Bairamis TN. Peritonsillar abscess in children. Is incision and
drainage an effective management? Int J Pediatr Otorhinolaryngol 1995;31(2–3):129–135.
8. Rosenfeld RM, Andes D, Bhattacharyya N, et al. Clinical practice guideline: adult sinusitis.
Otolaryngol Head Neck Surg 2007;137(3 Suppl):S1–S31.
9. Chow AW, Benninger MS, Brook I, et al. IDSA clinical practice guideline for acute bacterial
rhinosinusitis in children and adults. Clin Infect Dis 2012;54(8):e72–e112.
10. Duggal P, Wise SK. Chapter 8: Invasive fungal rhinosinusitis. Am J Rhinol Allergy 2013;27(Suppl
1):S28–S30.
11. Fattahi TT, Lyu PE, Van Sickels JE. Management of acute suppurative parotitis. J Oral Maxillofac
Surg 2002;60(4):446–448.
12. Strychowsky JE, Sommer DD, Gupta MK, et al. Sialendoscopy for the management of obstructive
salivary gland disease: a systematic review and meta-analysis. Arch Otolaryngol Head Neck Surg
2012;138(6):541–547.
13. Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck
Surg 1986;8(3):177–184.
14. Eveson JW, Cawson RA. Salivary gland tumours. A review of 2410 cases with particular reference
to histological types, site, age and sex distribution. J Pathol 1985;146(1):51–58.
15. American Joint Committee on Cancer. American Joint Committee for Cancer Staging Manual. 7th ed.
2010.
16. Pinkston JA, Cole P. Cigarette smoking and Warthin’s tumor. Am J Epidemiol 1996;144(2):183–187.
17. Razfar A, Heron DE, Branstetter BF, et al. Positron emission tomography-computed tomography
1033
booksmedicos.org
adds to the management of salivary gland malignancies. Laryngoscope 2010;120(4):734–738.
18. Schmidt RL, Hall BJ, Wilson AR, et al. A systematic review and meta-analysis of the diagnostic
accuracy of fine-needle aspiration cytology for parotid gland lesions. Am J Clin Pathol
2011;136(1):45–59.
19. Mantsopoulos K, Koch M, Klintworth N, et al. Evolution and changing trends in surgery for benign
parotid tumors. Laryngoscope 2015;125(1):122–127.
20. Albergotti WG, Nguyen SA, Zenk J, et al. Extracapsular dissection for benign parotid tumors: a
meta-analysis. Laryngoscope 2012;122(9):1954–1960.
21. Walvekar RR, Andrade Filho PA, Seethala RR, et al. Clinicopathologic features as stronger
prognostic factors than histology or grade in risk stratification of primary parotid malignancies.
Head Neck 2011;33(2):225–231.
22. Di Palma S. Carcinoma ex pleomorphic adenoma, with particular emphasis on early lesions. Head
Neck Pathol 2013;7(Suppl 1):S68–S76.
23. Zbaren P, Stauffer E. Pleomorphic adenoma of the parotid gland: histopathologic analysis of the
capsular characteristics of 218 tumors. Head Neck 2007;29(8):751–757.
24. Shanmugaratnam K. Nasal cavity and paranasal sinuses. In: Shanmugaratnam K, Sobin L, eds.
Histological Typing of Tumours of the Upper Respiratory Tract and the Ear. 2nd ed. Berlin: Springer;
1991:3–5.
25. Khademi B, Moradi A, Hoseini S, et al. Malignant neoplasms of the sinonasal tract: report of 71
patients and literature review and analysis. Oral Maxillofac Surg 2009;13(4):191–199.
26. Krouse JH. Endoscopic treatment of inverted papilloma: safety and efficacy. Am J Otolaryngol
2001;22(2):87–99.
27. Gotte K, Hormann K. Sinonasal malignancy: what’s new? ORL J Otorhinolaryngol Relat Spec
2004;66(2):85–97.
28. Reh DD, Lane AP. The role of endoscopic sinus surgery in the management of sinonasal inverted
papilloma. Curr Opin Otolaryngol Head Neck Surg 2009;17(1):6–10.
29. Hanna E, DeMonte F, Ibrahim S, et al. Endoscopic resection of sinonasal cancers with and without
craniotomy: oncologic results. Arch Otolaryngol Head Neck Surg 2009;135(12):1219–1224.
30. Higgins TS, Thorp B, Rawlings BA, et al. Outcome results of endoscopic vs craniofacial resection of
sinonasal malignancies: a systematic review and pooled-data analysis. Int Forum Allergy Rhinol
2011;1(4):255–261.
31. NCCN Clinical Practice Guidelines in Oncology: Head and Neck Cancers. 2014;
5/2014:http://www.nccn.org
32. Papel ID, Frodel JL, Richard Holt G, et al.,. Lip reconstruction. In: DeFatta RJ, Williams III EF, eds.
Facial Plastic and Reconstructive Surgery. 3rd ed: Thieme; 2009.
33. Huang SH, Hwang D, Lockwood G, et al. Predictive value of tumor thickness for cervical lymph-
node involvement in squamous cell carcinoma of the oral cavity: a meta-analysis of reported
studies. Cancer 2009;115(7):1489–1497.
34. de-The G. Epstein-Barr virus behavior in different populations and implications for control of
Epstein-Barr virus-associated tumors. Cancer Res 1976;36(2 pt 2):692–695.
35. Tsao SW, Tsang CM, To KF, et al. The role of Epstein-Barr virus in epithelial malignancies. J Pathol
2015;235(2):323–333.
36. Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol
Biomarkers Prev 2006;15(10):1765–1777.
37. Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with
advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol
1998;16(4):1310–1317.
38. Lee AW, Tung SY, Chua DT, et al. Randomized trial of radiotherapy plus concurrent-adjuvant
chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl
Cancer Inst 2010;102(15):1188–1198.
39. Chan JY. Surgical management of recurrent nasopharyngeal carcinoma. Oral Oncol
2014;50(10):913–917.
40. Al-Sheibani S, Zanation AM, Carrau RL, et al. Endoscopic endonasal transpterygoid
nasopharyngectomy. Laryngoscope 2011;121(10):2081–2089.
1034
booksmedicos.org
41. Tsang RK, To VS, Ho AC, et al. Early results of robotic assisted nasopharyngectomy for recurrent
nasopharyngeal carcinoma. Head Neck 2015;37(6):788–793.
42. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal
cancer incidence in the United States. J Clin Oncol 2011;29(32):4294–4301.
43. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with
oropharyngeal cancer. N Eng J Med 2010;363(1):24–35.
44. Posner MR, Lorch JH, Goloubeva O, et al. Survival and human papillomavirus in oropharynx cancer
in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 2011;22(5):1071–
1077.
45. Walvekar RR, Tyler PD, Tammareddi N, et al. Robotic-assisted transoral removal of a
submandibular megalith. Laryngoscope 2011;121(3):534–537.
46. Parsons JT, Mendenhall WM, Stringer SP, et al. Squamous cell carcinoma of the oropharynx:
surgery, radiation therapy, or both. Cancer 2002; 94(11):2967–2980.
47. Grant DG, Hinni ML, Salassa JR, et al. Oropharyngeal cancer: a case for single modality treatment
with transoral laser microsurgery. Arch Otolaryngol Head Neck Surg 2009;135(12):1225–1230.
48. Leonhardt FD, Quon H, Abrahao M, et al. Transoral robotic surgery for oropharyngeal carcinoma
and its impact on patient-reported quality of life and function. Head Neck 2012;34(2):146–154.
49. Shaw RJ, Holsinger FC, Paleri V, et al. Surgical trials in head & neck oncology: Renaissance and
revolution? Head Neck 2015;37(7):927–930.
50. Lefebvre JL, Chevalier D, Luboinski B, et al. Larynx preservation in pyriform sinus cancer:
preliminary results of a European Organization for Research and Treatment of Cancer phase III
trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst 1996;88(13):890–899.
51. Kotwall C, Sako K, Razack MS, et al. Metastatic patterns in squamous cell cancer of the head and
neck. Am J Surg 1987;154(4):439–442.
52. Park YM, Kim WS, De Virgilio A, et al. Transoral robotic surgery for hypopharyngeal squamous cell
carcinoma: 3-year oncologic and functional analysis. Oral Oncol 2012;48(6):560–566.
53. Karatzanis AD, Psychogios G, Waldfahrer F, et al. T1 and T2 hypopharyngeal cancer treatment with
laser microsurgery. J Surg Oncol 2010;102(1):27–33.
54. Higgins KM, Shah MD, Ogaick MJ, et al. Treatment of early-stage glottic cancer: meta-analysis
comparison of laser excision versus radiotherapy. J Otolaryngol Head Neck Surg 2009;38(6):603–
612.
55. Hartl DM, Ferlito A, Brasnu DF, et al. Evidence-based review of treatment options for patients with
glottic cancer. Head Neck 2011;33(11):1638–1648.
56. Caicedo-Granados E, Beswick DM, Christopoulos A, et al. Oncologic and functional outcomes of
partial laryngeal surgery for intermediate-stage laryngeal cancer. OtolaryngolHead Neck Surg
2013;148(2):235–242.
57. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with
advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N
Eng J Med 1991;324(24):1685–1690.
58. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ
preservation in advanced laryngeal cancer. N Eng J Med 2003;349(22):2091–2098.
59. Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91–11: a comparison of three
nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx
cancer. J Clin Oncol 2013;31(7):845–852.
60. Gourin CG, Conger BT, Sheils WC, et al. The effect of treatment on survival in patients with
advanced laryngeal carcinoma. Laryngoscope 2009; 119(7):1312–1317.
61. Tennant PA, Cash E, Bumpous JM, et al. Persistent tracheostomy after primary chemoradiation for
advanced laryngeal or hypopharyngeal cancer. Head Neck 2014;36(11):1628–1633.
62. Harrison BL, Sessions BR, Kies MS. Head and Neck Cancer: A Multidisciplinary Approach. 4th ed.
Philadelphia, PA: Wolters Kluwer/Lippincott-Raven; 2014.
63. Byers RM. Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg
1985;150(4):414–421.
64. Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the
upper respiratory and digestive tracts. Cancer 1972;29(6):1446–1449.
1035
booksmedicos.org
65. Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper
aerodigestive tract. Am J Surg 1990;160(4):405–409.
1036
booksmedicos.org
SECTION D: ESOPHAGUS
1037
booksmedicos.org
Chapter 42
Esophageal Anatomy and Physiology and

Gastroesophageal Reflux Disease
Daniel S. Oh and Steven R. DeMeester
Key Points
1 The esophagus can be considered to have distinct anatomical locations in the neck, chest, and
abdomen with distinct physiologic and pathophysiologic considerations.
2 The esophageal wall is composed of three distinct layers – the mucosa, submucosa, and muscularis
propria. The mucosa is separated from the submucosa by the muscularis mucosae. Tumors lying
within the mucosal layer may be managed endoscopically.
3 The mucosal lining of the esophagus is squamous mucosa at birth. Repeated injury of the esophageal
squamous mucosa with reflux may lead to metaplastic change to columnar mucosa such as cardiac
mucosa, oxyntocardiac mucosa, or cardiac mucosa with intestinal metaplasia (goblet cells).
4 Barrett esophagus is defined as having both an endoscopic columnar segment and a microscopic
finding of cardiac mucosa with goblet cells or intestinal metaplasia.
5 During a swallow, the peristaltic wave begins in the upper esophageal sphincter. The lower
esophageal sphincter relaxes at the initiation of the swallow and remains relaxed until the peristaltic
wave progresses down the esophageal body and through the lower sphincter.
6 The lower esophageal sphincter retains its competence as a barrier to gastric contents by three
factors: its length, its resting pressure, and its position.
7 The function of the esophagus can be evaluated by endoscopy, radiology (fluoroscopy), and
manometry. Measurement of acid exposure in the esophagus can be performed with ambulatory pH
monitoring.
8 The endoscopist should note three critical landmarks during an EGD: the squamocolumnar junction
(SCJ), the gastroesophageal junction (GEJ), and the crura or hiatus.
9 Preoperative functional assessment of the esophagus and lower esophageal sphincter are mandatory
when considering antireflux surgery to tailor the operation to the appropriate circumstances of the
patient.
10 Ambulatory pH monitoring remains the gold standard for documenting gastroesophageal reflux and
should be used to confirm the diagnosis of GERD.
ESOPHAGEAL ANATOMY AND FUNCTION

The esophagus is a muscular tube that starts as the continuation of the pharynx with the upper
esophageal sphincter (UES) or cricopharyngeus and ends with the lower esophageal sphincter at the
fundus of the stomach (Fig. 42-1). Knowledge of the anatomy of the esophagus and its relationship with
other organs and structures is essential for the surgeon to evaluate the location of lesions seen by
endoscopy, barium swallow study, or computed tomography (CT); to interpret esophageal function
studies; and to safely expose the esophagus during surgery.
Cervical Esophagus
The cervical portion of the esophagus is approximately 3 to 5 cm long. It starts below the
cricopharyngeus muscle and appears as a continuation of the inferior constrictor muscle of the pharynx.
A space between the right and left inferior constrictor muscles posteriorly just above the
cricopharyngeus muscle is an area of natural weakening and referred to as Killian triangle, the site
where a Zenker diverticulum develops (Fig. 42-2). The beginning of the cervical esophagus is marked
by the level of C6, and the end by the lower border of T1. The cervical esophagus curves slightly to the
1038
booksmedicos.org
left as it descends. Anteriorly, it abuts the trachea and larynx and can be dissected off both organs.
Posteriorly, the cervical esophagus lies on the vertebral bodies in a prevertebral or retroesophageal
space. This space is continuous with the retropharyngeal space superiorly and the posterior mediastinum
inferiorly, which is the primary route of descending mediastinitis from oropharyngeal infections.
Laterally, the omohyoid muscle crosses the cervical esophagus obliquely, and it is usually necessary to
divide this to expose that portion of the esophagus. The carotid sheaths lie laterally, and the lobes of the
thyroid and the strap muscles lie anteriorly. The recurrent laryngeal nerves lie in the grooves between
the esophagus and the trachea. The right recurrent nerve runs a more lateral and oblique course to
reach the groove and is more prone to anatomic variation. Although the surgical approach to the
cervical esophagus may be from either side of the neck through an incision along the medial border of
the sternocleidomastoid muscle, the left-sided approach is preferred to avoid injury to the more variable
course of the right recurrent nerve.
Thoracic Esophagus
The thoracic portion of the esophagus is approximately 18 to 20 cm long (Fig. 42-1) and starts at the
thoracic inlet. In the upper portion of the thorax, it is closely related to the posterior membranous wall
of the trachea. This close relationship is responsible for the early spread of cancer of the upper
esophagus into the trachea, and it may limit the surgeon’s ability to resect such a tumor. Above the
level of the tracheal bifurcation, the esophagus courses to the right of the aortic arch and the descending
aorta and then deviates to the left, passing behind the tracheal bifurcation and the left main bronchus.
In the lower portion of the thorax, the esophagus remains deviated to the left and passes anteriorly
through the diaphragmatic hiatus. There are three natural areas of constriction in the thoracic
esophagus: the cricopharyngeus or UES, the bronchoaortic constriction as it crosses behind the aortic
arch and left mainstem bronchus, and the lower esophageal sphincter.
Figure 42-1. Anatomy of the esophagus.
Unlike the remainder of the gastrointestinal tract, the esophagus does not have a serosal layer and its
strength is derived from its mucosa. The thoracic esophagus is covered only by parietal pleura, making
this portion the weakest and the most common site of perforation in Boerhaave syndrome, usually on
the left side where there is a lack of support from adjacent structures.
The azygos vein is closely related to the right of the esophagus as it ascends from the abdomen and
then arches from its paraspinal position over esophagus and the right main bronchus to enter the
superior vena cava.
The thoracic duct ascends behind and to the right of the distal thoracic esophagus between the azygos
vein and aorta. At approximately the level of T5, it passes alongside the aorta and ascends on the left
side of the esophagus to enter behind the junction of the left internal jugular and subclavian veins. Due
to the possibility of disrupting the thoracic duct during its course across the mediastinum during an
esophagectomy, ligation of the duct is generally performed low in the chest where it comes through the
aortic hiatus.
1039
booksmedicos.org
Figure 42-2. Posterior view of cervical esophagus.
Abdominal Esophagus
The abdominal portion of the esophagus is approximately 3 to 6 cm long and consists of the abdominal
portion of the LES. It begins as the esophagus passes through the diaphragmatic hiatus and is
surrounded by the phrenoesophageal membrane, a fibroelastic ligament that arises from the
subdiaphragmatic fascia as a continuation of the transversalis fascia lining the abdomen (Fig. 42-3). The
upper leaf of the membrane attaches in a circumferential fashion around the esophagus about 1 to 2 cm
above the level of the hiatus. The lower leaf of the phrenoesophageal membrane blends with the serosa
of the stomach, and its end is marked anteriorly by a prominent fat pad, which corresponds
approximately with the gastroesophageal junction. The lower esophageal sphincter is a zone of high
pressure 3 to 4 cm long at the lower end of the esophagus1 and does not correspond to any visible
macroscopic anatomic landmark either on the external surface of the esophagus, nor in the endoscopic
appearance of the mucosa. Its function is derived from the microscopic architecture of the muscle fibers.
The esophageal hiatus is surrounded by the right and left crura, which together form a sling of
diaphragmatic skeletal muscle around the esophagus that originates from tendinous bands attached to
the anterolateral surface of the first lumbar vertebra (Fig. 42-4). The relative contribution of the right
and left crura to this sling is variable. Posterior to the esophagus, the crura are united by a tendinous
arch, the median arcuate ligament, which lies just anterior to the aorta.
Figure 42-3. Anatomy of the esophageal hiatus and relationship to the phrenoesophageal membrane.
1040
booksmedicos.org
Figure 42-4. Inferior view of diaphragm and anatomy of the esophageal hiatus.
Structure of the Esophageal Wall and Mucosa

The esophagus is composed of three primary layers – mucosa, submucosa, and muscularis propria. The
mucosal layer is normally composed of nonkeratinized stratified squamous epithelium, as opposed to
the stomach where columnar epithelium is present. In the distal aspect of the esophagus within the
lower esophageal sphincter, repeated exposure of the squamous epithelium to gastric contents can result
in metaplasia of esophageal squamous mucosa to a columnar epithelium called cardiac mucosa. This
nomenclature was originally used to describe what was mistakenly thought to be the proximal stomach
or cardia, but there is now convincing evidence that this is in fact metaplastic esophageal mucosa.2 With
further injury and exposure to refluxed gastric juice such as bile acids, cardiac mucosa may further
transform into intestinal metaplasia or Barrett esophagus, characterized by the presence of goblet cells
within cardiac mucosa. Alternatively, cardiac mucosa can also differentiate further to acquire parietal
cells and is known as oxyntocardiac mucosa.3
A critical layer within the mucosa for determining the biologic behavior of a superficial cancer is the
muscularis mucosa. This thin, poorly developed layer lies below the basement membrane and above the
submucosa. It is often duplicated in patients with Barrett esophagus, and can lead to confusion during
pathologic evaluation of the depth of tumor invasion in endoscopic resection (ER) specimens.4 The
significance of the muscularis mucosa is that tumors confined to this layer rarely are associated with
lymph node metastases, but once tumors penetrate through this layer into the submucosa the frequency
of lymph node metastases increases substantially.
The submucosa is characterized by a rich lymphatic plexus that extends throughout the esophagus.
Lymphatic collecting branches arise from within the submucosa and pierce the muscularis propria to
communicate with regional lymph nodes and the thoracic duct outside of the esophagus. This network
of lymphatics allow for significant longitudinal spread of esophageal cancers and a high rate of skip
metastases. Clinically, tumor invasion beyond the muscularis mucosa into the submucosa is significant
due to this lymphatic system, with the rate of regional lymph node metastases increasing from <5%
with intramucosal tumors to 20% to 50% for submucosal tumors.5 Finally, the submucosa of the
esophagus also harbors mucous glands that drain into the lumen. These glands are helpful for
determining the true extent of the esophagus when metaplasia of the mucosa occurs.
The muscularis propria is composed of an inner circular layer and an outer longitudinal layer. The
muscles are striated in the upper portion and transition to completely smooth muscle near the upper
third of the esophagus. The longitudinal muscle layer courses down in an elongated spiral pattern,
turning approximately 90 degrees as it descends to the stomach. The circular muscle layer is thicker
than the longitudinal layer, which also takes on an elliptical or spiral orientation (Fig. 42-5). This
arrangement of muscle is responsible for the wormlike drive of peristalsis.
Blood Supply, Lymphatics, and Innervation

The cervical portion of the esophagus receives its main blood supply from the inferior thyroid artery.
The thoracic portion receives blood from the bronchial and esophageal arteries. Seventy-five percent of
individuals have one right-sided and two left-sided bronchial arteries, and usually two esophageal
branches arise directly from the aorta. There are rarely aortic branches directly to the esophagus in the
lower half of the esophagus in the chest, allowing the surgeon to perform an en bloc dissection of all of
the periesophageal tissue directly off the plane of the aortic adventitia from the right to the left pleural
spaces. The blood supply of the abdominal portion of the esophagus comes from the ascending branch of
the left gastric artery and from the right and left inferior phrenic arteries (Fig. 42-6). After the vessels
have entered the muscular wall of the esophagus, branching occurs at right angles to provide an
extensive longitudinal vascular plexus. The rich blood supply provided by this vascular plexus allows
mobilization of the esophagus from the stomach to the aortic arch without causing ischemic injury.6
1041
booksmedicos.org
Figure 42-5. Endoscopic view of esophageal muscle layers during a peroral endoscopic myotomy (POEM) for achalasia. The
endoscopic knife is lifting and cutting the circumferential circular muscle fibers, leaving the longitudinal muscle fibers intact.
Figure 42-6. Arterial anatomy of the esophagus.
The capillaries of the esophagus drain into a submucosal and periesophageal venous plexus, from
which the esophageal veins originate. In the cervical region, the esophageal veins empty into the
inferior thyroid vein; in the thoracic region, they empty into the bronchial, azygos, or hemiazygos
veins; and in the abdominal region, they empty into the coronary vein (Fig. 42-7).
The lymphatic channels are located almost exclusively below the muscularis mucosa in the submucosa
of the esophagus, constituting a dense and interconnected plexus with more lymph vessels than blood
capillaries (Fig. 42-8). Lymph flow in the submucosal plexus runs in a longitudinal direction, and after
the injection of a contrast medium, the longitudinal spread is six times that of the transverse spread. In
the upper two-thirds of the esophagus, the lymphatic flow is mostly cephalad; in the lower third, it is
mostly caudal. In the thoracic portion of the esophagus, the submucosal lymph plexus extends over a
long distance in a longitudinal direction before penetrating the muscle layer to enter lymph vessels in
1042
booksmedicos.org
the adventitia. As a consequence of this nonsegmental lymph drainage, the lymphatic spread of tumor
cells can extend for a considerable distance superiorly and inferiorly within the submucosal lymphatics
before the cells pass through lymphatic channels in the muscularis and on into the regional lymph
nodes. There is a high rate of skip metastases in esophageal cancer due to this arrangement. By contrast,
the cervical esophagus has a more segmental lymph drainage into the regional lymph nodes, and as a
result, tumors in this portion of the esophagus have less submucosal extension.
Lymph from the cervical esophagus drains into the paratracheal and deep cervical lymph nodes,
whereas lymph from the upper thoracic esophagus flows mainly into the paratracheal lymph nodes. The
lymph from the lower thoracic esophagus drains into the subcarinal and inferior pulmonary nodes.
Lymph from the distal thoracic and abdominal portion of the esophagus drains into the parahiatal and
perigastric nodes.7
Figure 42-7. Venous anatomy of the esophagus.
The parasympathetic innervation of the pharynx and esophagus is provided mainly by cranial nerve X
or the vagus nerves. The constrictor muscles of the pharynx receive branches from the pharyngeal
plexus, which is located on the posterior lateral surface of the middle constrictor muscle and is formed
by pharyngeal branches of the vagus nerve, with a small contribution from cranial nerves IX and XI.
The cricopharyngeal sphincter and the cervical portion of the esophagus receive branches from both the
right and left recurrent laryngeal nerves originating from the vagus nerves (Fig. 42-9). Damage to these
recurrent nerves interferes not only with the movement of the vocal cords but also with the function of
the cricopharyngeal sphincter and the motility of the cervical esophagus, predisposing the patient to
pulmonary aspiration on swallowing. The upper thoracic esophagus receives innervation from the left
recurrent laryngeal nerve and both vagus nerves. As the right and left vagus nerves descend into the
mediastinum, they join the outer surface of the esophagus. The esophageal plexus, which is formed by
the branches of the right and left vagus nerves and thoracic sympathetic chain, lies on the anterior and
posterior walls of the esophagus and innervates the lower thoracic portion.8 The branches of the plexus
coalesce into the left (anterior) and right (posterior) vagal trunks.
Afferent visceral sensory fibers from the esophagus end without synapse in the first four segments of
the thoracic spinal cord by a combination of sympathetic and vagal pathways. These pathways are also
occupied by afferent visceral sensory fibers from the heart, which explains the similarity of symptoms in
esophageal and cardiac diseases.
PHYSIOLOGY
1043
booksmedicos.org
To comprehend the mechanics of alimentation, it is useful to visualize the gullet as a series of pumps
and valves. In the pharyngeal segment, the tongue and pharyngeal muscle function as pumps, whereas
the soft palate, the epiglottis, and the cricopharyngeus serve as the valves that regulate flow. In the
esophageal segment, the esophageal body functions as the pump to propel the food bolus, whereas the
lower esophageal sphincter serves as a valve to allow transport into the stomach and to prevent the
flow of gastric contents back into the esophagus.
The Swallowing Mechanism

Swallowing can be started at will, or it can be reflexively elicited by the stimulation of the anterior and
posterior tonsillar pillars or the posterior lateral walls of the hypopharynx. The afferent sensory nerves
of the pharynx are the glossopharyngeal nerves and the superior laryngeal branches of the vagal nerves.
Once it is aroused by stimuli entering through these nerves, the swallowing center in the medulla
coordinates the complete act of swallowing by discharging impulses through cranial nerves V, VII, X,
XI, and XII and the motor neurons of C1 through C3. Discharges through these nerves always occur in a
specific pattern and last for approximately 0.5 second. Little is known about the swallowing center
except that it can trigger swallowing after a variety of different inputs. Once it is triggered, the swallow
response is always a rigidly ordered pattern of outflow neurogenic impulses.
The act of alimentation requires the passage of food and drink from the mouth into the stomach. Food
is taken into the mouth in a variety of bite sizes, after which it is broken up by the teeth, mixed with
saliva, and lubricated. When food is ready for swallowing, the tongue, acting as a pump, moves the
bolus into the posterior oropharynx and forces it into the hypopharynx (Fig. 42-10). Concomitantly with
the posterior movement of the tongue, the soft palate is elevated, thereby closing the passage between
the oropharynx and nasopharynx. With the initiation of the swallow, the hyoid moves superiorly and
anteriorly, thereby elevating the larynx and enlarging the retropharyngeal space. At the same time, the
epiglottis covers the laryngeal inlet to prevent aspiration.
Figure 42-8. Lymphatic anatomy of the esophagus.
1044
booksmedicos.org
During swallowing, the pressure in the hypopharynx rises abruptly to 60 mm Hg as a result of the
backward movement of the tongue and contraction of the posterior pharyngeal constrictors. A sizable
pressure difference develops between the hypopharyngeal pressure and the subatmospheric
midesophageal or intrathoracic pressure (Fig. 42-11). This pressure gradient speeds the movement of
food from the hypopharynx into the esophagus when the cricopharyngeus or UES relaxes. The bolus is
both propelled by the peristaltic contraction of the posterior pharyngeal constrictors and sucked into the
thoracic esophagus by this pressure gradient.
Critical to receiving the bolus is the compliance of the cervical esophageal muscle and the timing and
degree of relaxation of the UES. Abnormalities of compliance and UES opening can result in pharyngeal
dysphagia. During the transfer of the bolus from the mouth into the esophagus, the UES is mechanically
pulled open. Elevation of the larynx by muscles attached to the hyoid bone pulls the UES open at the
same time that relaxation of the UES is occurring. The active relaxation of the UES is caused by a
reduction in the tone of the tonic constriction of the cricopharyngeus muscle, and it is dependent on a
neurologically mediated reflex. This is an all-or-nothing event; partial relaxation does not normally
occur. The UES closes within 0.5 second of the initiation of the swallow, with a postrelaxation
contraction pressure that is approximately twice the resting pressure of 30 mm Hg. The postrelaxation
contraction continues down the esophagus as a peristaltic wave (Fig. 42-12). The high closing pressure
and the initiation of the peristaltic wave prevent reflux of the bolus from the esophagus into the
pharynx. After completion of the swallow, the pressure of the UES returns to its normal resting
pressure.
The pharyngeal activity in swallowing initiates the esophageal phase of swallowing. Because of the
helical arrangement of its circular muscles, the body of the esophagus functions as a worm-drive
propulsive pump, and it is responsible for transmitting a bolus of food into the stomach. With the act of
swallowing, the longitudinal muscle of the esophageal body shortens, thus enlarging the lumen to
accept the bolus (the “on response”), after which the circular smooth muscle contraction forms the
peristaltic wave (the “off response”). During the esophageal phase of swallowing, the bolus is moved
into the stomach over a gradient of 12 mm Hg (i.e., from a negative intrathoracic pressure environment
of −6 mm Hg to a positive intra-abdominal pressure environment of +6 mm Hg). Effective and
coordinated smooth muscle function in the lower two-thirds of the esophageal body is important to
allow this movement to occur.
Figure 42-9. Relationship of the esophagus to the vagus nerves and their branches.
The peristaltic wave generates an occlusive pressure that varies from 30 to 120 mm Hg. The wave
rises to a peak in 1 second, remains at the peak for about 0.5 second, and then subsides in about 1.5
seconds. The whole course of the rise and fall of an occlusive contraction may occupy one point in the
esophagus for 3 to 5 seconds.9,10 The peak of the primary peristaltic contraction moves down the
esophagus at a rate of 2 to 4 cm per second and reaches the distal esophagus about 9 seconds after
swallowing starts. The lower esophageal sphincter relaxes at the initiation of the peristaltic wave and
remains open until the peristaltic wave passes through the body and into the sphincter muscle, and this
1045
booksmedicos.org
is followed by a distinctive postrelaxation contraction of the lower esophageal sphincter. A consecutive
swallow after 20 seconds produces a similar primary peristaltic wave; however, if repetitive swallowing
occurs sooner, the esophagus becomes unresponsive (deglutitive inhibition).
Figure 42-10. Overview of the act of swallowing.
Figure 42-11. Pressure profile of the esophagus in the neck, chest, and abdomen. (From Waters PF, DeMeester TR. Foregut motor
disorders and their surgical management. Med Clin North Am 1981;65:1237, with permission.)
Figure 42-12. Overview of esophageal body peristalsis. (From Waters PF, DeMeester TR. Foregut motor disorders and their
surgical management. Med Clin North Am 1981;65:1237, with permission.)
1046
booksmedicos.org
To be effective, peristaltic contractions must be of sufficient amplitude to occlude the esophageal
lumen and sufficiently organized in a peristaltic waveform to propel a bolus toward the stomach. Low-
amplitude contractions that do not occlude the lumen merely indent a semisolid bolus rather than propel
it, and simultaneous contractions throughout the body of the esophagus result in splitting the bolus or
propelling it orally which can be observed on a barium esophagram as bolus segmentation or cephalic
escape.
Clinically, defects in peristalsis occur in three broad categories, depending on which major feature is
the most impaired. First, there is a neural abnormality that results in the defective organization of the
peristaltic wave; this is recognized by the presence of simultaneous contractions with a loss of the
peristaltic sequence and results in typical primary motility disorders (e.g., diffuse esophageal spasm).
The second category defect is evident when there is a reduction of the amplitude of the contraction but
the peristaltic sequence remains; this is usually due to muscle damage and the formation of fibrous
tissue within the muscle. Examples include end-stage gastroesophageal reflux disease (GERD) and
connective tissue disorders such as scleroderma. The third category defect results from altered anatomy
of the esophageal body. A loss in the efficiency of the peristaltic sequence can result when the
esophagus is not anchored distally, as occurs with a large paraesophageal hernia (PEH); which can
result in the appearance of an accordion esophagus on a barium swallow esophagram with ineffective
clearance of barium.
Lower Esophageal Sphincter

The LES represents the barrier that confines the gastric juice to the stomach and protects the acid-
sensitive squamous esophageal mucosa from injury by refluxed gastric juice. As is true for any valve,
failure of the LES can occur in two completely opposite ways, which lead to two distinct clinical disease
entities. Regardless of the type of LES failure, the secondary effects are produced proximally in the
esophagus. Failure of the LES to relax or to open appropriately leads to the inability of the esophagus to
propel food into the stomach, esophageal distention, and the condition known as achalasia. On the other
hand, failure of the LES to remain closed leads to an increased exposure of the squamous epithelium to
gastric juice and the condition known as GERD.
The LES has no anatomic landmarks and cannot be seen endoscopically; it is identified on manometry
as a rise in pressure over gastric baseline pressure. This high-pressure zone is normally present except in
two situations: (1) after a swallow, when it is momentarily dissipated or relaxes to allow passage of
food into the stomach; and (2) during a belch, when it allows gas to be vented from a distended fundus.
The common denominator for virtually all episodes of gastroesophageal reflux is the loss of this normal
high-pressure zone or barrier. When the barrier is absent, resistance to the flow of gastric juice from an
environment of higher pressure (the stomach) to an environment of lower pressure (the esophagus) is
lost. In early GERD, this is usually caused by a transient loss of the barrier. In advanced GERD, there is
usually a permanent loss of the barrier.11
There are three characteristics of the LES or high-pressure zone that maintain its function as a barrier
to intragastric and intra-abdominal pressure challenges. Two of these characteristics – the overall length
and pressure of the LES – work together and depend on each other to provide resistance to the flow of
gastric juice from the stomach into the esophagus.12 The shorter the overall length, the higher the
pressure must be for the LES to maintain sufficient resistance to remain competent (Fig. 42-13).
Consequently, the effect of a normal LES pressure can be nullified by a short overall LES length, and the
effect of a normal overall LES length can be nullified by a low LES pressure. A fundamental principle for
surgeons to understand is that the length of the barrier or LES is critical to its function.
1047
booksmedicos.org
Figure 42-13. Relationship of the length and pressure of the lower esophageal sphincter in maintaining competence of the
gastroesophageal barrier.
Foreshortening of LES length occurs naturally with gastric filling as the terminal esophagus is “taken
up” by the expanding fundus (Fig. 42-14);13 this is similar to the shortening of the neck of a balloon as
it is inflated. With excessive gastric distention (e.g., with overeating), the length of the LES shortens to
a critical point at which it gives way, the pressure drops precipitously, and reflux occurs (Fig. 42-15).14
If the length of the LES is permanently shortened, then further shortening caused by the normal gastric
distention with normal-volume meals results in postprandial reflux. In this situation, competency of the
barrier is an ever-constant clinical problem. The observation that gastric distention results in shortening
of the LES down to a critical length so that the pressure dissipates, the lumen opens, and reflux occurs
provides a mechanical explanation for transient LES relaxations without invoking a neuromuscular
reflex. If only the LES pressure and not its length is measured (e.g., with a Dent sleeve), the event
appears as a spontaneous relaxation of LES pressure.15 In reality, it is the progressive shortening of the
LES rather than the transient LES relaxations that results in the loss of LES pressure.
Variations in the anatomy of the cardia, from a normal acute angle of His to an abnormal dome
architecture of a sliding hiatal hernia, influence the ease with which the sphincter is shortened by
gastric distention. A hernia can result from the pulsion force of abdominal pressure on the esophageal
hiatus or from the traction produced by inflammatory fibrosis of the esophageal body. The resulting
alteration in the geometry of the cardia places the sphincter at a mechanical disadvantage in
maintaining its length with progressive degrees of gastric distention. Greater gastric distention is
necessary to open the barrier in patients with an intact angle of His than in those with a hiatal hernia.16
The reason is that the dome or funnel shape of a hiatal hernia allows the wall tension forces that pull
open the barrier with gastric distention to be more effectively applied to the gastroesophageal
junction,17 and it accounts for the common association of a hiatal hernia with GERD. Kahrilas et al.18
demonstrated this mechanical disadvantage by studying the effect of intragastric air infusion on the
number of transient LES relaxations or “shortenings” per hour. Patients with hiatal hernias had
significantly more transient LES relaxations per hour than did control subjects without hernias. The
reduction in length became significant 20 to 30 minutes after the beginning of air infusion and occurred
in a distal to cephalad direction before a loss of LES pressure was observed.
Figure 42-14. Effect of increasing gastric volume on the shortening of the lower esophageal sphincter length. As the stomach
expands, the gastric body takes up the inferior aspect of the sphincter causing its length to shorten. (From Mason RJ, Lund RJ,
DeMeester TR, et al. Nissen fundoplication prevents shortening of the sphincter during gastric distention. Arch Surg 1997;132:719–
726, with permission.)
1048
booksmedicos.org
Figure 42-15. Representation of the loss of competence of the lower esophageal sphincter with shortening of its length. As a
critical length is reached, there is a precipitous drop in sphincter pressure reflecting loss of competence. (From Pettersson GB,
Bombeck CT, Nyhus LM. The lower esophageal sphincter: mechanisms of opening and closure. Surgery 1980;88:307–314, with
permission.)
The third characteristic of the LES high-pressure zone is its position. A portion of the overall length of
the high-pressure zone is normally exposed to the positive intra-abdominal pressure environment and is
commonly referred to as the abdominal length of the LES.19 During periods of increased intra-abdominal
pressure, the resistance of the LES would easily be overcome if its position were such that abdominal
pressure was unable to be applied equally to the LES and the stomach.20–22 This is analogous to sucking
on a soft soda straw immersed in a bottle of liquid; the positive hydrostatic pressure of the fluid and the
negative pressure inside the straw from sucking cause the straw to collapse instead of allowing the
liquid to flow up the straw in the direction of the negative pressure. When the abdominal length of the
LES is inadequate, increases in intra-abdominal pressure will be applied to the stomach but not the LES
thereby encouraging reflux to occur. Studies have shown that the critical length of abdominal LES is 1
cm, below which almost no LES pressure will be sufficient to maintain competency of the sphincter.15
In the fasting state deficits in LES pressure, overall length, or abdominal length will lead to an
increased likelihood of sphincter incompetence. An LES defective in all three parameters is particularly
likely to be associated with increased reflux of gastric juice into the esophagus. This reflux can result in
inflammatory injury to the mucosa and ultimately to the muscularis propria of the esophageal body,
thereby causing a reduced contraction amplitude of the esophageal body and interrupted or dropped
peristaltic sequences. Continued reflux can lead to progressive loss of effective esophageal clearance,
protracted esophageal exposure to the refluxed material and ultimately further organ injury (Fig. 42-
16).23,24
Causes and Consequences of the Failure of the Gastroesophageal Barrier

Early GERD is initiated by increased transient losses of the barrier as a result of gastric overdistention
from excessive air and food ingestion.11,25 The tension vectors produced by gastric wall distention pull
on the gastroesophageal junction, which results in the terminal esophagus being “taken up” into the
stretched fundus, thereby reducing the length of the LES. With overeating, a critical length is reached
(usually about 1 to 2 cm) at which the sphincter gives way; its pressure drops precipitously, and reflux
occurs (Fig. 42-15). If the swallowed air is vented, gastric distention is reduced, the length of the LES is
restored, and competency returns until subsequent distention again shortens it and further reflux occurs.
Aerophagia is common in patients with GERD because they swallow their saliva more frequently to
neutralize the acidic gastric juice that is refluxed into the esophagus.26 Together, the actions of
overeating and air swallowing result in the common complaint of postprandial bloating, repetitive
belching, and heartburn in patients with early GERD. The high prevalence of the disease in the Western
world is thought to be a result of the eating habits of Western society.27 Gastric distention from
overeating, along with delayed gastric emptying resulting from the increased ingestion of fatty foods,
leads to prolonged periods of postprandial gastric distention with shortening of the LES and repetitive
transient loss of the barrier. Surgical correction with a fundoplication prevents the shortening of the
barrier with progressive degrees of gastric distention by diverting the forces that pull on the
gastroesophageal junction.14
Figure 42-16. Overview of the progressive nature of GERD and the effect of the lower esophageal sphincter and esophageal body
on reflux in the upright and supine positions.
1049
booksmedicos.org
In advanced GERD, permanent loss of sphincter length occurs from inflammatory injury that extends
from the mucosa into the muscular layers of the LES. Fletcher et al.28 showed that in the fasting state,
there is a persistent region of high acidity in the area of the gastroesophageal junction and that this
region of acidity migrates 2 cm proximally after meals.29 This migration occurs from distention of the
stomach with eating and pulling apart of the distal high-pressure zone or LES, thus allowing the area of
high acidity to move proximal to the squamocolumnar junction. This proximal movement exposes the
distal esophageal squamous mucosa to acid and results in the formation of cardiac mucosa. Cardiac
mucosa is an acquired mucosa that replaces chronically injured squamous mucosa in the terminal
esophagus.30 The inflammatory process can extend into the muscular layer of the LES, thereby resulting
in muscle cell injury with permanent shortening of the high-pressure zone or LES and a concomitant
reduction in the amplitude of the high-pressure zone or barrier pressure.30–32 A defective barrier is
recognized when the length or pressure of the LES measured during the fasting state is below the 2.5
percentile of normal.33
For clinicians, the finding of a permanently defective LES has several implications. First, symptoms in
patients with a defective LES can be difficult to manage, and mucosal damage may persist with medical
therapy.34 Surgery is usually required to achieve consistent long-term symptom relief in these patients
to restore a gastroesophageal barrier and interrupt the natural history of the disease. It has been shown
repeatedly that a laparoscopic Nissen fundoplication can consistently restore the length and pressure of
the LES to normal parameters.35 Newer techniques of sphincter augmentation such as with a magnetic
bracelet is an alternative means of restoring the LES that is gaining in popularity.36 Second, a
permanently defective LES is commonly associated with reduced contractility and abnormal wave
progression of the esophageal body.37 For this reason, careful evaluation of the esophageal body is
critical in the evaluation for antireflux surgery for potential tailoring of the operation with a partial
fundoplication. Third, a permanently defective LES and the loss of effective esophageal clearance can
lead to mucosal injury such as erosive esophagitis or Barrett metaplasia, repetitive regurgitation and
aspiration events and ultimately pulmonary fibrosis. Without reestablishing a barrier, chronic use of
acid suppression therapy may simply mask the symptoms due to modification of the pH; however, in
the setting of a structurally defective LES, reflux will continue unabated.38
EVALUATION OF ESOPHAGEAL FUNCTION

A thorough understanding of the patient’s underlying anatomic and functional deficits is fundamental to
the successful treatment of esophageal disease. The diagnostic tests that are employed to evaluate the
esophagus are those used to visualize structural abnormalities, to detect functional abnormalities, and to
measure esophageal exposure to gastric juice. At the authors’ center a panel of four diagnostic tests are
used routinely in the evaluation of known or suspected reflux disease: barium esophagram, upper
endoscopy, high-resolution esophageal manometry, and ambulatory pH monitoring.
Radiographic Evaluation
Radiographic assessment of the anatomy and function of the esophagus and stomach is one of the most
important aspects of the esophageal evaluation, provided the surgeon has a working knowledge of
esophageal physiology. Classically, the barium esophagram has been described as a road map for the
esophagus. The first diagnostic test in patients with suspected esophageal disease should be a barium
swallow that includes a full assessment of the stomach and the duodenum.39 Video recording of the
study greatly aids in the evaluation by providing the surgeon with a real-time visualization of bolus
transport and the size and reducibility of the hiatal hernia. The study also provides anatomic
information, such as the presence of obstructing lesions and structural abnormalities of the foregut.
The pharynx and the UES are evaluated in the upright position, allowing assessment of the timing and
coordination of the events of pharyngeal transit.40 This includes oropharyngeal bolus transport,
pharyngeal contraction, opening of the pharyngoesophageal segment, and degree of airway protection
during swallowing. It readily identifies a diverticulum, stasis of the contrast medium in the valleculae,
cricopharyngeal bar, or narrowing of the pharyngoesophageal segment. These are anatomic
manifestations of neuromuscular disease and result from the loss of muscle compliance from the
deinnervation of the skeletal muscle of the pharynx and the cervical esophagus.41
The assessment of bolus transport on video esophagography often adds to or complements the
information obtained by esophageal manometry. Esophageal clearance is optimally assessed by
1050
booksmedicos.org
observing several individual swallows of barium with the patient in both the upright and supine
positions; the study can be performed with both liquid and solid bolus material. During normal
swallowing, a primary peristaltic wave is generated that completely strips the bolus out of the
esophagus and into the stomach. Residual material rarely stimulates a secondary peristaltic wave;
rather, an additional pharyngeal swallow is usually required.
The protocol developed and utilized at the authors’ institution has previously been reported.42 Normal
subjects in the prone position should be able to clear at least three of five 10-mL liquid barium boluses
with one swallow and have only one episode of proximal escape or distal retention of a barium bolus
with the five swallows. Normal subjects can also clear a solid barium bolus with four or fewer swallows
in the upright position. Motility disorders with disorganized or simultaneous esophageal contraction
give a segmented appearance to the barium column. This can often give a beading or corkscrew
appearance to the barium within the esophagus. In patients with dysphagia, the use of a barium-
impregnated marshmallow, piece of bread, or hamburger can identify an esophageal transport
disturbance that is not evident on the liquid barium study. A 13-mm barium tablet is another useful
adjunct that can be used to determine how well solid material can clear the esophagus, and identify
areas of clinically significant narrowing since solid food dysphagia typically is present with luminal
narrowing below 13 mm.
A hiatal hernia is present in a high percentage of patients with gastroesophageal reflux.43 These are
best demonstrated with the patient in the prone position; the increased intra-abdominal pressure
produced in this position promotes displacement of the hernia above the diaphragm. The hiatal hernia is
an important component of the underlying pathophysiology of reflux. A large (>5 cm) or irreducible
hiatal hernia may be associated with chronic reflux and esophageal foreshortening. The diagnosis of
reflux disease is not accurately made on video esophagram. Spontaneous reflux to the level of the
thoracic inlet seems to correlate with a positive pH test, but evoked reflux and spontaneous reflux into
the distal esophagus are not. Moreover, failure to observe reflux during a video esophagram does not
indicate the absence of disease.
A full-column technique with distention of the esophageal wall can discern extrinsic compression of
the esophagus, and a fully distended esophagogastric region is necessary to identify narrowing from a
Schatzki ring, stricture, or obstructing lesion. Mucosal relief or double-contrast films can be obtained to
enhance the detection of small neoplasms, esophagitis, and varices. Assessment of the stomach and
duodenum during the barium study is helpful for the evaluation of the patient with esophageal
symptoms (ESs). A gastric or duodenal ulcer, a neoplasm, or poor gastroduodenal transit can mimic
many of the symptoms that are suggestive of an esophageal disorder.
Endoscopic Examination
Endoscopic evaluation of the esophagus is essentially the physical examination of the foregut. It is a
critical part of the assessment of a patient with esophageal disease and is indicated in essentially every
patient who is being evaluated for GERD. A barium study obtained before esophagoscopy is helpful to
the endoscopist by directing attention to locations of subtle change and alerting the examiner to such
potential danger spots as a cervical vertebral osteophyte, an esophageal diverticulum, a deeply
penetrating ulcer, or a carcinoma. Regardless of the radiologist’s interpretation of an abnormal finding,
each structural abnormality of the esophagus should be examined visually with an endoscope.
During every endoscopic examination, the locations of three specific landmarks are routinely obtained
relative to the front incisors: the squamocolumnar junction, gastroesophageal junction, and the
diaphragmatic crura. The crura are usually evident by having the patient sniff. The gastroesophageal
junction is the location at which the gastric rugal folds meet the tubular esophagus; it is normally
aligned with the squamocolumnar junction. The squamocolumnar junction is the location at which the
velvet and darker rose-colored columnar epithelium changes to the lighter squamous epithelium. When
this junction is not clear, narrow band imaging (NBI), a feature that is standard on all modern
endoscopic systems, is extremely helpful in distinguishing columnar from squamous mucosa. Particular
effort should be made to detect any tongues, islands, or a circumferential segment of columnar-lined
esophagus (CLE) in the distal esophagus.
When erosive esophagitis is found, an objective grading system should be utilized to communicate the
severity of the findings. Currently, the Los Angeles classification is the most commonly utilized
system.44 Grade A is defined as one or more mucosal break ≤5 mm that does not extend between the
tops of mucosal folds. Grade B is defined as one or more mucosal break >5 mm that does not extend
between the tops of the mucosal folds. Grade C is defined as one or more mucosal break that is
1051
booksmedicos.org
continuous between the tops of two or more mucosal folds but involves <75% of the circumference.
Grade D is defined as one or more mucosal break that involves ≥75% of the circumference.
Barrett esophagus is a pathologic condition in which the tubular esophagus is lined with columnar
epithelium as opposed to the normal squamous epithelium. It is suspected at endoscopy when there has
been separation of the squamocolumnar junction from the gastroesophageal junction. When columnar
metaplasia is observed, it must be biopsied to confirm the presence of intestinal metaplasia in order to
make the diagnosis of Barrett esophagus; the finding of cardiac metaplasia without goblet cells does not
meet this criteria in the United States. On histologic examination, it appears as columnar mucosa with
goblet cells and is called intestinal metaplasia. Early metaplasia is often manifest as an irregular or
eccentric squamocolumnar junction. Routine four-quadrant biopsies with jumbo forceps are necessary
every 2 cm of columnar metaplasia. In addition, the likelihood of identifying goblet cells is greatest at
the cephalad portion of a columnar segment, especially at the squamocolumnar junction.45 Barrett
esophagus is susceptible to ulceration, bleeding, stricture formation, and malignant degeneration. The
earliest histologic sign of malignant degeneration is high-grade dysplasia (HGD) or intramucosal
adenocarcinoma. These dysplastic changes have a patchy distribution, so a minimum of four biopsy
specimens every 2 cm should be taken from the Barrett mucosa–lined portion of the esophagus. A study
of intramucosal adenocarcinomas arising in Barrett esophagus showed that most of the tumors arose in
the distal Barrett segment, closer to the stomach.46
Abnormalities of the cardia or gastroesophageal junction can be visualized by retroflexion of the
endoscope and provide a complementary assessment regarding the competency of the gastroesophageal
barrier. Hill et al. have graded the appearance of the gastroesophageal valve from I to IV according to
the degree of unfolding or deterioration of the normal architecture (Fig. 42-17).47 This commonly used
grading system has allowed endoscopists to maintain uniformity in their reporting. The Hill grade
correlates well with the competence of the gastroesophageal barrier, with increasing acid exposure
prevalent in patients with worsening Hill grade.
A hiatal hernia is diagnosed by observing separation of the gastroesophageal junction from the crura.
By definition, a hiatal hernia is present when at least 2 cm of the top of the rugal folds has migrated
above the pinch of the diaphragmatic crura. A prominent sliding hiatal hernia is frequently associated
with GERD. When a hernia is observed, particular care is taken to exclude Cameron ulcers or gastritis
within the herniated stomach.
As the endoscope is slowly withdrawn, the esophagus is again examined, and biopsy samples are
taken. The location of the cricopharyngeus is identified, and the larynx and vocal cords are visualized.
Acid reflux may result in inflammation of the larynx. Vocal cord movement should also be recorded,
both as a reference for subsequent surgery and as an assessment of the patient’s ability to protect the
airway.
Esophageal Manometry
Fundamental to the evaluation of a patient with benign esophageal disease is the assessment of
esophageal contractility, coordination, and sphincter function. Manometry is indicated whenever an
abnormality of the esophagus is suggested by the symptoms of dysphagia, odynophagia, chest pain,
heartburn, and regurgitation. It is particularly necessary to confirm the diagnosis of specific primary
esophageal motility disorders, such as achalasia, diffuse esophageal spasm, nutcracker esophagus, or
hypertensive LES. It can also identify ineffective esophageal body motility as a result of GERD or
systemic diseases such as scleroderma, dermatomyositis, polymyositis, or mixed connective tissue
disorders. In patients with symptomatic GERD, esophageal manometry can identify a mechanically
defective LES and evaluate the adequacy of the esophageal body contraction amplitudes and waveform.
Finally, manometry is mandatory for accurate placement of an ambulatory pH monitor in relationship
to the upper border of the LES.
High-resolution manometry (HRM) has now become standard technology over the past several years
and represents an improvement in methodology that leads to a more detailed data collection and
simpler data interpretation, especially with regard to the esophageal body. The concept behind this
technology is that by vastly increasing the number of sensors and reducing the space between the
sensors, it can provide representation of the entire pressure profile along the esophagus from the
pharynx to the proximal stomach without the need to reposition or to pull back the catheter as in
conventional manometry.
The most commonly used HRM system is a solid-state manometric assembly with 36 circumferential
sensors spaced at 1-cm intervals and are available from different manufacturers. These transducers
1052
booksmedicos.org
detect the pressure over a length of 25 mm in each of 12 radially dispersed sectors. The recorded
pressure at each sector is then averaged, making each of the 36 sensors a circumferential pressure
detector with the extended frequency response characteristic of solid-state manometric systems and free
of the hydrostatic influence characteristic of water-perfused systems. The increased number of
circumferential pressure sensors results in a vastly greater amount of data and detail. Interpretation of
the data has been simplified by a sophisticated topographic plotting algorithm that converts the
traditional linear waveform tracings into an esophageal pressure topography or Clouse plot (Fig. 42-18).
Sphincter characteristics and esophageal motor function are represented by isocontour manometric
plots, eliminating the need for the tedious analysis of the increased waveform data that are generated
by the 36 sensors.
Figure 42-17. Endoscopic grading of the gastroesophageal junction during the retroflex view. (From Oberg S, Peters JH, DeMeester
TR, et al. Endoscopic grading of the gastroesophageal valve in patients with symptoms of gastroesophageal reflux disease (GERD).
Surg Endoscopy 1999;13(12):1184–1188, with permission.)
Figure 42-18. High-resolution manometry with line tracings and converted pressure topography or Clouse plot view. (From
Pandalfino JE, Roman S. High-resolution manometry: an atlas of esophageal motility disorders and findings of GERD using
esophageal pressure topography. Thor Surg Clin 2011;21:465–475, with permission.)
1053
booksmedicos.org
The manometry procedure is performed by passing the catheter into the stomach and esophagus to
measure contraction pressures and waveform in the esophageal body and the sphincters’ resting
pressure and response to swallowing. The lubricated catheter is passed through the nostril and into the
esophagus. The catheter is advanced until a portion of the sensors are in the stomach. In patients who
have a dilated or tortuous esophagus such as suspected achalasia or a large PEH, it is recommended that
the catheter be passed endoscopically to ensure that it is properly positioned into the stomach and not
coiled in the esophagus. The pressure topogram is assessed to ensure that the catheter is completely
traversing the UES and the LES. Unlike with traditional manometry, a HRM study can be performed
with 10 swallows without the need to repeatedly move the catheter back and forth for different
portions of the examination. The patient is then asked to refrain from swallowing for 30 seconds with
quiet breathing, which allows the capture of a landmark frame for assessment of the resting UES and
LES. The patient is positioned supine with the head elevated and is asked to swallow 5 mL aliquots of
water separated by a minimum of 30 seconds to prevent deglutitive inhibition. A complete manometric
study includes the assessment of the structural characteristics of the LES, the degree of LES relaxation,
the esophageal body coordination, contraction amplitude and waveform, and the UES function.
Lower Esophageal Sphincter

The resting LES is assessed during the landmark frame (Fig. 42-19). The lower (distal) border of the LES
is the point at which the resting pressure rises above the gastric baseline; the upper border is the point
at which sphincter pressure reaches the esophageal baseline. The respiratory inversion point is identified
when the positive excursions that occur with breathing in the abdominal environment change to
negative deflections in the thoracic environment. The respiratory inversion point is the functional
division between the abdomen and thorax. The resting pressure of the LES is the pressure above gastric
baseline measured during midrespiration at the respiratory inversion point. The overall length of the
sphincter is the distance from the distal border to the proximal border. The abdominal length is the
distance from the distal border to the respiratory inversion point and represents the portion of the LES
that is subject to fluctuations in intra-abdominal pressure. The measurements for each of these
components from each transducer are expressed as an average during the landmark frame, which
extends for 30 seconds.
Figure 42-19. High-resolution esophageal manometry showing the landmark frame. The upper and lower esophageal sphincters
are observed at the top and bottom of the frame, respectively. Resting pressure and length measurements of the sphincters can be
determined in this portion of the study while the patient is refraining from any swallowing. (From Pandalfino JE, Roman S. High-
resolution manometry: an atlas of esophageal motility disorders and findings of GERD using esophageal pressure topography. Thor
Surg Clin 2011;21:465–475, with permission.)
A structurally defective sphincter is identified by one that has low resting pressure or short length.
Based on conventional manometry in normal volunteers, the following characteristics have traditionally
been used to identify a structurally defective LES: (1) an average LES pressure of less than 6 mm Hg,
(2) an average abdominal length of less than 1 cm, and (3) an average overall length of less than 2 cm.
1054
booksmedicos.org
Based on normative data, these values are below the 2.5 percentile. A defect in one or even two
components of the LES may be compensated by good esophageal body function, but when all three
components are defective, excessive esophageal acid exposure is inevitable. With the HRM technique,
normal overall LES length should be 2.7 to 4.8 cm and mean basal resting pressure of the LES should be
13 to 43 mm Hg.
It should be noted that while HRM has revolutionized the assessment of the esophageal body due to
improved resolution of contraction waves, the assessment of the LES has been less optimal. This is
primarily due to the nature of the HRM catheter, which functions as a sleeve manometry catheter and
results in circumferential averaging of pressure data. For this reason, length assessment of the LES and
UES is believed to be less detailed than that obtained with conventional manometry with a manually
pulled through catheter.48 It is believed that the newly developed 3D HRM catheter will allow more
precise or detailed evaluation of the LES structure, but clinical experience is necessary to fully evaluate
its additive value.
Lower Esophageal Sphincter Relaxation

The LES pressure normally drops to gastric baseline immediately after initiation of a swallow, and
remains open until the oncoming peristaltic wave reaches the stomach (Fig. 42-18). A characteristic
postrelaxation contraction of the LES is subsequently observed as the LES closes with passage of the
bolus. Using HRM, relaxation is assessed during a 4-second segment of the time between initiation of
the swallow and when the peristaltic wave reaches the LES. This 4-second window is often captured in a
noncontiguous manner during the swallow to eliminate the effect of respiratory variation from the crura
and is termed the integrated relaxation pressure (IRP). An IRP >15 mm Hg is considered elevated and
may result in clinically significant outflow resistance through the LES.
Esophageal Body Motility

The esophageal body is evaluated by assessing contraction amplitude, duration, slope, velocity, and
morphology (i.e., single, double, or triple peaked). A physiologic gap in contraction or proximal
peristaltic break typically occurs in the upper one-third of the esophagus, and corresponds to the
transition zone between the striated muscle above and smooth muscle below. Pathologic breaks are
those that are >2 cm long or if a break occurs in the distal esophagus. HRM has had its greatest
improvement in the assessment of esophageal body function. It is important to allow 30 seconds
between swallows to prevent deglutitive inhibition of the body, a physiologic dampening or absence of
peristalsis with repetitive swallowing.
Figure 42-20. High-resolution esophageal manometry during a swallow. The initiation of swallowing is reflected by transient
relaxation of the UES followed by a peristaltic pressure wave progressing down the esophageal body. Note the LES relaxes at the
initiation of swallowing. A characteristic peristaltic break is observed in the upper third of the esophageal body at the transition
zone between the striated and smooth muscle. (From Pandalfino JE, Roman S. High-resolution manometry: an atlas of esophageal
motility disorders and findings of GERD using esophageal pressure topography. Thor Surg Clin 2011;21:465–475, with permission.)
Further improvement in assessing esophageal body function with HRM has been the use of the distal
contractile integral (DCI) which gives a global assessment of esophageal contractile function. This is an
integrated summation of the contractile pressures generated between the proximal peristaltic break and
the upper border of the LES and is calculated as the product of amplitude (mm Hg) × duration
(seconds) × length (cm), with normal values ranging from 500 to 4,300 (Fig. 42-20). Based on
1055
booksmedicos.org
conventional manometry, it was believed that a minimum of distal contraction amplitude of >20 mm
Hg 5 cm above the LES was necessary to overcome the resistance of an antireflux procedure. With HRM
it is currently believed that a DCI >500 mm Hg*sec*cm is necessary to minimize the possibility of
postoperative dysphagia; however, clinical validation of this cutoff has not been performed.
Upper Esophageal Sphincter

The position, length, and resting pressure of the UES and its relaxation with swallowing are assessed
with a technique similar to that used for the LES. The key features to be assessed are the adequacy of
pharyngeal contraction and the timing and extent of UES relaxation. An indirect measure of UES
stiffness or loss of compliance is the intrabolus pressure, which appears as a pressure rise or shoulder on
the upstroke of the pharyngeal contraction.
High-Resolution Impedance
Even with the addition of high-resolution topography, manometric data often does not correlate with
the effective passage of the swallowed bolus. To overcome this shortcoming, the barium video
esophagram has been used to complement manometry; however, one drawback is that these tests
cannot be performed simultaneously. Not infrequently, a discrepancy may exist between these studies
with a normal video esophagram but poor esophageal body manometry characteristics, or vice versa.
Currently, the authors are utilizing combined HRM with high-resolution impedance to gain additional
information on bolus transport.
Ambulatory pH Monitoring
The development of ambulatory pH monitoring by DeMeester and Johnson49 was a major advance in
the unraveling of the pathophysiology of GERD. All previous tests had relied on the identification of
reflux by a provocative maneuver, which had little relevance to the patient’s daily activities. The 24-
hour pH monitoring test allowed objective assessment of esophageal exposure to gastric juice in a
patient in a continuous setting. It is considered the gold standard for the diagnosis of GERD because it
has the highest sensitivity and specificity of all tests currently available. It is indicated in any patient
with symptoms suggestive of GERD, unless the symptoms are trivial or permanently abolished by a
short course of acid suppression therapy. The need for continued acid suppression should stimulate
objective study. A 24-hour pH monitoring study is especially important in patients who are being
considered for antireflux surgery. Atypical presentations of GERD are also a common indication; they
include such symptoms as noncardiac chest pain (i.e., pain despite a normal cardiac evaluation) and
respiratory symptoms (RSs) such as shortness of breath, cough, nocturnal wheezing, and chronic
hoarseness. In such patients, 24-hour pH monitoring allows confirmation of the diagnosis of GERD and
can relate the occurrence of the symptoms to an episode of reflux.
To perform the standard pH test, a thin catheter containing a pH electrode is passed transnasally into
the esophagus and placed 5 cm above the upper border of the LES, a position that has been previously
determined by manometry. Different probes are available, but bipolar glass electrodes are preferred for
their greater reliability and their elimination of the need for an external reference electrode. The
electrode is connected to an external portable digital storage device that is kept at the patient’s side,
and pH values are continuously recorded at 6-second intervals for 24 hours (i.e., a complete circadian
cycle). Precalibration and postcalibration of the system to pH levels of 1 and 7 is important to exclude
electrode drift. A gastric “dipstick” maneuver is performed prior to securing the location of the catheter
to confirm acid in the stomach and that the patient does not have atrophic gastritis. The patient is then
instructed to carry out normal daily activities but to avoid strenuous exertion. He or she is asked to
remain in the upright position while awake during the day, lying down supine only at night while
sleeping, and to ingest two meals at the usual time. The diet is standardized only by its absence of food
and beverages with a pH value of less than 5.0 and greater than 6.0. The patient notes in a diary the
times of meals, retiring for sleep, and rising the following morning as well as the presence and duration
of any symptoms. At the authors’ institution, patients are also asked to consume a challenge meal
consisting of a hamburger, French fries, and a milk shake. It has been found that a refluxogenic meal
can often uncover early acid reflux disease that would not ordinarily be detected during a typical 24-
hour period.50 Figure 42-21 shows typical 24-hour pH tracings from a healthy subject and from a patient
with GERD. Medications such as H2 blockers and prokinetics should be discontinued for 48 hours before
the testing begins. Proton pump inhibitors (PPIs) (e.g., omeprazole) should be stopped for 2 weeks
before pH monitoring because of their long-lasting action.
1056
booksmedicos.org
It is important to emphasize that 24-hour esophageal pH monitoring should not be considered a test
for reflux; rather, it is a measurement of the esophageal exposure to gastric juice. The measurement is
expressed as the percentage of time that the esophageal pH was below 4 during the 24-hour period. Just
measuring the percentage of time that the pH is less than 4, although concise, does not reflect how the
exposure has occurred; for example, it may have occurred in a few long or several short reflux episodes.
Consequently, two other assessments are necessary: (1) the frequency of the reflux episodes and (2)
their duration. For this reason, esophageal exposure to gastric juice is best assessed by the following
measurements:
Figure 42-21. Dual-probe 24-hour pH tracing of patient. The top tracing is of the pH sensor located below the upper esophageal
sphincter and the bottom tracing is of the pH sensor located 5 cm above the top of the lower esophageal sphincter. Episodes of pH
<4 are considered acid events. In this example the patient has abnormal acid exposure in the distal esophagus with several reflux
events extending into the proximal esophagus.
The cumulative time that the esophageal pH is below 4 expressed as the percentage of the total,
upright, and supine monitored times;
The frequency of reflux episodes, when the pH drops below 4, expressed as the number of episodes
per 24 hours;
The number of episodes during which the pH remained below 4 for longer than 5 minutes per 24
hours; and
The time in minutes of the longest recorded reflux episode, the longest time the pH consistently
remained below 4.
Normal values for these six components of the 24-hour record were derived from 50 asymptomatic
control subjects. The upper limits of normal were established at the 95th percentile.51 If the values of
symptomatic patients are outside of the 95th percentile of normal subjects, they are considered to be
abnormal for the component measured. There is a uniformity of normal values for these six components
as reported by centers throughout the world. The normal values for the six components obtained from
50 healthy volunteers are shown in Table 42-1. A composite scoring system was developed by
DeMeester and Johnson that integrates the different components of the pH record into a single
measurement of esophageal acid exposure. This composite score is calculated from the six parameters
with use of their standard deviations as weighing factors.51
Advances in technology have made pH testing more comfortable for the patient with the development
of a catheter-free miniaturized pH electrode. The Bravo system (Medtronic, Minneapolis, MN) allows
the transnasal or transoral deployment of a small capsule that attaches to the esophageal mucosa and
transmitting pH data by radiotelemetry to a pager-sized receiver, thus eliminating the need for an
unpleasant transnasal catheter. It may also provide a more accurate physiologic picture by allowing
patients to perform their normal daily activities without the social and behavioral restrictions imposed
by the catheter. Another major advantage of the Bravo capsule is the ability to record for prolonged
periods, and routine monitoring of 48 hours is now performed with improved diagnostic capabilities.52
New normal thresholds have been defined and validated for the 48-hour Bravo pH test, with the normal
composite score for the first 24 hours being 14.0, the second 24 hours being 14.0, and the combined 48-
1057
booksmedicos.org
hour score being 16.0.51
Table 42-1 Normal Manometric Values of the Distal Esophageal Sphincter in 50

Subjects
In patients with symptoms of chronic cough, hoarseness, or pulmonary aspiration, placement of an

additional pH electrode in the proximal part of the esophagus or pharynx can be helpful.53 Such dual-
probe catheters are particularly helpful in determining if gastroesophageal reflux events extend
proximally, which could give indirect evidence of acid exposure into pharyngeal area and subsequent
irritation. If the accumulated acid exposure in the proximal esophagus is greater than 1% or the number
of reflux episodes is more than 24 (particularly if there is a temporal relationship between the reflux
episodes and the onset of the symptoms), reflux can be documented and assumed to be the cause of the
patient’s RSs.53 A composite score has been developed for proximal pH monitoring, analogous to that
developed for the distal probe, with the normal threshold composite score being 16.4.52
Additional testing is sometimes necessary if the standard methods of assessing esophageal function
fail to yield conclusive results, particularly when investigating the relationship of acid reflux and
extraesophageal symptoms. A novel pharyngeal pH system has been developed that allows a pH probe
to be positioned directly into the pharynx just below the uvula (Restech pH probe, Respiratory
Technology Corp, San Diego, CA, USA).53 This probe utilizes a novel antimony sensor that allows
measurement of pH within the humidified air of that environment without drying out and creating
artifacts. Early clinical experience with this technique indicates that it is a useful adjunct diagnostic test
in patients suspected of having laryngopharyngeal reflux (LPR).
Testing for reflux that is nonacidic or weakly acidic can be gained by multichannel intraluminal
esophageal impedance monitoring. This type of measurement determines the resistance to the flow of
current through a given medium (impedance). The impedance to current changes as the composition of
the medium in which the current is traveling changes (i.e., air, liquids, or solids). Coupled with a pH
probe, it can differentiate acid reflux from nonacid reflux, which may be particularly useful in patients
who remain symptomatic on acid suppression therapy.
Lastly, the assessment of gastric function can be important in many patients with ESs. Disorders of
gastric emptying frequently can contribute to or be confused with esophageal disease, especially GERD.
Nuclear medicine radioisotope with solid food matter such as scrambled eggs has been utilized for this
purpose, and is indicated in any patient being evaluated for GERD who also has a history of nausea,
early satiety, and vomiting. Such information may be invaluable to prevent performing an antireflux
operation in the setting of gastroparesis. The most reliable results are obtained with the use of a 4-hour
study rather than one that just determines a half-time of emptying.
CONCLUSIONS
Although seemingly simple, the anatomy and physiology of the esophagus is complex. Understanding
the anatomic relationships is critical to enable safe surgery on the esophagus. Functional studies allow
identification of abnormalities in the upper or lower esophageal sphincter as well as the esophageal
body, and pH testing can determine the presence of increased exposure of the esophagus to refluxed
gastric juice. An understanding of the relevant pathophysiology is critical to allow functional restoration
of LES competence in patients with reflux disease, or to reduce the LES outflow resistance in patients
with achalasia. While complex, restoration of esophageal function can bring tremendous improvements
in quality of life and social satisfaction for patients, and is gratifying for esophageal surgeons.
GASTROESOPHAGEAL REFLUX DISEASE

Definition and Epidemiology
1058
booksmedicos.org
GERD is a very common disease, but developing an accurate definition of GERD is surprisingly difficult.
In 2004, a group of experts came together in Montreal and concluded that GERD can be best defined as
“a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or
complications.”54 Population-based studies have reported that one-third of Western populations
experience the symptoms of GERD at least once a month, with 4% to 7% of the population experiencing
daily symptoms.55,56 Its prevalence varies considerably around the globe and is highest in North
America, Australia, and Western Europe and lowest in Africa and Asia.57 It is also likely that both the
prevalence and severity of GERD are increasing in many parts of the world. Time trend analyses have
shown that the prevalence of GERD symptoms has increased progressively in most longitudinal studies,
including those from the United States, Singapore, and China (Fig. 42-22).58 Further, recent data
reported by the Agency for Healthcare Research and Quality (AHRQ) indicate a marked increase (103%)
in hospitalizations for treating disorders caused by GERD; a 216% increase in hospitalization of patients
who, in addition to the ailment for which they were admitted, have milder forms of GERD; and a 39%
increase in admission for GERD with severe symptoms including anemia, weight loss, and vomiting.59
These data suggest that the current therapeutic approach to GERD may be inadequate.
Figure 42-22. Time trends for the prevalence of weekly heartburn from 1980 to 2005. (Reproduced with permission from El-Serag
H. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol Hepatol 2007;5:17–26.)
Most patients with mild symptoms self-medicate with over-the-counter antacids or antisecretory
agents, whereas those with more severe and persistent symptoms seek out medical attention. In contrast
to duodenal ulcer disease, where the prevalence has markedly decreased, the prevalence and severity of
GERD seem to be increasing (Fig. 42-23).60 The diagnosis of a CLE is also increasing at a rapid rate, and
deaths from end-stage benign esophageal disease are on an upward trend.61 These changes have
occurred despite dramatic improvements in the efficacy of treatment options.
Two epidemiologic trends may be contributing to the increasing prevalence and severity of GERD
over the past several decades. Population-based studies have shown that GERD is positively associated
with obesity and negatively associated with gastric colonization with Helicobacter pylori. Over the past
20 to 30 years, the former has increased and the latter has decreased markedly in most Western
countries. The relationship between GERD and body mass index (BMI) has been evaluated in a number
of well-designed clinical studies. The frequency, duration, and severity of reflux symptoms were studied
in 10,500 women of the Nurses’ Health Study and a dose-dependent relationship between increasing
BMI frequency of GERD symptoms was identified.62 Compared to normal-weight women (BMI 20 to
22.4), underweight women (BMI <20) were one-third less likely and overweight women (BMI 25 to
27.4) two times more likely to have frequent GERD symptoms. Obese women (BMI >30) had a nearly
three times higher risk of frequent GERD symptoms. Recent meta-analyses confirm these findings, with
studies from the United States demonstrating an association between increasing BMI and the presence of
GERD.63 High-resolution motility studies have shown a significant correlation with BMI and both
intragastric pressure and gastroesophageal pressure gradients, providing a physiologic explanation for
the BMI–GERD association.64 These studies suggest that obese subjects are more likely to have
esophagogastric junction disruption and abnormal pressure gradients favoring the development of
reflux. Finally, the risk of Barrett esophagus has been correlated with the presence of central obesity.
Measures of central obesity, including waist circumference and waist-to-hip ratios, were associated with
both short- and long-segment Barrett esophagus, with a 4.1 higher odds ratio of long-segment Barrett in
patients with a high waist-to-hip ratio.65
1059
booksmedicos.org
Figure 42-23. Trends in hospitalization for duodenal ulcer and gastroesophageal reflux disease from the 1970s to 1990s in U.S.
veterans. (Reproduced with permission from El-Serag HB, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease.
Gut 1998;43:327–333.)
The possible pathogenic role of helical-shaped bacteria found in gastric fluids was first suggested in
the late 19th century by the Polish scientist Walery Jaworski of the University of Krakow.66 It was the
publication of two Australian scientists in 1983 that convincingly demonstrated the pathogenic role of
H. pylori.67 These pioneering studies of Barry Marshall and Robin Warren from Perth, Australia,
included self-experiments and were later awarded the Nobel Prize. H. pylori induces a significant
inflammatory and immune response in the affected host, resulting in persistent inflammation in
virtually all infected subjects.
The relationship between H. pylori and GERD has been of interest for decades. The observation that
gastric mucosal atrophy was less frequent in patients with reflux esophagitis was made well before the
H. pylori era. Evolutionary hypotheses assume, and the majority of available epidemiologic data show,
that the decline of H. pylori infection is one of the reasons behind the increasing incidence of GERD-
related diseases including esophageal and cardia adenocarcinoma in the Western world. This inverse
relationship is strongest between H. pylori and esophageal adenocarcinoma, although significant
evidence relates H. pylori and the development of Barrett esophagus and GERD. Over the period from
1970 to 1995, the incidence of both duodenal ulcer, compared to erosive esophagitis, and distal gastric
cancer, compared to gastric cardia cancer, displays strikingly opposing time trends. It has been
postulated that H. pylori–induced chronic corpus gastritis may protect against the development of GERD
and its malignant transformation. A detailed report by Labenz et al.68 in 1997 provided some of the first
evidence in support of this theory. In a case-control study of 460 duodenal ulcer patients, new-onset
GERD symptoms were significantly higher in patients who had successful H. pylori eradication than in
those with persisting infection. Although a number of subsequent studies have raised doubts as to
whether a true relationship exists, the available evidence suggests that the prevalence of H. pylori
infection in patients with GERD is lower than non-GERD control populations and that there is likely an
inverse epidemiologic relationship between GERD and H. pylori.
The relationship of Barrett esophagus to gastric H. pylori colonization is also debated, although most
studies show an even stronger inverse relationship than that of GERD alone. Bowrey et al. reported an
H. pylori prevalence of 27% in patients with Barrett esophagus compared to 41% in healthy control
subjects.69 Werdmuller and Loffeld70 also found significantly lower H. pylori infection rates in Barrett
than non-Barrett patients (23% vs. 51%), whereas Loffeld et al.71 reported very high rates (62%) in a
retrospective analysis of 107 consecutive patients with CLE. Investigations focused on the role of
subpopulations of H. pylori have implicated cagA+ strains as particularly relevant to the development of
GE reflux and its complications.72 Vicari et al.73 demonstrated that in patients with H. pylori infection,
the prevalence of cagA+ strains progressively decreased with the severity of GERD, including Barrett
esophagus and esophageal adenocarcinoma. Other studies have confirmed an inverse relationship
between the presence of cagA positivity and adenocarcinoma of the esophagus and the GE junction.74
Most authors postulate that cagA+ strains may protect from the development of adenocarcinoma by
inducing more severe mucosal inflammation and atrophic gastritis and thereby decreasing acid reflux.
Present data regarding gastric acid secretion are conflicting, however, and further studies are required
to test whether this hypothesis is true.
Previously there was a concept that GERD was a categorical disease with little movement between
categories. In other words, patients with nonerosive disease (NERD) seldom developed erosive
1060
booksmedicos.org
esophagitis. This concept was disproven by one of the most detailed studies on the natural history of
GERD from investigators in Europe.75 The progression or regression of GERD complications was
assessed in a cohort of nearly 4,000 patients with predominant heartburn over a 2-year period. After 2
years, 25% of patients with nonerosive GERD progressed to erosive disease, 1.6% with mild erosive
esophagitis worsened to more severe esophagitis, and nearly 8% progressed to Barrett esophagus, the
latter predominantly in patients with Los Angeles grade C/D erosive disease at baseline. On the other
hand, 50% to 60% of patients with baseline esophagitis improved to a milder grade or no erosive
disease and 22% were off medications at 2 years. Given that virtually all patients were receiving
significant antisecretory therapy, the study shows that a substantial minority of patients will continue to
worsen despite pharmacologic treatment. A follow-up study at 5 years on 2,721 of the originally
enrolled patients reported that while in most the disease was stable or esophagitis had improved, a
sizeable portion of patients progressed.76 At 5 years, 6% of patients with NERD, 12% with LA grade A/B
esophagitis, and 20% of those with LA grade C/D esophagitis had developed Barrett esophagus. On
multivariable analysis risk factors for progression to esophagitis or Barrett esophagus were family
history of GERD, baseline esophagitis or remaining unhealed after initial treatment, alcohol intake, and
regular use of PPI medication.76
Investigators in Lausanne, Switzerland, reported an intensive endoscopic follow-up of a defined
population of 959 patients over a 30-year period.77 The study involved only patients who had
endoscopic esophagitis and did not include those who had symptoms without mucosal injury. In 42% of
patients esophagitis progressed on therapy to more severe mucosal injury. Further, 18% of the initial
population acquired a columnar-lined lower esophagus with intestinal metaplasia at late follow-up.
Clinical Presentation
The most common complaints in patients with GERD are heartburn, regurgitation, and dysphagia. These
represent the so-called typical symptoms of GERD. Although none of these are specific to GERD,
dysphagia may be an indication of more serious underlying pathology, including esophageal carcinoma,
and should prompt an upper endoscopy. Heartburn means different things to different people and it is
important to ask a patient what heartburn means to them. Typically, heartburn should be characterized
as a substernal “burning” discomfort often radiating from the epigastrium to sternal notch. Occasionally
patients will refer to it as chest or epigastric pain or indigestion. The typical pattern for early reflux
disease is heartburn that occurs postprandially and made worse by “spicy” foods such as tomato sauce,
citrus juices, chocolate, coffee, and alcohol. It is commonly relieved by antacids, histamine-2 blockers or
PPIs. Importantly, the severity of symptoms is not necessarily related to the severity of the underlying
disease (Fig. 42-24).
Figure 42-24. Prevalence of erosive esophagitis in 994 patients with varying severity and frequency of reflux symptoms.
(Reproduced with permission from Venables TL, Newland RD, Patel AC, et al. Omeprazole 10 mg once daily, omeprazole 20 mg
once daily, or ranitidine 150 mg twice daily, evaluated as initial therapy for the relief of symptoms of gastro-oesophageal reflux
disease in general practice. Scand J Gastroenterol 1997;32:965.)
Regurgitation is the spontaneous return of gastric contents proximal to the GE junction. Its
spontaneous nature distinguishes it from vomiting. The patient often gets a sensation that fluid or food
is returning into the esophagus, even if it does not reach as high as the pharynx or mouth. It is typically
worse at night in the recumbent position or when bending over or lying down after a meal. Patients
commonly compensate by not eating late at night or by sleeping partially upright with several pillows
1061
booksmedicos.org
or in a chair. This symptom is often less well relieved with antacids or antisecretory agents, although it
may change in character from acidic to a more “bland” nature.
Dysphagia is generally manifested by a sensation of food hanging up in the esophagus rather than
difficulty transferring the bolus from the mouth to the esophageal inlet (oropharyngeal dysphagia).
Classically, dysphagia limited to only solid food, with normal passage of liquids, suggests a mechanical
disorder such as a large hernia, stricture, or tumor, whereas difficulty with both solids and liquids
suggests a functional or motor disorder such as achalasia. Dysphagia often develops slowly enough that
the patient may adjust his or her eating habits and not be particularly alarmed or aware of the problem.
Thus, a thorough esophageal history includes an assessment of the patient’s dietary history. Questions
should be asked regarding the consistency of food that is typically eaten and whether the patient
requires liquids with the meal, is the last to finish, has interrupted a social meal, chokes or vomits with
eating, or has been admitted on an emergency basis for food impaction. These assessments, in addition
to the ability to maintain nutrition, help to quantify the dysphagia and are important in determining the
indications for surgical therapy.
Many patients with GERD often manifest “atypical” or extraesophageal symptoms, such as cough,
asthma, hoarseness, and noncardiac chest pain. Atypical symptoms are the primary complaint in 20% to
25% of patients with GERD and are secondarily present in association with heartburn and regurgitation
in many more. It is considerably more difficult to prove a cause-and-effect relationship between atypical
symptoms and GE reflux than it is to do so for the typical symptoms, and the etiology of these
symptoms is often multifactorial. Often a trial of high-dose PPIs is helpful, but it takes several months
to evaluate the full impact of the therapy since if GERD is causing the inflammation that leads to the
symptoms, it takes time for that inflammation to improve or resolve with GERD therapy. Antireflux
surgery can provide excellent symptom relief in these patients, but careful testing to document GERD is
critical particularly in those with little or no response to medical therapy.
The diagnosis of GERD based on symptoms alone is correct in only approximately two-thirds of
patients.78 This is because these symptoms are not specific for GE reflux and can be caused by other
diseases such as achalasia, diffuse spasm, esophageal carcinoma, pyloric stenosis, cholelithiasis, gastritis,
gastric or duodenal ulcer, and coronary artery disease. This fact underscores the need for objective
diagnosis before the decision is made for surgical treatment.
Physiology of the Antireflux Barrier

The common denominator for virtually all episodes of gastroesophageal reflux, whether physiologic or
pathologic, is the loss of the normal gastroesophageal high-pressure zone and the resistance it imposes
to the flow of gastric juice from an environment of higher pressure, the stomach, to an environment of
lower pressure, the esophagus. This barrier, composed of both anatomic (flap valve and diaphragm) and
physiologic (LES) components, acts to prevent reflux during stressed and unstressed conditions. The key
determinates of the barrier include:
1. The frequency of swallow- and non–swallow-induced transient relaxations of the LES

2. The structural integrity of the LES
3. Anatomic alterations of the diaphragmatic crura and gastroesophageal flap valve represented by the
angle of His
The presence or absence of pathologic esophageal acid exposure (i.e., abnormal 24-hour pH studies) is
not only influenced by the degree of barrier loss but also by esophageal and gastric functional
characteristics including esophageal clearance, intra-abdominal pressure, and gastric emptying
abnormalities.
Transient Relaxation of the Lower Esophageal Sphincter

The lower esophageal high-pressure zone is normally present except in two situations: (a) after a
swallow, when it momentarily relaxes to allow passage of food into the stomach, and (b) when the
fundus is distended with gas, and it is reflexly relaxed to allow venting of the gas (a belch). In 1982,
Dodds et al.79 reported that non–swallow-induced transient relaxations of the lower esophageal
sphincter (TLESRs) were a significant mechanism of gastroesophageal reflux in normal individuals and
patients with GERD. These spontaneous relaxations occurred without pharyngeal contraction, were
prolonged (>10 seconds), and, when reflux occurred, were associated with relaxation of the crural
diaphragm. Underscoring the importance of the crural diaphragm to barrier integrity, Mittal et al.80
1062
booksmedicos.org
later showed that pharmacologic elimination of lower esophageal sphincter pressure to zero did not
result in reflux unless crural diaphragmatic contraction was also absent. Gastric distention, upright
posture, and meals high in fat have all been shown to increase the frequency of TLESRs.80,81 The latter
observations suggest that unfolding of the sphincter may be responsible for the loss of sphincter
pressure.
As a result of these findings, TLESRs became commonly accepted as the major mechanism of
gastroesophageal reflux regardless of the underlying severity of disease, despite evidence to the
contrary. The facts that in over 80% of patients with symptomatic gastroesophageal reflux a hiatal
hernia could be identified and that most patients with erosive esophagitis and Barrett esophagus had
incompetent lower esophageal sphincter characteristics at rest were largely ignored by many. When
these facts are taken into account, particularly in association with the known characteristics of TLESRs,
it seems likely that transient relaxations are (a) a physiologic response to gastric distention by food or
gas, (b) the mechanism of belching, and (c) responsible for physiologic reflux episodes in individuals
with normal lower esophageal sphincter and hiatal anatomy, but not the primary mechanism of GERD.
Evidence supporting this has been provided via studies of Van Herwaarden et al.,82 in which ambulatory
esophageal manometry and esophageal pH monitoring were performed on patients with and without
hiatal hernia. Patients with hiatal hernia had greater esophageal acid exposure and more reflux
episodes, but the frequency of TLESRs, and the proportion associated with reflux, was similar in both
groups. They concluded that excess reflux in patients with GERD and hiatal hernia is caused by a
combination of low LES pressure, swallow-induced relaxation, and straining.
Structural Integrity of the Lower Esophageal Sphincter

In humans a zone of high pressure can be identified at the junction of the esophagus and stomach. This
lower esophageal “sphincter” provides an important component of the barrier between the esophagus
and stomach that normally prevents gastric contents from entering the esophagus. It has no anatomic
landmarks, but its presence can be identified by a rise in pressure over gastric baseline as a pressure
transducer is pulled from the stomach into the esophagus.
There are three characteristics of the lower esophageal sphincter that maintain its resistance or
barrier function to intragastric and intra-abdominal pressure challenges. They are its pressure, its
overall length, and the length exposed to the positive pressure environment of the abdomen (Table 42-
1). The tonic resistance of the lower esophageal sphincter is a function of both its pressure and the
length over which this pressure is exerted.21 The shorter the overall length of the high-pressure zone,
the higher the pressure must be to maintain sufficient resistance to remain competent (Fig. 42-13).
Consequently, a short overall sphincter length can nullify a normal sphincter pressure.12 Further, as the
stomach fills, the length of the sphincter decreases, rather like the neck of a balloon shortening as the
balloon is inflated. If the overall length of the sphincter is abnormally short when the stomach is empty,
then with minimal gastric distention there will be insufficient sphincter length for the existing pressure
to maintain sphincter competency, and reflux will occur.
The third characteristic of the lower esophageal sphincter is its position, in that a portion of the
overall length of the high-pressure zone should be exposed to positive intra-abdominal pressure. During
periods of increased intra-abdominal pressure, the resistance of the lower esophageal sphincter would
be overcome if the abdominal pressure were not applied equally to the high-pressure zone and stomach.
This is akin to sucking on a soft soda straw immersed in a bottle of Coke; the hydrostatic pressure of the
fluid and the negative pressure inside the straw due to sucking cause the straw to collapse instead of
allowing the liquid to flow up the straw in the direction of the negative pressure. If the abdominal
length is inadequate, the sphincter cannot respond to an increase in applied intra-abdominal pressure by
collapsing, and reflux is more liable to result. If the high-pressure zone has an abnormal low pressure, a
short overall length, or minimal exposure to the abdominal pressure environment in the fasting state,
then there is a permanent loss of lower esophageal sphincter resistance and the unhampered reflux of
gastric contents into the esophagus throughout the circadian cycle. This is referred to as a permanently
defective sphincter and is identified by having one or more of the following characteristics: a high-
pressure zone with an average pressure of less than 6 mm Hg, an average overall length of 2 cm or less,
and an average length exposed to the positive pressure environment of the abdomen of 1 cm or less.83
Compared with normal subjects, these values are below the 2.5th percentile for each parameter. The
most common cause of a permanently defective sphincter is an inadequate abdominal length, most
likely a consequence of the development of a hiatal hernia. It is important to note that an inadequate
abdominal length or an abnormally short overall length can nullify the efficiency of a sphincter with a
1063
booksmedicos.org
normal pressure.
The presence of a permanently defective sphincter has several implications. First, it is commonly
associated with esophageal mucosal injury and predicts that the patient’s symptoms may be difficult to
control with medical therapy.23,34 It is now accepted that when the sphincter is permanently defective,
it is irreversible, even when the associated esophagitis is healed. The presence of a permanently
defective sphincter is commonly associated with reduced esophageal body function,84 and if the disease
is not brought under control, the progressive loss of effective esophageal clearance can lead to severe
mucosal injury, repetitive regurgitation, aspiration, and pulmonary failure.
Anatomic Alterations
With the advent of clinical roentgenology, it became evident that a hiatal hernia was a relatively
common abnormality although not always accompanied by symptoms. Philip Allison, in his classic
treatise published in 1951, suggested that the manifestations of GERD were caused by the presence of a
hiatal hernia. For most of the next two decades, hiatal hernia was considered the primary
pathophysiologic abnormality leading to GERD. Indeed, the Allison repair, among the first surgical
attempts to treat GERD, consisted of a hernia repair only. As techniques of esophageal manometry were
developed in the late 1950s and 1960s, allowing identification and study of the lower esophageal
sphincter, attention was slowly diverted away from the hernia as the main pathophysiologic
abnormality of GERD. In 1971, Cohen and Harris85 published a study of the contributions of hiatal
hernia to lower esophageal sphincter competence in 75 patients, concluding that hiatal hernia had no
effect on GE junction competence. This paper, published in the New England Journal of Medicine, and the
growing use of esophageal manometry shifted the emphasis away from the hernia almost exclusively
toward features of the lower esophageal sphincter as the primary abnormality in symptomatic GERD.
Perhaps serendipitously, studies of the phenomenon of TLESRs identified the diaphragmatic crura as
an important factor in preventing reflux during periods of loss of LES pressure.86 In normal subjects,
even with absent LES pressure, reflux does not occur without relaxation of the crural diaphragm.
Coincidentally, Hill et al.87 stressed the importance of the physiologic flap valve created by the angle of
His as a barrier to gastroesophageal reflux. The endoscopic appearance of the flap valve can be
correlated with abnormal esophageal acid exposure, emphasizing that the geometry of the
gastroesophageal region is also important to barrier competence.47 If mechanical forces set in play by
gastric distention are important in pulling on the terminal esophagus and shortening the length of the
high-pressure zone or “sphincter,” then the geometry of the cardia, that is, the presence of a normal
acute angle of His or the abnormal dome architecture of a sliding hiatus hernia, should influence the
ease with which the sphincter is pulled open. Evidence that this occurs was provided by Ismail et al.,16
who showed a close relationship between the degree of gastric distention necessary to overcome the
high-pressure zone (yield pressure) and the morphology of the cardia (Fig. 42-25). No relationship
between the yield pressure and lower esophageal sphincter resting pressure and length was found. A
higher intragastric pressure was needed to open the sphincter in patients with an intact angle of His
when compared to patients with a hiatal hernia. The presence of a hiatal hernia also disturbs esophageal
clearance mechanisms likely due to loss of anchorage of the esophagus in the abdomen. Kahrilas et al.
have shown that complete esophageal emptying was achieved in 86% of swallows in control subjects
without a hiatal hernia, 66% in patients with a reducing hiatal hernia, and only 32% of patients with a
nonreducing hiatal hernia.88 Impaired clearance in patients with nonreducing hiatal hernias further
supports the contribution of hiatal hernia to the pathogenesis of GERD. Thus, present evidence is
overwhelming that hiatal hernia does indeed play a significant, if not primary, role in the
pathophysiology of GERD.
1064
booksmedicos.org
Figure 42-25. The intragastric pressure at which the lower esophagus endoscopically opened in response to gastric distention by
air during endoscopy. Note that the dome architecture of a hiatus hernia (HH) influences the ease with which the sphincter can be
pulled open by gastric distention. (Reproduced with permission from Ismail T, Bancewicz J, Barlow J. Yield pressure, anatomy of
the cardia and gastro-oesophageal reflux. Br J Surg 1995;82:943–947.)
A transient loss of the high-pressure zone can also occur and usually results from a functional problem
of the gastric reservoir.33 Excessive air swallowing or food can result in gastric dilatation and, if the
active relaxation reflex has been lost, an increased intragastric pressure. When the stomach is distended,
the vectors produced by gastric wall tension pull on the GE junction with a force that varies according
to the geometry of the cardia; that is, the forces are applied more directly when a hiatal hernia exists
than when a proper angle of His is present. The forces pull on the terminal esophagus, causing it to be
“taken up” into the stretched fundus and thereby reducing the length of the high-pressure zone or
“sphincter.” This process continues until a critical length is reached, usually about 1 to 2 cm, when the
pressure drops precipitously and reflux occurs. The mechanism by which gastric distention contributes
to shortening of the length of the high-pressure zone, so that its pressure drops and reflux occurs,
provides a mechanical explanation for “transient relaxations” of the LES without invoking a
neuromuscular reflex. Rather than a “spontaneous” muscular relaxation, there is a mechanical
shortening of the high-pressure zone, secondary to progressive gastric distention, to the point where it
becomes incompetent. These “transient sphincter” shortenings occur in the initial stages of GERD and
are the mechanism for the early complaint of excessive postprandial reflux. After gastric venting, the
length of the high-pressure zone is restored and competence returns until distention again shortens it
and encourages further venting and reflux. This sequence results in the common complaints of repetitive
belching and bloating in patients with GERD. The increased swallowing frequency seen in patients with
GERD contributes to gastric distention and is due to their repetitive ingestion of saliva in an effort to
neutralize the acid refluxed into their esophagus.26 Thus, GERD may begin in the stomach, secondary to
gastric distention resulting from overeating and the increased ingestion of fried foods, which delay
gastric emptying. Both characteristics are common in Western society and may explain the high
prevalence of the disease in the Western world.
A recent series of studies from Glasgow assesses the nature of the acid environment at the GE
junction,28 including possible inciting factors in the development of cardia and distal esophageal
adenocarcinoma. The studies were initiated to investigate a long-recognized observation that esophageal
pH monitoring reveals postprandial esophageal acidification at the same time as the gastric contents are
alkalinized. This paradox is hard to explain given that reflux of gastric content into the esophagus is the
primary mechanism underlying GERD. Hypothesizing that acidic material must be present somewhere in
the upper stomach, the investigators studied luminal pH at 1-cm increments across the upper stomach
and lower esophagus in healthy volunteers before and after meals. Surprisingly, they identified a
“pocket” of acid at the GE junction unaffected by the buffering action of the meal, which extended
across the squamocolumnar junction an average of 1.8 cm into the lumen of the esophagus (Fig. 42-26).
The authors concluded that this was the source of postprandial esophageal acid exposure. They
expanded these initial studies, confirming that the same process occurs in patients with endoscopy-
negative dyspepsia and normal conventional esophageal pH monitoring 5 cm above the upper border of
the LES.89 Perhaps more important, they also identified that dietary nitrate consumed in the form of
green vegetables results in the generation of concentrations of nitric oxide at the GE junction high
1065
booksmedicos.org
enough to be potentially mutagenic (Fig. 42-27).90 These observations provide the fundamental basis for
the observations of inflammation and other alterations in the epithelium long known to occur at the
squamocolumnar junction in both overt and unrecognized GERD.
Figure 42-26. Fasting and postprandial gastric and esophageal pH measurements in 1 cm increments during a pull through the
gastroesophageal junction. The postprandial tracing reveals an “acid pocket” from 44 to 41 cm from the nares. The fasting tracing
reveals this to be the same area as the pH “step-up” corresponding to the transition from the stomach to the esophagus.
(Reproduced with permission from Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the
gastroesophageal junction after a meal. Gastroenterology 2001;121:775–783.)
Figure 42-27. Mean (±SEM) nitric oxide concentrations in the upper stomach and lower esophagus after administration of water
with 2 mmol nitrate (upper tracing) and water alone (lower tracing) (**p < 0.01, *p < 0.05 compared with value at
gastroesophageal junction pH step-up). (Reproduced with permission from Iljima K, Henry E, Moriya A, et al. Dietary nitrate
generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction. Gastroenterology 2002;122:1248–
1257.)
The data support the likelihood that GERD begins in the stomach. Fundic distention occurs because of
overeating and delayed gastric emptying secondary to the high-fat Western diet. The distention causes
the sphincter to be “taken up” by the expanding fundus, exposing the squamous epithelium with the
high-pressure zone, which is the distal 3 cm of the esophagus, to gastric juice. Repeated exposure causes
inflammation of the squamous epithelium, columnarization, and carditis. This is the initial step and
explains why in early disease the esophagitis is mild and commonly limited to the very distal esophagus.
The patient compensates by increased swallowing, allowing saliva to bathe the injured mucosa and
alleviate the discomfort induced by exposure to gastric acid. Increased swallowing results in aerophagia,
bloating, and repetitive belching. The distention induced by aerophagia leads to further exposure and
repetitive injury to the terminal squamous epithelium and the development of cardiac-type mucosa. This
is an inflammatory process, commonly referred to as “carditis,” and explains the complaint of epigastric
pain so often registered by patients with early disease. The process can lead to a fibrotic mucosal ring at
the squamocolumnar junction and explains the origin of a Schatzki ring. Extension of the inflammatory
process into the muscularis propria causes a progressive loss in the length and pressure of the distal
esophageal high-pressure zone associated with an increased esophageal exposure to gastric juice and the
symptoms of heartburn and regurgitation. The loss of the barrier occurs in a distal-to-proximal direction
and eventually results in the permanent loss of LES resistance and the explosion of the disease into the
esophagus with all the clinical manifestations of severe esophagitis. This accounts for the observation
that severe esophageal mucosal injury is almost always associated with a permanently defective
sphincter. At any time during this process and under specific luminal conditions or stimuli, such as
1066
booksmedicos.org
exposure time to a specific pH range, intestinalization of the cardiac-type mucosa can occur and set the
stage for malignant degeneration.
Implications
Implications of recognizing anatomic alterations as component of GE barrier:
1. Transient lower esophageal sphincter relaxation is likely a consequence of sphincter shortening by

gastric distention and is the underlying mechanism for belching and physiologic reflux. It does not
play a major role in patients with symptomatic gastroesophageal reflux, particularly those with
erosive disease, Barrett esophagus, or those referred for surgery.
2. Efforts to augment the gastroesophageal barrier either pharmacologically or endoscopically will
commonly fail when a hiatal hernia is present.
3. Patients with abnormal esophageal acid exposure in the presence of normal LES characteristics and no
hiatal hernia have an uncommon reason for reflux and these patients require additional evaluation
since gastric or esophageal clearance failure may be present and may impair the outcome of a
fundoplication.
4. Both reduction of hiatal hernia and augmentation of the lower esophageal sphincter are necessary to
maximally restore gastroesophageal barrier competence.
5. Although acid control without regard to barrier incompetence will improve heartburn and heal
esophageal erosive disease, it results in increasing numbers of patients with pulmonary manifestations
of GERD.
Complications of Gastroesophageal Reflux Disease

The complications of gastroesophageal reflux result from the damage caused by the reflux of gastric
juice onto the esophageal mucosa or laryngeal or respiratory epithelium (Fig. 42-28). Complications can
be conceptually divided into (a) mucosal complications such as esophagitis and stricture; (b)
extraesophageal or respiratory complications such as chronic cough, asthma, and pulmonary fibrosis;
and (c) metaplastic (Barrett esophagus) and neoplastic (adenocarcinoma). The prevalence and severity
of complications is related to the degree of loss of the gastroesophageal barrier, defects in esophageal
clearance, and the content of refluxed gastric juice (Fig. 42-29).
Figure 42-28. Schematic representation of the types of complications of gastroesophageal reflux disease.
Figure 42-29. Prevalence of esophageal mucosal injury related to the presence of a defective lower esophageal sphincter,
1067
booksmedicos.org
esophageal body motility, or both.
Mucosal Complications
The potential injurious components that reflux into the esophagus include gastric secretions, such as acid
and pepsin; biliary and pancreatic secretions that regurgitate from the duodenum into the stomach; and
toxic compounds generated in the mouth, esophagus, and stomach by the action of bacteria on dietary
substances.
Our current understanding of the role of the various ingredients of gastric juice in the development of
esophagitis is based on classic animal studies performed by Lillimoe et al.91,92 These studies have shown
that acid alone does minimal damage to the esophageal mucosa, but the combination of acid and pepsin
is highly deleterious. Hydrogen ion injury to the esophageal squamous mucosa occurs only at a pH
below 2. In acid refluxate, the enzyme pepsin appears to be the major injurious agent. Similarly, the
reflux of duodenal juice alone does little damage to the mucosa, while the combination of duodenal
juice and gastric acid is particularly noxious. Reflux of bile and pancreatic enzymes into the stomach can
either protect or augment esophageal mucosal injury. For instance, the reflux of duodenal contents into
the stomach may prevent the development of peptic esophagitis in a patient whose gastric acid secretion
maintains an acid environment, because the bile salts would attenuate the injurious effect of pepsin and
the acid would inactivate the trypsin. Such a patient would have bile-containing acid gastric juice that,
when refluxed, would irritate the esophageal mucosa but cause less esophagitis than if it were acid
gastric juice–containing pepsin. In contrast, the reflux of duodenal contents into the stomach of a patient
with limited gastric acid secretion can result in esophagitis, because the alkaline intragastric
environment would support optimal trypsin activity and the soluble bile salts with a high pKa would
potentiate the enzyme’s effect. Hence, duodenal-gastric reflux and the acid-secretory capacity of the
stomach interrelate by altering the pH and enzymatic activity of the refluxed gastric juice to modulate
the injurious effects of enzymes on the esophageal mucosa.
This disparity in injury caused by acid and bile alone as opposed to the gross esophagitis caused by
pepsin and trypsin provides an explanation for the poor correlation between the symptom of heartburn
and endoscopic esophagitis. The reflux of acid gastric juice contaminated with duodenal contents could
break the esophageal mucosal barrier, irritate nerve endings in the papillae close to the luminal surface,
and cause severe heartburn. Despite the presence of intense heartburn, the bile salts present would
inhibit pepsin, the acid pH would inactivate trypsin, and the patient would have little or no gross
evidence of esophagitis. In contrast, the patient who refluxed alkaline gastric juice may have minimal
heartburn because of the absence of hydrogen ions in the refluxate but have endoscopic esophagitis
because of the bile salt potentiation of trypsin activity on the esophageal mucosa. This is supported by
recent clinical studies that indicate that the presence of alkaline reflux is associated with the
development of mucosal injury.93
Although numerous studies have suggested the reflux of duodenal contents into the esophagus in
patients with GERD, few have measured this directly. The components of duodenal juice thought to be
most damaging are the bile acids, and as such, they have been the most commonly studied. Most studies
have implied the presence of bile acids using pH measurements. Studies using either prolonged
ambulatory aspiration techniques (Fig. 42-30) or spectrophotometric bilirubin measurement have shown
that, as a group, patients with GERD have greater and more concentrated bile acid exposure to the
esophageal mucosa than normal subjects.23,34 This increased exposure occurs most commonly during the
supine period while asleep and during the upright period following meals. Most studies have identified
the glycine conjugates of cholic, deoxycholic, and chenodeoxycholic acids as the predominant bile acids
aspirated from the esophagus of patients with GERD, although appreciable amounts of taurine
conjugates of these bile acids were also found. Other bile salts were identified but in small
concentrations. This is as one would expect because glycine conjugates are three times more prevalent
than taurine conjugates in normal human bile.
The potentially injurious action of toxic compounds either ingested or newly formed on the mucosa of
the gastroesophageal junction and distal esophagus has long been postulated. Until recently, however,
few studies have substantiated this possibility. Expanding upon studies of acid exposure at the
gastroesophageal junction, investigators from Glasgow, Scotland, have recently shown that dietary
nitrate consumed in the form of green vegetables and food contaminated by nitrate-containing
fertilizers results in the generation of nitric oxide at the gastroesophageal junction in concentrations
high enough to be potentially mutagenic.90 Previous studies have shown that nitrate ingested in food is
reabsorbed in the small bowel, with approximately 25% resecreted into the mouth via the salivary
1068
booksmedicos.org
glands. Oral bacteria chemically transforms the relatively innocuous nitrate to the more toxic nitrite,
which is swallowed and subsequently converted to nitric oxide and other toxic nitroso-compounds by
acid and ascorbic acid in the stomach. Whether this mechanism in fact contributes to injury and/or
neoplastic transformation in the upper stomach, gastroesophageal junction, and distal esophagus is
currently unknown.
Figure 42-30. Peak bile acid concentration (μmol/L) for patients and normal subjects during upright, postprandial, and supine
aspiration periods. The shaded area represents the mean and the bar the 95th percentile values.
Respiratory Complications
It is increasingly recognized that a significant proportion of patients with gastroesophageal reflux will
have either primary RSs or RSs in association with more prominent heartburn and regurgitation.94
Reflux has been implicated as causative of asthma and idiopathic pulmonary fibrosis (IPF) and can
complicate advanced lung diseases including chronic obstructive pulmonary disease (COPD) and cystic
fibrosis (CF). Thirty-five to fifty percent of asthmatics have been shown to have abnormal esophageal
pH, esophagitis, and a hiatal hernia.95 Others have shown that the prevalence of reflux symptoms
exceeded 50% in patients with asthma and CF.96,97 In addition, patients with COPD and
gastroesophageal reflux are twice as likely to have significant COPD exacerbations than their nonreflux
counterparts,98 and reflux symptoms correlate with airway obstruction in COPD patients. These reports
suggest that the frequency of dual pathology is higher than would be expected by chance alone.
Pathophysiology of Reflux-Induced Respiratory Symptoms. Two mechanisms have been proposed

as the pathogenesis of reflux-induced RSs. The first, the so-called “reflux” theory, maintains that RSs are
the result of the aspiration or microaspiration of gastric contents. The second or “reflex” theory
maintains that vagally mediated bronchoconstriction follows acidification of the lower esophagus via a
reflex neurologic arc.
The evidence supporting a reflux mechanism was shown in animals in the 1950s to 1970s, with studies
of acid instillation in the lungs resulting in pneumonitis,99,100 epithelial damage,101 and increased airway
resistance.102 The evidence in humans can be categorized as follows. First, there is radiographic
evidence. Patients with pulmonary fibrosis have an increased prevalence of hiatal hernia on upper GI
series,103,104 while elderly patients with large hiatal hernias have a significantly increased frequency of
pleural scarring on chest CT scans.105 Second, erosive esophagitis was found at a high frequency in a
large series of Veterans Affairs patients with asthma, pneumonia, chronic bronchitis, and pulmonary
fibrosis.94 Third, patients with chronic lung diseases, including asthma and pulmonary fibrosis in
particular, have a significantly higher frequency of positive 24-hour pH studies.105,106 With dual pH
monitoring of the proximal and distal esophagus, prolonged exposure of the proximal esophagus to
gastric juice occurs at a higher frequency in patients with gastroesophageal reflux and RSs than in
patients without respiratory complaints.107,108 Fourth, simultaneous tracheal and esophageal pH
monitoring in patients with reflux disease have documented tracheal acidification in concert with
esophageal acidification.102 Finally, medications used to treat chronic lung diseases, in particular,
bronchodilators, relax esophageal sphincter tone.109
A reflex mechanism is primarily supported by the fact that bronchoconstriction occurs following the
infusion of acid into the lower esophagus.110–112 This can be explained by the common embryologic
1069
booksmedicos.org
origin of the tracheoesophageal tract and its shared vagal innervation.
The primary challenge in implementing treatment for reflux-associated RSs lies in establishing the
diagnosis. In those patients with predominantly typical reflux symptoms and secondary respiratory
complaints, the diagnosis may be straightforward. However, in a substantial number of patients with
reflux-induced RSs, the RSs dominate the clinical scenario. Gastroesophageal reflux in these patients is
often silent and is only uncovered when investigation is initiated.106,113 A high index of suspicion is
required, notably in patients with poorly controlled asthma in spite of appropriate bronchodilator
therapy. Supportive evidence for the diagnosis can be gleaned from endoscopy and stationary
esophageal manometry. Endoscopy may show erosive esophagitis or Barrett esophagus. Manometry
may indicate a hypotensive lower esophageal sphincter or ineffective body motility, defined by 30% or
more contractions in the distal esophagus of less than 30 mm Hg in amplitude.114 D’Ovidio et al.115
studied 78 patients awaiting lung transplant for IPF, scleroderma, COPD, or CF and found that 72% had
a hypotensive lower esophageal sphincter, 33% abnormal esophageal body motility, and 38% abnormal
24-hour pH testing, although, interestingly, patients with IPF in other series have been shown to have
normal manometry.108
The current “gold standard” for the diagnosis of reflux-induced respiratory complaints is ambulatory
dual-probe pH monitoring, often combined with multichannel intraluminal impedance (MII-pH). One
probe is positioned in the distal esophagus and the other at a more proximal location. Sites for proximal
probe placement have included the trachea, pharynx, and proximal esophagus. Most authorities would
agree that the proximal esophagus is the preferred site for proximal probe placement. While ambulatory
esophageal pH monitoring allows a direct correlation between esophageal acidification and RSs, the
chronologic relationship between reflux events and bronchoconstriction is complex. Further, the
proximal probe must be positioned close to, but not above, the UES. Failure to properly place the probe
can lead to artifact or errors in pH assessment. In addition, the use of a pH threshold of 4 as is used in
the distal esophagus is questioned. Normal subjects should have a pH ≥7 in the cervical esophagus for
at least 19.6% of the monitored period. Looking at pH exposure in reverse, in other words as loss of the
normal alkalinity in the cervical esophagus, was shown to be a more sensitive indicator of proximal
reflux.116 Recently the use of a special pH probe designed for the environment of the pharynx has been
advocated in patients with RSs to evaluate for proximal reflux. This probe, called the Restech pH probe
(Respiratory Technology Corp, San Diego, CA, USA), has been shown to better predict successful relief
of extraesophageal RSs with a fundoplication compared to the traditional dual-probe pH test.117 Of
importance, the Restech analysis uses a pH threshold of 5.5 for upright and 5.0 for supine reflux, and
the Ryan score is used to determine normal from abnormal pharyngeal reflux exposure.116 Probably the
best pH monitoring method in these patients is to start with a 48-hour Bravo pH and if that is normal on
both days then add a Restech pH test.117
Laryngopharyngeal Reflux
The term LPR is used for a broad category of atypical symptoms that may be secondary to
gastroesophageal reflux. These may include laryngitis, pharyngitis, hoarseness, sinusitis, sleep
disturbance, dental erosions, and globus.118,119 Mechanisms for these symptoms are difficult to prove
and substantial evidence remains lacking.120
Treatment of Extraesophageal Complications. Once gastroesophageal reflux is suspected or thought

to be responsible for extraesophageal symptoms, treatment may be with either prolonged PPI therapy
or antireflux surgery. Initially, a 3- to 6-month trial of high-dose PPI therapy (b.i.d. or t.i.d. dosing)
may help confirm (by virtue of symptom resolution) the fact that reflux is partly or completely
responsible for the symptoms. If symptoms are improved, patients can be treated with maintenance
medical therapy or may be offered surgical treatment to control the reflux. The persistence of symptoms
despite PPI treatment, however, does not necessarily rule out reflux as being a potential contributor.
Algorithm 42-1 bases clinical decisions on the results of dual-probe 24-hour pH monitoring and is a
useful starting point.
1070
booksmedicos.org
Algorithm 42-1. 24-Hour Esophageal pH Monitoring
Based on reported observations, relief of RSs can be anticipated for 25% to 50% of patients with
reflux-induced asthma treated with antisecretory medications,121–123 although patients with pulmonary
fibrosis in particular may have an inherent resistance to standard-dose PPIs.124 Fewer than 15% of
asthmatics with symptom relief, however, can be expected to have objective improvements in their
pulmonary function. The reason for this apparent paradox may be that most studies employed relatively
short courses of antisecretory therapy (<3 months). This time period may have been sufficient for
symptomatic improvement but insufficient for recovery of pulmonary function. The chances of success
with medical treatment are likely directly related to the extent of reflux elimination. The conflicting
findings of reports of antisecretory therapy may well be due to inadequate control of gastroesophageal
reflux in some studies. The literature indicates that antireflux surgery improves RSs in nearly 90% of
children and 70% of adults with asthma and reflux disease.123,125 Improvements in pulmonary function
were demonstrated in around one-third of patients. Comparison of the results of uncontrolled studies of
each form of therapy and the evidence from the two randomized controlled trials of medical versus
surgical therapy indicate that fundoplication is the most effective therapy for reflux-induced asthma.125
The superiority of the surgical antireflux barrier over medical therapy is probably most noticeable in the
supine posture, which corresponds with the period of acid breakthrough with PPI therapy and is the
time in the circadian cycle when asthma symptoms and peak expiratory flow rates are at their worst.
More convincing data establishing the benefit of antireflux surgery in improving RSs and pulmonary
function tests derives from the lung transplantation literature. Bronchiolitis obliterans syndrome (BOS),
synonymous with chronic rejection of the transplanted lung, is diagnosed by a greater than 20% decline
in pulmonary function tests from posttransplant baseline. Lau et al. showed in the early 2000 that 67%
of 18 patients with BOS had an improvement in their pulmonary function tests after antireflux
surgery.126 More recently, several groups have reported improvements in oxygen requirements and
stabilization of declining pulmonary function tests when pre–lung transplant patients underwent
antireflux surgery.127,128 In addition, pulmonary and other extraesophageal symptoms can improve after
laparoscopic Nissen fundoplication with minimal perioperative morbidity.129
It is also important to realize that, in asthmatic patients with a non–reflux-induced motility
abnormality of the esophageal body, performing an antireflux operation may not prevent the aspiration
of orally regurgitated, swallowed liquid or food. This can result in RSs and airway irritation that may
elicit an asthmatic reaction. This factor may be the explanation why surgical results appear to be better
in children than adults, since disturbance of esophageal body motility is more likely in adult patients.
Metaplastic (Barrett) and Neoplastic (Adenocarcinoma) Complications
The condition whereby the tubular esophagus is lined with columnar epithelium rather than squamous
epithelium was first described by Norman Barrett in 1950 (Fig. 42-31).130 He incorrectly believed it to
be congenital in origin. It is now realized that it is an acquired abnormality, occurring in 7% to 10% of
patients with GERD, and represents the end stage of the natural history of this disease.131 It is also
understood to be distinctly different from the congenital condition in which islands of mature gastric
columnar epithelium are found in the upper half of the esophagus.
The definition of Barrett esophagus has evolved considerably over the past decade.130–133
Traditionally, Barrett esophagus was identified by the presence of any columnar mucosa extending at
1071
booksmedicos.org
least 3 cm into the esophagus. Recent data indicating that specialized intestinal-type epithelium is the
only tissue predisposed to malignant degeneration, coupled with the finding of a similar risk of
malignancy in segments of intestinal metaplasia less than 3 cm long, have resulted in the diagnosis of
Barrett esophagus, given any length of endoscopically visible tissue that is intestinal metaplasia on
histology (Fig. 42-32). Whether to call long segments of columnar mucosa without intestinal metaplasia
Barrett esophagus is unclear. The hallmark of intestinal metaplasia is the presence of goblet cells.
Recent studies have identified a high prevalence of biopsy-proven intestinal metaplasia at the cardia, in
the absence of endoscopic evidence of a CLE. The significance and natural history of this finding remain
unknown. The term Barrett esophagus should currently be used in the setting of an endoscopically visible
segment of intestinal metaplasia of any length or columnar replacement of the esophagus of 3 cm or
more.
Figure 42-31. Endoscopic appearance of Barrett esophagus. Note the pink metaplastic mucosa as opposed to the normal whitish
squamous lining of the esophagus.
Factors predisposing to the development of Barrett esophagus include early-onset GERD, abnormal
lower esophageal sphincter and esophageal body physiology, and mixed reflux of gastric and duodenal
contents into the esophagus.133 Direct measurement of esophageal bilirubin exposure as a marker for
duodenal juice has shown that 58% of the patients with GERD have increased esophageal exposure to
duodenal juice and that this exposure is most dramatically related to Barrett esophagus.134
Pathophysiology of Barrett Metaplasia. Recent studies suggest that the metaplastic process at the
gastroesophageal junction may begin by conversion of distal esophageal squamous mucosa to cardiac-
type epithelium, heretofore presumed to be a normal finding.132 This is likely due to exposure of the
distal esophagus to excess acid and gastric contents via prolapse of esophageal squamous mucosa into
the gastric environment. This results in inflammatory changes at the gastroesophageal junction and/or a
metaplastic process, both of which may result in the loss of muscle function and a mechanically
defective sphincter allowing free reflux with progressively higher degrees of mucosal injury. Intestinal
metaplasia within the sphincter may result, as in Barrett metaplasia of the esophageal body. This
mechanism is supported by the finding that as the severity of GERD progresses, the length of columnar
lining above the anatomic gastroesophageal junction is increased.
Figure 42-32. Histologic appearance of Barrett esophagus. To the left of the photograph, columnar mucosa with abundant goblet
1072
booksmedicos.org
cells is seen. This is intestinal metaplasia, which is the histologic hallmark of Barrett esophagus. To the right of the
photomicrograph, cardiac epithelium is present.
Treatment. The relief of symptoms remains the primary force driving antireflux surgery in patients
with Barrett esophagus. Healing of esophageal mucosal injury and the prevention of disease progression
are important secondary goals. In this regard, patients with Barrett esophagus are no different than the
broader population of patients with gastroesophageal reflux. Antireflux surgery should be considered
when patient factors suggest severe disease or predict the need for long-term medical management,
both of which are almost always true in patients with Barrett esophagus.
PPI therapy, both to relieve symptoms and to control any coexistent esophagitis or stricture, is an
acceptable treatment option in patients with Barrett esophagus. Once initiated, however, most patients
with Barrett esophagus will require life-long treatment. Complete control of reflux with PPI therapy can
be difficult, however, as has been highlighted by studies of acid breakthrough while on therapy. Katzka
and Castell, and Ouatu-Lascar and Triadafilopolous have shown that 40% to 80% of patients with
Barrett esophagus continue to experience abnormal esophageal acid exposure despite up to 20 mg twice
daily of PPI.135,136 Ablation trials have shown that mean doses of 56 mg of omeprazole are necessary to
normalize 24-hour esophageal pH studies.137 Antireflux surgery likely results in more reproducible and
reliable elimination of reflux of both acid and duodenal content, although long-term outcome studies
suggest that as many as 25% of patients postfundoplication will have persistent pathologic esophageal
acid exposure confirmed by 24-hour pH studies.138
An important consideration is that patients with Barrett esophagus generally have severe GERD, with
its attendant sequelae such as large hiatal hernia, stricture, shortened esophagus, and poor motility.
Compared to mild and nonerosive reflux disease, severe erosive disease and Barrett esophagus are
associated with significantly greater loss of the mechanical antireflux barrier because of associated
hiatal hernias and a hypotensive lower esophageal sphincter. Surgical treatment with a laparoscopic
Nissen fundoplication reduces the hiatal hernia, improves the antireflux barrier, and consequently
provides similarly excellent symptom control.139 Large studies in patients with typical acid reflux
symptoms have been published from the United States and Europe.140–143 In patients having
laparoscopic Nissen fundoplication at Emory University, relief of heartburn and regurgitation occurred
in 90%, and 70% were off all reflux medications at a mean follow-up of 11 years.144 These results
emphasize the durability of the procedure as well as the persistent relief of typical symptoms. Risk
factors for persistent use of antacids after antireflux surgery include a partial fundoplication, older age,
and female gender.145
Studies focusing on the symptomatic outcome following antireflux surgery in patients with Barrett
esophagus document excellent to good results in 72% to 95% of patients at 5 years following
surgery.138–140 The outcome of laparoscopic Nissen fundoplication in patients with Barrett esophagus has
been assessed at 1 to 3 years after surgery. Hofstetter et al. reported the experience at the University of
Southern California (USC) in 85 patients with Barrett esophagus at a median of 5 years after surgery.
Fifty-nine had long- and 26 short-segment Barrett esophagus and 50 underwent a laparoscopic antireflux
procedure.138 Reflux symptoms were absent postoperatively in 79% of the patients. Postoperative 24-
hour pH was normal in 17 of 21 patients (81%). Ninety-nine percent of the patients considered
themselves cured or improved and 97% were satisfied with the surgery. In addition to symptomatic
improvement in reflux after surgery, there is evidence that mediators of esophageal inflammation
implicated in carcinogenesis are decreased as well. Cyclooxygenase-2 (COX-2) gene expression is
elevated in the distal esophagus of reflux patients, but the expression of COX-2 and another
inflammatory mediator, interleukin 8, can be decreased in the distal esophageal mucosa after a
fundoplication.146–148
1073
booksmedicos.org
Figure 42-33. Histologic appearance of Barrett esophagus. To the left of the photograph, columnar mucosa with abundant goblet
cells is seen. This is intestinal metaplasia, which is the histologic hallmark of Barrett esophagus. To the right of the
photomicrograph, cardiac epithelium is present.
The Development of Dysplasia in Barrett Esophagus. The prevalence of dysplasia at diagnosis in

patients presenting with Barrett esophagus ranges from 15% to 25%, and approximately 5% of patients
will develop dysplasia each year. The identification of dysplasia in Barrett epithelium rests on histologic
examination of biopsy specimens. The cytologic and tissue architectural changes are similar to those
described in ulcerative colitis (Fig. 42-33). By convention, Barrett metaplasia is currently classified into
four broad categories:
1. No dysplasia
2. Indefinite for dysplasia
3. Low-grade dysplasia
4. High-grade dysplasia
There are few prospective studies documenting the progression of nondysplastic Barrett epithelium to
low- or high-grade dysplasia. Those that are available suggest that 5% to 6% per year will progress to
dysplasia and 0.5% to 1% per year to adenocarcinoma (Table 42-2). Several newer studies have
suggested a lower rate, but these studies excluded patients that progressed within the first year of
follow-up, and in one study included those with a CLE with or without intestinal metaplasia. Once
identified, Barrett esophagus complicated by dysplasia should undergo aggressive therapy. Patients
whose biopsies are interpreted as indefinite for dysplasia should be treated with a medical regimen
consisting of 60 to 80 mg of PPI therapy for 3 months and rebiopsied. Importantly, esophagitis should
be healed prior to interpretation of the presence or absence of dysplasia. The presence of severe
inflammation makes the microscopic interpretation of dysplasia difficult. The purpose of acid
suppression therapy is to resolve inflammation that may complicate the interpretation of the biopsy
specimen. Persistent indefinite or low-grade dysplasia should be a relative indication for a Nissen
fundoplication given the evidence that in most patients low-grade dysplasia reverts to nondysplastic
intestinal metaplasia after a fundoplication. Alternatively, or if dysplasia persists after a fundoplication,
it should be ablated using radiofrequency or cryotherapy devices given evidence that ablation reduces
the risk of progression to cancer in these patients.
DIAGNOSIS
Table 42-2 Development of Dysplasia: Prospective Evaluation of 62 Patients
HGD should be confirmed by two pathologists knowledgeable in GI pathology. Numerous

esophagectomy series have shown that approximately 50% of patients thought to have only HGD will
harbor a focus of invasive carcinoma somewhere in the columnar mucosa.149–151 Any patient with
dysplasia, particularly HGD, requires careful endoscopic evaluation preferably with a high-definition
endoscope and NBI or similar technology to look for any nodules or lesions. These lesions are sites of
potential invasive cancer. If no lesion is present then the columnar mucosa should be ablated since
randomized trials have confirmed the benefit of ablation to reduce the risk of progression to cancer in
patients with HGD.
If a lesion is present it must be excised using ER techniques to determine if it is malignant and allow
assessment of the depth of invasion and tumor characteristics. The aim of EMR is to excise the area of
interest including the mucosal and submucosal layers down to the muscularis propria allowing optimal
histologic interpretation. Over a decade ago the authors showed in a small series that EMR reliable
1074
booksmedicos.org
removed superficial esophageal adenocarcinomas and provided an excellent pathologic specimen for
evaluation. Until recently, esophagectomy was considered the standard of care for patients with HGD or
a superficial adenocarcinoma. Subsequently, high-volume esophageal centers in Europe and the United
States began offering endoscopic therapy for these lesions in appropriate patients. The authors have
confirmed that the oncologic outcome is similar in patients with HGD or intramucosal adenocarcinoma
whether they were treated with esophagectomy or endoscopic therapy, but the morbidity and mortality
rates were significantly lower with endoscopic therapy. The largest study on endoscopic therapy alone
for intramucosal adenocarcinoma comes from Wiesbaden, Germany. In this study of 1,000 patients there
was no procedure-related mortality and only a 2% major complication rate. After a mean follow-up
period of 56.6 months 96% of patients had achieved a complete response. Esophagectomy for failed
endotherapy was necessary in only 12 patients (3.7%). Metachronous lesions or local recurrence
developed in 140 patients (14.5%), but was successfully retreated endoscopically in 79% of patients.
The calculated 10-year overall survival was 75%, and only two patients died from esophageal
adenocarcinoma. These excellent results should make endoscopic therapy the preferred therapy for
intramucosal adenocarcinoma in appropriate patients. Risk factors for failure of endoscopic therapy are
still being identified, but include ultra–long segment (>8 cm) Barrett’s, poorly controlled reflux
disease, and high-grade tumor differentiation. Tumors associated with an increased risk for lymph node
metastases include those with lymphovascular invasion, size >2 cm, and invasion into the submucosa.
Treatment of Gastroesophageal Reflux Disease

Medical Treatment
GERD is one of the most prevalent conditions encountered in general medical practice. As a result,
medications for control of GERD comprise one of the largest pharmaceutical markets in the United
States and abroad. Since PPIs were introduced in the United States in 1989, a number of different agents
have emerged, each with substantial penetration in the marketplace. Data from the year 2004 reveal
that, of the top 10 expenditures for medications in the United States, the third highest dollar amount
was spent on Prevacid (lansoprazole, TAP Pharmaceutical Products, Inc., Lake Forest, Illinois; $4.0
billion), while the fourth highest was on Nexium (esomeprazole magnesium, AstraZeneca
Pharmaceuticals, Wilmington, Delaware; $3.6 billion).152,153
GERD is such a common condition that most patients with mild symptoms carry out self-medication,
particularly now that generic and over-the-counter H2-receptor antagonists (H2RAs) and PPIs have
become widely available. When first seen with symptoms of heartburn or regurgitation without obvious
complications, patients can reasonably be placed on 8 to 12 weeks of acid suppression therapy before
extensive investigations are carried out. In many situations, symptoms successfully resolve. Patients
should be advised to elevate the head of the bed; avoid tight clothing; eat small, frequent meals; avoid
eating their nighttime meal shortly before retiring; lose weight; and avoid alcohol, coffee, chocolate,
and peppermints, which may aggravate the symptoms. Medications to promote gastric emptying, such
as metoclopramide, are beneficial in early disease but of little value in more severe disease.
The mainstay of maintenance medical therapy is acid suppression. Patients with persistent symptoms
should be given PPIs, such as omeprazole. In doses as high as 40 mg/day, they can effect an 80% to
90% reduction in gastric acidity. Such a regimen usually heals mild esophagitis, but healing may occur
in only three-fourths of patients with severe esophagitis. It is important to realize that in patients who
reflux a combination of gastric and duodenal juice, inadequate acid suppression therapy may give
symptomatic improvement while still allowing mixed reflux to occur. This can result in an environment
that allows persistent mucosal damage in an asymptomatic patient. Unfortunately, within 6 months of
discontinuation of any form of medical therapy for GERD, 80% of patients have a recurrence of
symptoms.154
In patients with reflux disease, esophageal acid exposure is reduced by up to 80% with H2RAs and up
to 95% with PPIs. Despite the superiority of the latter class of drug over the former, periods of acid
breakthrough still occur.155,156 Breakthrough occurs most commonly at nighttime and is some
justification for a split rather than a single dosing regimen. Katzka et al.155 studied 45 patients with
breakthrough reflux symptoms while on omeprazole 20 mg b.i.d. and found that 36 patients were still
refluxing, defined by a total distal esophageal acid exposure greater than 1.6%. Peghini et al.156
employed intragastric pH monitoring in 28 healthy volunteers and 17 patients with reflux disease and
found that nocturnal recovery of acid secretion (more than 1 hour) occurred in 75% of the individuals.
1075
booksmedicos.org
Recovery of acid secretion occurred within 12 hours of the oral evening dose of PPI, the median
recovery time being 7.5 hours. This is particularly pertinent because it is during the nighttime and early
morning that asthma symptoms are most pronounced and that peak expiratory flow rate is at its lowest.
Ranitidine 300 mg at bedtime appears superior to omeprazole 20 mg at bedtime in preventing acid
breakthrough, likely due to the abolition of histamine-mediated acid secretion in the fasting state.
An accumulating body of literature suggests potential adverse consequences to long-term acid
suppressive therapy. A population-based cohort study from the Netherlands covering the years 1995–
2002 revealed higher incidence rates of community-acquired pneumonia in patients using H2RAs or PPIs
compared to those who never used them or those who had used them previously but stopped.157 The
risk was most pronounced for PPIs and showed a clear dose–response relationship. Other studies have
focused on the association between acid suppression and the development of osteoporosis-related
fractures.158–160 Of note, a population-based study from the United Kingdom assessed the risk of hip
fractures from long-term PPI therapy.158 The study covered the years 1987–2003 and compared users of
PPI therapy to nonusers of any acid suppressive medication. The risk of hip fracture was significantly
increased in patients prescribed long-term high-dose PPI, and the strength of the association increased
with increasing duration of PPI therapy. The authors conjectured that calcium malabsorption secondary
to chronic acid suppression may potentially explain the positive association. Other concerning side
effects of PPI use have surfaced and include interactions with antiplatelet medications and a recent
association with an increased risk for acute myocardial infarction.
Failure of acid suppression to control symptoms or immediate return of symptoms after stopping
treatment suggests that either the diagnosis is incorrect or the patient has relatively severe disease.
Endoscopic examination at this stage of the patient’s evaluation provides the opportunity for assessing
the severity of mucosal damage and the presence of Barrett esophagus. Both of these findings on initial
endoscopy predict a high risk for medical failure. A measurement of the degree and pattern of
esophageal exposure to gastric juice, with 24-hour pH monitoring, should be obtained at this point. The
status of the LES and the function of the esophageal body should also be assessed. These studies identify
features that predict a poor response to medical therapy, frequent relapses, and the development of
complications and include supine reflux, poor esophageal contractility, erosive esophagitis, a CLE, and a
structurally defective sphincter. Patients who have these risk factors should be given the option of
surgery as a primary therapy with the expectation of long-term control of symptoms and complications.
Antireflux Surgery
Indications. Antireflux surgery is indicated for the treatment of objectively documented, relatively
severe GERD. Candidates for surgery include not only patients with erosive esophagitis, stricture, and
Barrett esophagus but also those without severe mucosal injury who are dependent on PPIs for
symptom relief. Patients with atypical or RSs who have a good response to intensive medical treatment
are also candidates. The option of antireflux surgery should be given to all patients who have
demonstrated the need for long-term medical therapy, particularly if escalating doses of PPIs are needed
to control symptoms. Antireflux surgery may be the preferred option in patients younger than 50 years,
those who are noncompliant with their drug regimen, those for whom medications are a financial
burden, and those who favor a single intervention over long-term drug treatment. It may be the
treatment of choice in patients who are at high risk of progression despite medical therapy. Although
this population is not well defined, risk factors that predict progressive disease and a poor response to
medical therapy include (a) nocturnal reflux on 24-hour esophageal pH study, (b) a structurally
deficient LES, (c) mixed reflux of gastric and duodenal juice, and (d) mucosal injury at presentation.161
Preoperative Evaluation. Successful antireflux surgery is largely defined by two objectives: the
achievement of long-term relief of reflux symptoms and the absence of complications or complaints
after the operation. In practice, achieving these two deceptively simple goals is difficult. Both are
critically dependent on establishing that the symptoms for which the operation is performed are the
result of excess esophageal exposure to gastric juice, as well as the proper performance of the
appropriate antireflux procedure. Success can be expected in the vast majority of patients if these two
criteria are met. The status of the LES is not as important a factor as in the days of open surgery.
Patients with normal resting sphincters are often selected for antireflux surgery in the era of
laparoscopic fundoplication. The outcome is not dependent on sphincter function. There are four
important goals of the diagnostic approach to patients suspected of having GERD and being considered
for antireflux surgery (Table 42-3).
1076
booksmedicos.org
DIAGNOSIS
Table 42-3 Goals of the Diagnostic Approach to Patients Suspected of Having
GERD and Being Considered for Antireflux Surgery
The introduction of laparoscopic access, coupled with the growing recognition that surgery is a safe
and durable treatment for GERD, has dramatically increased the number of patients being referred for
laparoscopic fundoplication compared to the prelaparoscopic era. Recent data suggest that the peak use
of antireflux surgery in the United States occurred in 1999, with an estimated 15.7 cases per 100,000
adults at that time.162 Since then, the frequency of antireflux surgery has declined, such that an
estimated 11 antireflux procedures were performed per 100,000 adults in 2003. This recent decline may
reflect the availability of generic and over-the-counter PPIs, a constantly evolving menu of endoscopic
antireflux therapies, increased utilization of Roux-en-Y gastric bypass for control of GERD in morbidly
obese individuals, and the long-term efficacy of fundoplication being called into question. Given the
various therapies for GERD, each with its potential advantages and shortcomings, accurate and
contemporary data regarding outcomes after antireflux surgery are necessary as a basis against which
other established and novel therapies must be judged.
Given the large number of surgical referrals, the importance of selecting patients for surgery who are
likely to have a successful outcome cannot be overemphasized. Although a Nissen fundoplication will
reliably and reproducibly halt the return of gastroduodenal juice into the esophagus, little benefit is
likely if the patient’s symptoms are not caused by this specific pathophysiologic derangement. Thus, in
large part, the anticipated success rate of laparoscopic fundoplication is directly proportional to the
degree of certainty that GERD is the underlying cause of the patient’s complaints.
Table 42-4 Predictors of Outcome after Laparoscopic Fundoplication: Stepwise

Logistic Regression Results of 199 Patients
Three factors predictive of a successful outcome following antireflux surgery have emerged (Table 42-
4).163 These are (a) an abnormal score on 24-hour esophageal pH monitoring; (b) the presence of typical
symptoms of GERD, namely, heartburn or regurgitation; and (c) symptomatic improvement in response
to acid suppression therapy prior to surgery. It is immediately evident that each of these factors helps to
establish that GERD is indeed the cause of the patient’s symptoms and that they have little to do with
the severity of the disease.
Endoscopic Assessment. Endoscopic visualization of the esophagus equates to the physical

examination of the foregut and is a critical part of the preoperative evaluation of patients with GERD.
Its main aim is to detect complications of GE reflux, the presence of which may influence therapeutic
decisions.
In every patient, the locations of the diaphragmatic crura, the GE junction, and the squamocolumnar
junction are determined. These anatomic landmarks are commonly at three different sites in patients
with GERD. The crura are usually evident and can be confirmed by having the patient sniff during the
1077
booksmedicos.org
examination. The anatomic GE junction is identified as the point where the gastric rugal folds meet the
tubular esophagus and is often below the squamocolumnar junction, even in patients without otherwise
obvious Barrett esophagus.
Endoscopic esophagitis is defined by the presence of mucosal erosions (Table 42-5). When present,
the grade and length of esophageal mucosal injury are recorded. The presence and length of columnar
epithelium extending above the anatomic GE junction is also noted. CLE is suspected at endoscopy when
there is difficulty in visualizing the squamocolumnar junction at its normal location and by the
appearance of a velvety red luxuriant mucosa. The presence of Barrett esophagus is confirmed by biopsy
evidence of specialized intestinal metaplasia involving the tubular esophagus and is considered
histologic evidence of GERD. Endoscopic visualization of columnar lining without histologic
confirmation of specialized intestinal metaplasia is not considered Barrett esophagus and likely has no
premalignant potential. Multiple biopsies should be taken in a cephalad direction to determine the level
at which the junction of Barrett epithelium and normal squamous mucosa occurs. Barrett esophagus is
susceptible to ulceration, bleeding, stricture formation, and malignant degeneration. Dysplasia is the
earliest sign of malignant change. Because dysplastic changes typically occur in a random distribution
within the distal esophagus, a minimum of four biopsies (each quadrant) every 2 cm should be obtained
from the metaplastic epithelium. Particular attention must be paid to the squamocolumnar junction in
these patients, where a mass, ulcer, nodularity, or inflammatory tissue is always considered suspicious
for malignancy and requires thorough biopsy or ER. The GE junction is defined endoscopically where
the tubular esophagus meets gastric rugal folds, and the squamocolumnar junction is where there is an
obvious change from the velvety and darker columnar epithelium to the lighter squamous epithelium.
CLASSIFICATION
Table 42-5 Modified Los Angeles Classification of Esophagitis
After completion of the esophageal examination, the first and second portions of the duodenum and
the stomach are systematically inspected. This is commonly done on withdrawal of the endoscope.
When the antrum is visualized, the incisura angularis appears as a constant ridge on the lesser curve.
Turning the lens of the scope 180 degrees allows inspection of the fundus and cardia. Attention is paid
to the frenulum (angle of His) of the esophagogastric junction and to the closeness with which the
cardia grips the scope. Hill et al.87 have graded the appearance of this valve on a scale from I to IV
according to the degree of unfolding or deterioration of the normal valve architecture. This grading
system has been correlated with the presence of increased esophageal acid exposure, occurring
predominantly in patients with a grade III or IV valve.
A hiatal hernia is endoscopically confirmed by finding a pouch lined with gastric rugal folds lying 2
cm or more above the margins of the diaphragmatic crura. A prominent sliding hernia is frequently
associated with increased esophageal exposure to gastric juice. When a PEH exists, particular attention
is given to exclude a gastric ulcer or gastritis within the pouch. The term Cameron erosions refers to such
mucosal erosions occurring in large sliding or PEHs, typically at the level of the diaphragmatic hiatus.
The intragastric retroflex or “J” maneuver is important in evaluating the full circumference of the
mucosal lining of the herniated stomach. As the endoscope is removed, the esophagus is again examined
and biopsies taken. The location of the cricopharyngeus is identified and the larynx and vocal cords are
visualized. Acid reflux may result in inflammation of the larynx. Vocal cord movement is recorded both
as a reference for subsequent surgery and an assessment of the patient’s ability to protect the airway.
Twenty-Four Hour Ambulatory pH Monitoring. The most direct method of assessing the relationship
between symptoms and GERD is to measure the esophageal exposure to gastric juice with an indwelling
1078
booksmedicos.org
pH electrode. Miller164 first reported prolonged esophageal pH monitoring in 1964, although it was not
until 1973 that its clinical applicability and advantages were demonstrated by Johnson and
DeMeester.165 Ambulatory pH testing is considered by many to be the “gold standard” for the diagnosis
of GERD, because it has the highest sensitivity and specificity of all tests currently available. Some
experts have suggested that 24-hour pH monitoring be used selectively, limited to patients with atypical
symptoms or no endoscopic evidence of GE reflux. Given present-day referral patterns, more than half
of the patients referred for antireflux surgery will have no endoscopic evidence of mucosal injury. For
these patients, 24-hour pH monitoring provides the only objective measure of the presence of
pathologic esophageal acid exposure. Although it is true that most patients with typical symptoms and
erosive esophagitis have a positive 24-hour pH result, the pH study provides other useful information. It
quantifies the actual time that the esophageal mucosa is exposed to gastric juice, measures the ability of
the esophagus to clear refluxed acid, and correlates esophageal acid exposure with the patient’s
symptoms. It is the only way to quantitatively express the overall degree and pattern of esophageal acid
exposure, both of which may impact the decision toward surgery.166 Patients with nocturnal or
bipositional reflux have a higher prevalence of complications and failure of long-term medical control.
For these reasons, we continue to advocate the routine use of pH monitoring in clinical practice.
Table 42-6 Normal Values for Esophageal Exposure to pH <4 in 50 Subjects
Present technology includes both transnasal catheter-based pH probes and an implantable capsule
(Bravo pH system, Medtronic Corporation, Minneapolis, Minnesota) placed under endoscopic
guidance.166–168 The units used to express esophageal exposure to gastric juice are (a) cumulative time
the esophageal pH is below a chosen threshold, expressed as the percent of the total, upright, and
supine monitored time; (b) frequency of reflux episodes above a chosen threshold, expressed as number
of episodes per 24 hours; and (c) duration of the episodes, expressed as the number of episodes greater
than 5 minutes per 24 hours and the time in minutes of the longest episode recorded. Table 42-6 shows
the normal values for these components of the 24-hour record at the whole number pH threshold
derived from 50 normal, asymptomatic subjects. The upper limits of normal were established at the
95th percentile. Most centers use pH 4 as the threshold. Combining the result of the six components into
one expression that reflects the overall esophageal acid exposure below a pH threshold, a pH score was
calculated by using the standard deviation of the mean of each of the six components measured.
Several limitations exist, however, to standard pH monitoring: nonacid reflux events are not detected,
the height and quantity of refluxate above the gastroesophageal junction are not defined, and the
physical nature of the refluxed material (i.e., liquid, gas, or a mixture) cannot be differentiated. As
reflux symptoms such as regurgitation and cough may be present in the absence of demonstrable reflux
of acid, improved modalities for detection of nonacid refluxate may be clinically important.
Ambulatory Combined Impedance–pH Monitoring. New technology has been introduced into
clinical practice that allows for detection of both acid and nonacid refluxate. The Sleuth system (Sandhill
Scientific, Denver, Colorado) combines pH monitoring and intraluminal impedance measurements using
a single catheter (Fig. 42-34). The technology identifies refluxate via changes in impedance caused by
the presence of a bolus in the esophagus, and the reflux event can be categorized as acid or nonacid by
the contemporaneous change in intraluminal pH. Multichannel intraluminal impedance (MII) has been
validated as an appropriate method for the evaluation of gastrointestinal function and reflux.169 All
episodes of gastroesophageal reflux can be detected using this technology without regard to their
chemical composition. Surprisingly, recent studies using this technology have shown that, in normal
subjects, PPI therapy does not alter the number of reflux episodes; it simply converts them to neutral
pH.170 This observation may have important implications in the treatment of GERD.
1079
booksmedicos.org
Figure 42-34. Combined multichannel intraluminal impedance–pH catheter. (Reproduced with permission from Mainie I, Tutuian
R, Agrawal A, et al. Combined multichannel intraluminal impedance-pH monitoring to select patients with persistent gastro-
oesophageal reflux for laparoscopic Nissen fundoplication. Br J Surg 2006;93:1483–1487.)
Combined MII-pH monitoring has recently been used to select patients, both with typical and atypical
manifestations of GERD and who are resistant to medical treatment, for fundoplication.171 Patients with
a positive symptom index, as assessed by combined MII-pH testing while on PPI therapy, were noted to
respond well to surgery. Another recent trial demonstrated that combined MII-pH testing is more
accurate for the preoperative assessment of GERD in patients off of PPI therapy compared to pH
monitoring alone.172
Assessment of Esophageal Length. Esophageal shortening is a consequence of scarring and fibrosis

associated with repetitive esophageal injury. Anatomic shortening of the esophagus can compromise the
ability to perform an adequate tension-free fundoplication and may result in an increased incidence of
breakdown or thoracic displacement of the repair. Esophageal length is best assessed preoperatively
using video roentgenographic contrast studies and endoscopic findings. Endoscopically, hernia size is
measured as the difference between the diaphragmatic crura, identified by having the patient sniff, and
the GE junction, identified as the loss of gastric rugal folds. We consider the possibility of a short
esophagus in patients with strictures or those with large hiatal hernias (>5 cm), particularly when the
latter fail to reduce in the upright position on a video barium esophagram.173
The definitive determination of esophageal shortening is made intraoperatively when, after thorough
mobilization of the esophagus, the GE junction cannot be reduced below the diaphragmatic hiatus
without undue tension on the esophageal body. Surgeons performing fundoplication have reported
varying incidences of esophageal shortening, attesting to the judgment inherent in defining and
recognizing “undue tension.” An advantage of transthoracic fundoplication is the ability to mobilize the
esophagus extensively from the diaphragmatic hiatus to the aortic arch. With the GE junction marked
with a suture, esophageal shortening is defined by an inability to position the repair beneath the
diaphragm without tension. In this situation, a Collis gastroplasty coupled with either a partial or
complete fundoplication may be performed.174
Potential pitfalls of laparoscopic fundoplication include the elevation of the diaphragm due to
pneumoperitoneum, potentially contributing to a false impression that esophageal length is adequate,
and the limited ability to mobilize the esophagus relative to the transthoracic approach.175 In our
experience, the failure to appreciate esophageal shortening is a major cause of fundoplication failure
and is often the explanation for the “slipped” Nissen fundoplication. In many such instances, the initial
repair is incorrectly constructed around the proximal tubularized stomach rather than the terminal
esophagus. Surgeons opting to perform fundoplication laparoscopically in the setting of potential
esophageal shortening must be vigilant of esophageal tension, technically facile at extensive mediastinal
mobilization of the esophagus while preserving vagal integrity, and able to perform a laparoscopic or
open transabdominal Collis gastroplasty should esophageal lengthening be necessary.
Radiographic Evaluation. Radiographic assessment of the anatomy and function of the esophagus and
stomach is one of the most important parts of the preoperative evaluation. Critical issues are assessed,
including the presence of esophageal shortening (Fig. 42-35), the size and reducibility of a hiatal hernia,
and the propulsive function of the esophagus for both liquids and solids.
The definition of radiographic GE reflux varies depending on whether reflux is spontaneous or
1080
booksmedicos.org
induced by various maneuvers. In only about 40% of patients with classic symptoms of GERD is
spontaneous reflux observed by the radiologist (i.e., reflux of barium from the stomach into the
esophagus with the patient in the upright position). In most patients who show spontaneous reflux on
radiography, the diagnosis of increased esophageal acid exposure is confirmed by 24-hour esophageal
pH monitoring. Therefore, the radiographic demonstration of spontaneous regurgitation of barium into
the esophagus in the upright position is a reliable indicator that reflux is present. On the contrary,
failure to see radiographic reflux does not prove the absence of reflux disease.
Figure 42-35. Barium-filled esophagogastric segment in a patient with a short esophagus. Note that the gastroesophageal junction
is well above the hiatus.
DIAGNOSIS
Table 42-7 University of Southern California Protocol for Video Esophagram
Studies
A carefully performed video esophagram can provide an enormous amount of information on the
structure and function of the esophagus and stomach. The modern barium swallow emphasizes motion
recording (video), utilizes a tightly controlled examination protocol (Table 42-7), and requires an
understanding of esophageal physiology.
Videotaping the study greatly aids the evaluation, providing the surgeon with a real-time assessment
of swallowing function, bolus transport, and the size and reducibility of an associated hiatal hernia.
Given routine review before antireflux surgery, the value of the study becomes increasingly clear. The
examination provides structural information including the presence of obstructing lesions and anatomic
1081
booksmedicos.org
abnormalities of the foregut. A hiatal hernia is present in more than 80% of patients with GE reflux and
is best demonstrated with the patient in the prone position, which causes increased abdominal pressure
and promotes distention of the hernia above the diaphragm. The presence of a hiatal hernia is an
important component of the underlying pathophysiology of GE reflux. Other relevant findings include a
large (>5 cm) or irreducible hernia, suggesting the presence of a shortened esophagus; a tight crural
“collar” that inhibits barium transit into the stomach, suggesting a possible cause of dysphagia; and the
presence of a PEH.
Lower esophageal narrowing resulting from a ring, stricture, or obstructing lesion is optimally viewed
with full distention of the esophagogastric region. A full-column technique with distention of the
esophageal wall can be used to discern extrinsic compression of the esophagus. Mucosal relief or double-
contrast films should be obtained to enhance the detection of small esophageal neoplasms, mild
esophagitis, and esophageal varices. The pharynx and UES are evaluated in the upright position, and an
assessment of the relative timing and coordination of pharyngeal transit is possible.
The assessment of peristalsis on video esophagram often adds to, or complements, the information
obtained by esophageal motility studies. This is in part because the video barium study can be done
both upright and supine and with liquid and solid bolus material, which is not true of a stationary
motility examination. This is particularly true with subtle motility abnormalities. During normal
swallowing, a stripping wave (primary peristalsis) is generated that completely clears the bolus.
Residual material can stimulate a secondary peristaltic wave, but usually a second pharyngeal swallow
is required. Motility disorders with disorganized or simultaneous esophageal contractions have “tertiary
waves” and provide a segmented appearance to the barium column, often referred to as beading or
corkscrewing. In dysphagic patients, a barium-impregnated marshmallow, bread, or hamburger is a
useful adjunct, which can discern a functional esophageal transport disturbance not evident on the liquid
barium study. Reflux is not easily seen on video esophagram, and motility disorders that cause
retrograde barium transport may be mistaken for reflux.
Assessment of the stomach and duodenum during the barium study is a necessity for proper
preoperative evaluation of the patient with GERD. Evidence of gastric or duodenal ulcer, neoplasm, or
poor gastroduodenal transit has obvious importance in the proper preoperative evaluation.
Assessment of Esophageal Function. The presence of poor esophageal body function can impact the
likelihood of relief of regurgitation, dysphagia, and RSs following surgery and may influence the
decision to undertake a partial rather than a complete fundoplication. When peristalsis is absent or
severely disordered, many surgeons would opt for a partial fundoplication, although recent studies
would suggest a complete fundoplication may be appropriate even in this setting. The less favorable
response of atypical, compared with typical, reflux symptoms after fundoplication may be related to
persistent poor esophageal propulsive function and the continued regurgitation of esophageal
contents.176,177
The function of the esophageal body is assessed with esophageal manometry. Conventional water-
perfused or solid-state manometry is performed with five pressure transducers located in the esophagus
(Fig. 42-36). To standardize the procedure, the most proximal pressure transducer is located 1 cm below
the well-defined cricopharyngeal sphincter. With this method, a pressure response along the entire
esophagus can be obtained during one swallow. The study consists of recording 10 wet swallows with 5
mL of water. Amplitude, duration, and morphology of contractions following each swallow are all
calculated at the five discrete levels within the esophageal body (Fig. 42-37). The delay between onset
or peak of esophageal contractions at the various levels of the esophagus is used to calculate the speed
of wave propagation and represents the degree of peristaltic activity.
1082
booksmedicos.org
Figure 42-36. Illustration of the position of a five-channel esophageal motility catheter during the esophageal body portion of the
study.
Recently, HRM (ManoScan360, Sierra Scientific Instruments, Los Angeles, CA) has been introduced
into clinical practice and may possess several advantages over the other manometric systems currently
available.178 The high-resolution catheter is 4.2 mm in diameter and has 36 solid-state transducers
spaced at 1-cm intervals, compared to the standard 3- to 5-cm spacing of traditional water-perfused or
solid-state catheters. Pressure transduction technology allows each of the sensors to detect pressure over
a length of 2.5 mm in 12 radially dispersed sectors. The pressure of each sector is averaged, making
each of the 36 sensors a circumferential pressure detector. This construct allows a more thorough and
precise evaluation of esophageal function than standard manometry. In addition, given the number and
span of transducers across the length of the catheter, the UES, esophageal body, and lower esophageal
sphincter can be assessed simultaneously without moving the catheter. Thus, the study can be
performed more quickly and with improved patient comfort compared to conventional manometry in
that multiple repositionings of the catheter are not required to complete the evaluation. The experience
in our laboratory has been that HRM takes, on average, only 8.1 minutes to complete, whereas standard
manometry with a solid-state catheter takes 24.4 minutes (p < 0.0001).141 Finally, the color-coded
readouts allow for a better, more intuitive, graphic description of the motor activity of the esophagus,
the characteristics of the lower esophageal sphincter, and the presence of a hiatal hernia compared to
the other technologies (Fig. 42-38). The catheter, however, is expensive with a high replacement cost
should it break. With increasing experience and further study, the pros and cons of this new technology
will continue to be elucidated.
Assessment of Gastric Function. Esophageal disorders are frequently associated with abnormalities of
duodenogastric function. Symptoms suggestive of gastroduodenal pathology include nausea, epigastric
pain, anorexia, and early satiety. Abnormalities of gastric motility or increased gastric acid secretion can
be responsible for increased esophageal exposure to gastric juice. If not identified before surgery,
unrecognized gastric motility abnormalities are occasionally “unmasked” by an antireflux procedure,
resulting in disabling postoperative symptoms.43 Considerable experience and judgment are necessary to
identify the patient with occult gastroduodenal dysfunction. The surgeon should maintain a keen
awareness of this possibility and investigate the stomach given any suggestion of problems. Tests of
duodenogastric function that are helpful when investigating the patient with GE reflux include gastric
emptying studies, gastric acid analysis, 24-hour gastric pH monitoring, and ambulatory bilirubin
monitoring of the esophagus and stomach.
1083
booksmedicos.org
Figure 42-37. Computer-generated graphic representation of esophageal body contraction amplitudes, duration of contraction, and
wave progression.
Figure 42-38. High-resolution manometry (HRM) display. Note the color-coded graphic description of esophageal body wave
amplitudes and lower esophageal sphincter function.
Poor gastric emptying or transit can provide for reflux of gastric contents into the distal esophagus.
Standard gastric emptying studies are performed with radionuclide-labeled meals. They are often poorly
standardized and difficult to interpret. Emptying of solids and liquids can be assessed simultaneously
when both phases are marked with different tracers. After ingestion of a labeled standard meal, gamma
camera images of the stomach are obtained at 5- to 15-minute intervals for 1.5 to 2 hours. After
correction for decay, the counts in the gastric area are plotted as percentage of total counts at the start
of the imaging. The resulting emptying curve can be compared with data obtained in normal volunteers.
In general, normal subjects will empty 59% of a meal within 90 minutes.
Evolving Technologies for Assessment of Extraesophageal Manifestations of GERD. Given the

difficulty inherent in proving that GERD is etiologic to extraesophageal symptoms, such as cough, sore
throat, or hoarseness, or to more chronic and insidious conditions, such as repetitive aspiration or
pulmonary fibrosis, a great interest exists to develop testing modalities that are both more sensitive and
more specific than the technologies widely utilized at present. Several recent testing paradigms have
emerged that appear promising, despite lacking extensive data.
Simultaneous 24-hour MII-pH and continuous pulse oximetry recently was evaluated in 20 subjects
with primary RSs and 10 with primary ESs.179 Oxygen saturation monitoring was performed using a
finger clip probe (Pulsox-300i, Konica Minolta Sensing, Inc., Ramsey, NJ) that measures the arterial
oxygen saturation (SpO2) and pulse rate every second via standard photometrics (Fig. 42-39). An
oxygen desaturation event was defined by either (a) SpO2 less than 90% or (b) SpO2 drop of 6% or
greater (Fig. 42-40). Reflux events, both acid and nonacid, were temporally correlated to desaturation
events. Markedly more reflux events were associated with desaturation in patients with RSs (74.5%,
832/1,117 reflux events) than in patients with ESs (30.4%, 223/734 reflux events, p < 0.0001) (Fig.
42-41). In addition, the difference in reflux desaturation association was more pronounced with
1084
booksmedicos.org
proximal reflux (80.3% with RSs vs. 20.4% with ESs, p < 0.0001). While a number of issues still need
to be resolved with this technique for it to be considered reliable and useful, the observation of oxygen
desaturations in temporal proximity to reflux events, particularly in patients with RSs, is intriguing and
may prove meaningful.
A pharyngeal pH catheter (Restech, San Diego, CA) also was recently developed and consists of a thin
(1.5-mm diameter) nasally passed catheter that can be positioned in the pharynx with the assistance of a
light-emitting diode (LED) mounted on the tip. The catheter, being small, is well tolerated and measures
both liquid and aerosolized reflux events. Optimal pH thresholds are currently being evaluated to
predict the responsiveness of extraesophageal symptoms to antireflux therapy, either medical or
surgical.
Finally, several centers have investigated the utility of salivary/sputum or laryngoscopic biopsy
specimen assays for pepsin as a marker for underlying GERD.180–182 As pepsin is produced only in the
gastric mucosa, its presence in the sputum or larynx reflects gastric reflux. Pepsin assays, when
compared to ambulatory pH monitoring, showed a high correlation to proximal reflux events. Positive
assays were also highly correlated with the presence of LPR symptoms. Still lacking are data showing
that a positive sputum or laryngeal pepsin assay predicts a successful symptomatic response to
antireflux therapy. With additional study, the utility and reliability of each of these modalities will be
determined in the clinical marketplace.
Partial Versus Complete Fundoplication. The decision between partial and complete fundoplication
and an open or laparoscopic approach requires considerable judgment. Two randomized studies of
unselected patients undergoing laparoscopic fundoplication have shown equivalence of complete and
partial fundoplications, anterior in one study183 and posterior in the other,83 in terms of operative time,
perioperative morbidity, and hospital stay. Watson et al.183 noted that resting and residual LES
pressures were greater after complete fundoplication and that esophageal clearance of liquid
radioisotope was prolonged in these patients compared with after partial fundoplication. Six months
after operation, partial fundoplication was linked to a greater overall level of patient satisfaction
manifested by a lower incidence of the symptoms of dysphagia, inability to belch, and excessive flatus.
Laws et al.184 did not identify any difference in symptomatic outcome between patients treated by
complete and those treated by posterior partial fundoplication at a mean follow-up time of 27 months.
Figure 42-39. Pulsox-300i with finger probe used to assess ambulatory oxygen saturation (Konica Minolta Sensing, Inc.).
1085
booksmedicos.org
Figure 42-40. Example of the association between a reflux episode detected by multichannel intraluminal impedance–pH study
and oxygen desaturation detected by pulse oximetry. (Reproduced with permission from Salvador R, Watson TJ, Herbella F, et al.
Association of gastroesophageal reflux and O2 desaturation: a novel study of simultaneous 24-h MII-pH and continuous pulse
oximetry. J Gastrointest Surg 2009;13:854–861.)
Hagedorn et al.185 reported on the results of a randomized, controlled trial comparing total (Nissen-
Rossetti) and posterior partial (Toupet) fundoplication in which long-term efficacy was assessed. A total
of 110 patients (54 undergoing a total wrap, 56 a partial wrap) completed a median follow-up of 11.5
years. No significant differences were observed between the groups in terms of heartburn,
regurgitation, or dysphagia scores. A significant difference, however, was noted in the prevalence of
rectal flatus and postprandial fullness, which were reported more often by those having undergone a
total fundoplication.
Figure 42-41. Scatterplot of association between reflux episodes and desaturation events by patient group. The prevalence of
reflux-associated desaturations was remarkably different between the two groups (p < 0.0001). (Reproduced with permission from
Salvador R, Watson TJ, Herbella F, et al. Association of gastroesophageal reflux and O2 desaturation: a novel study of
simultaneous 24-h MII-pH and continuous pulse oximetry. J Gastrointest Surg 2009;13:854–861.)
A recent prospective, randomized trial from Australia comparing laparoscopic Nissen fundoplication
to an anterior 180-degree partial fundoplication similarly revealed no significant differences between
the two groups with regard to reflux symptoms, dysphagia, abdominal bloating, ability to belch, and
overall satisfaction at 10 years’ follow-up.186
These observations, however, must be tempered by reports questioning the durability of partial
fundoplications. Jobe et al.187 found that 51% of patients studied by 24-hour esophageal pH monitoring
after Toupet fundoplication still had pathologic acid exposure. Disturbingly, only 40% of the refluxers
were symptomatic. Two studies have identified the presence of a defective LES function, an aperistaltic
distal esophagus, and higher grades of esophagitis (Savary-Miller grades 2 to 4) as risk factors for
partial fundoplication failure.185,187 Bell et al.188 reported recurrent reflux in 14% after Toupet
fundoplication. The presence of mild esophagitis and a normal LES were associated with a 3-year
success rate of 96%, whereas the presence of complicated esophagitis or a defective LES lowered this
value to 50% (Fig. 42-35).
These findings highlight an apparent paradox, in that partial fundoplications afford suboptimal reflux
protection in those most at risk from the effects of unabated GERD. The question arises, therefore,
whether total fundoplication should be applied more liberally to patients with severe reflux disease and
associated esophageal dysmotility. Patti et al. recently reported on 357 patients undergoing antireflux
surgery, 235 undergoing a “tailored approach” with either a partial or total fundoplication depending on
the results of preoperative manometry, and 122 more recent patients undergoing a total fundoplication
regardless of the quality of esophageal peristalsis.189 In the first group, heartburn from pathologic
reflux, confirmed by postoperative ambulatory esophageal pH monitoring, recurred in 19% after partial
fundoplication and in 4% after total fundoplication. In the latter group, heartburn recurred in 4% after
total fundoplication. Importantly, the incidence of postoperative dysphagia was similar in the two
groups. This recent evidence, as well as our own experience, has led us to utilize the complete
fundoplication more readily, particularly in patients with Barrett esophagus. Currently, partial
fundoplication is best reserved for patients with severe esophageal dysmotility approaching aperistalsis,
1086
booksmedicos.org
such as occurs in scleroderma, or in combination with a distal esophageal myotomy for achalasia.190
Laparoscopic Nissen Fundoplication. The performance of laparoscopic fundoplication should include

the steps identified in Table 42-8.
MANAGEMENT
Table 42-8 Elements of Laparoscopic Fundoplication
Port Placement. Five ports are used. The camera is placed above and to the left of the umbilicus,
roughly one-third of the distance to the xiphoid process. In most patients, placement of the camera in
the umbilicus is too low to allow adequate visualization of the hiatal structures once dissected. A
transrectus location is preferable to midline to minimize the prevalence of port site hernia formation.
The liver is retracted with a Nathensen retractor placed through a 5-mm incision on the right side of the
xiphoid. A retraction port is placed slightly above the level of the umbilicus, in the left anterior axillary
line. Placement of these ports too far lateral or too low on the abdomen will compromise the excursion
of the instruments and thus the ability to retract. The left-sided operating port (surgeon’s right hand) is
placed 1 to 2 cm below the costal margin approximately at the lateral rectus border. Such placement
allows triangulation between the camera and the two instruments and avoids the difficulty associated
with the instruments being in direct line with the camera. The right-sided operating port (surgeon’s left
hand) is placed last, after the left lateral segment of the liver has been retracted. This placement
prevents “sword fighting” between the liver retractor and the left-handed instrument. The falciform
ligament hangs low in many patients and provides a barrier around which the left-handed instrument
must be manipulated.
Hiatal Dissection. In patients without a large or PEH dissection begins with division of the
gastrohepatic omentum and identification of the right crus of the diaphragm. Alternatively, when a PEH
is present sac excision is started at the 2 o’clock position at the hiatus to avoid injuring the left gastric
vessels which are routinely up in the chest on the right side of the hiatus.
Crural Dissection. A large left hepatic artery arising from the left gastric artery is present in up to 25%
of patients (Fig. 42-42); it should be identified and can typically be divided without consequence but a
pulse in the hepatoduodenal ligament should be confirmed. After incising the gastrohepatic omentum,
the outside of the right crus will become evident. The peritoneum overlying the anterior aspect of the
right crus is incised and the plane between the esophagus and right crus developed.
Following dissection of the right crus, attention is turned toward the phrenoesophageal ligament
anteriorly. These tissues are held upward by the left-handed grasper and the esophagus and anterior
vagus nerve are swept downward away from the phrenoesophageal ligament. The anterior crural tissues
are then divided and the left crus identified. The anterior vagus nerve often “hugs” the left crus and can
be injured in this portion of the dissection if not carefully searched for and protected. The left crus is
dissected as completely as possible, including taking down the angle of His and the attachments of the
fundus to the left diaphragm (Fig. 42-43). The short gastric vessels are divided along with the posterior
pancreatic vessels to completely mobilize the gastric fundus. Failure to do so will result in difficulty
encircling the esophagus, and increase the risk of a perforation of the posterior esophagus when
developing the retroesophageal window. A window behind the GE junction can generally now be easily
created and a Penrose drain passed for esophageal retraction.
1087
booksmedicos.org
Figure 42-42. Illustration of the initial dissection of the esophageal hiatus. The right crus is identified and dissected toward its
posterior confluence with the left crus.
Esophageal Mobilization and Crural Closure. The esophagus is mobilized into the posterior
mediastinum for several centimeters to provide maximal intra-abdominal esophageal length. Posterior
and right lateral mobilization is readily accomplished. In performing the anterior and left lateral
mobilization, the surgeon must take care not to injure the anterior vagus nerve. Gentle traction on the
Penrose drain around the GE junction facilitates exposure. The right and left pleural reflection often
come into view and should be avoided, although if a pleural opening is created it is well tolerated
provided the hole is made large enough to prevent a ball-valve tension pneumothorax from developing.
Continue the crural dissection to enlarge the space behind the GE junction as much as possible.
Following mobilization and an assessment of intra-abdominal esophageal length, the hiatus is closed in
all patients. The esophagus is held anterior and to the left and the crura approximated with two to four
interrupted figure-of-eight 0-Ethibond sutures, starting just above the aortic decussation and working
anterior. The authors prefer a large needle (CT1) passed down the left upper 10-mm port to facilitate a
durable crural closure using absorbable pledgets in a horizontal mattress fashion. The aorta may be
punctured while suturing the left crus. Identification of the anterior aortic surface and retracting the left
crus via the left-handed grasper will help avoid inadvertent aortic puncture. The authors prefer
extracorporeal knot tying using a “tie knot” device (LSI Solutions, Victor, New York). More recently, we
have inspected the crural closure at the completion of the procedure following creation of the
fundoplication and removal of the bougie. Doing so will often reveal that the bougie has dilated the
hiatal opening such that a final stitch should be placed to further approximate it. Although there have
been no randomized studies evaluating the role of routine crural closure, there is compelling evidence
to indicate that closure should be standard. Watson et al.191 identified paraesophageal herniation in 17
of 253 patients (7%), the frequency being 3% in those who had undergone crural repair and 11% in
those who had not.
Figure 42-43. Left-sided crural dissection. The left crus is dissected as completely as possible and the attachments of the fundus of
1088
booksmedicos.org
the stomach to the diaphragm are taken down.
Creation of the Fundoplication. A short, loose fundoplication is fashioned with particular attention to
the geometry of the wrap (Fig. 42-44). The midposterior fundus is grasped and passed left to right
behind the esophagus rather than pulling right to left. This ensures that the posterior fundus is used for
the posterior aspect of the fundoplication. This is accomplished by placing a Babcock clamp through the
left lower port and grasping the midportion of the posterior fundus (Fig. 42-45). One should gently
bring the posterior fundus behind the esophagus to the right side with an upward, rightward, and
clockwise twisting motion. This maneuver can be difficult, particularly for the novice. If so, placement
of a 0-silk suture in the midposterior fundus 6 cm down from the GEJ and grasping it from the right
side facilitates bringing the posterior fundus around to create the fundoplication. The anterior wall of
the fundus is then folded over the esophagus to meet the posterior at about the 9 o’clock position such
that the esophagus is imbricated within the fundus rather than having the fundus twisted or spiraled
around the esophagus.
Figure 42-44. Schematic representations of the various possibilities of orientation of a Nissen fundoplication. The top set of figures
represents the preferred approach, whereas the bottom two sets can be seen to result in twisting of the fundoplication.
The posterior and anterior fundic lips should be maneuvered (as in a “shoe shine”) to allow the fundus
to envelope the esophagus without twisting. Laparoscopic visualization has a tendency to exaggerate the
size of the posterior opening that has been dissected. Consequently, the space for the passage of the
fundus behind the esophagus may be tighter than thought and the fundus relatively ischemic when
brought around. If the right lip of the fundoplication has a bluish discoloration, the stomach should be
returned to its original position and the posterior dissection enlarged. A 60-French bougie is passed to
properly size the fundoplication, and the “lips” of the fundoplication sutured utilizing a single U-stitch of
2-0 Prolene buttressed with absorbable pledgets. The most common error is an attempt to grasp the
anterior portion of the stomach to construct the right lip of the fundoplication rather than the posterior
fundus. The esophagus should comfortably lie in the untwisted fundus prior to suturing. If the posterior
fundus tries to pull away back under the esophagus there is tension likely from inadequate mobilization
of the fundus, particularly posteriorly along the pancreas. This should be addressed to release the
tension and reduce the risk of disruption of the fundoplication postoperatively. Finally, two anchoring
sutures of 2-0 silk or Ethibond are placed above and below the U-stitch to complete the fundoplication.
When finished, the suture line of the fundoplication should be facing in a right anterior direction (Fig.
42-46). The abdomen is then irrigated, hemostasis checked, and the Penrose drain and any sponges
placed into the abdomen removed.
1089
booksmedicos.org
Figure 42-45. Placement of Babcock on the posterior fundus in preparation for passing it behind the esophagus to create the
posterior or right lip of the fundoplication. Inset: To achieve the proper angle for passage, the Babcock is placed through the left
lower trocar. The posterior fundus is passed left to right and grasped from the right via a Babcock through the right upper trocar.
A: Location of posterior fundus for passage to the right side. B: The posterior fundus passed underneath the esophagus and grasped
on the right.
Figure 42-46. Fixation of the fundoplication. The fundoplication is sutured in place with a single U-stitch of 2-0 Prolene pledgeted
on the outside. A 60-French mercury-weighted bougie is passed through the gastroesophageal junction prior to fixation of the wrap
to ensure a floppy fundoplication. Inset illustrates the proper orientation of the fundic wrap.
Transthoracic Nissen Fundoplication. The indications for performing an antireflux procedure by a

transthoracic approach are given in Table 42-9.
In the thoracic approach the hiatus is exposed through a left posterior lateral thoracotomy incision in
the sixth intercostal space (i.e., over the upper border of the seventh rib). When necessary, the
diaphragm is incised circumferentially 2 to 3 cm from the lateral chest wall for a distance of
approximately 10 to 15 cm. The esophagus is mobilized from the level of the diaphragm to underneath
the aortic arch. Mobilization up to the aortic arch is usually necessary to place the repair in a patient
with a shortened esophagus into the abdomen without undue tension. Failure to do this is one of the
major causes for subsequent breakdown of a repair and return of symptoms. The cardia is then freed
from the diaphragm. When all the attachments between the cardia and diaphragmatic hiatus are
divided, the fundus and part of the body of the stomach are drawn up through the hiatus into the chest.
The vascular fat pad that lies at the GE junction is excised. Crural sutures are then placed to close the
hiatus though are not tightened until later. The fundoplication is constructed by enveloping the fundus
around the distal esophagus in a manner similar to that described for the abdominal approach. When
complete, the fundoplication is placed into the abdomen by compressing the fundic ball with the hand
and manually maneuvering it through the hiatus. The previously placed crural stitches are then
tightened and knotted.
1090
booksmedicos.org
Collis Gastroplasty. In patients with a short esophagus secondary to a stricture, Barrett esophagus, or a
large hiatal hernia, the esophagus is lengthened with a Collis gastroplasty. The gastroplasty lengthens
the esophagus by forming a gastric tube or “neoesophagus” along the lesser curvature. The procedure
allows a tension-free construction of a total or partial fundoplication around the newly formed gastric
tube, with placement of the repair in the abdomen. A gastroplasty can be readily performed via either
an abdominal or thoracic approach. A number of techniques have been reported for the laparoscopic
performance of Collis gastroplasty, and the surgeon opting to manage the shortened esophagus
laparoscopically must be able to perform such a procedure should the need arise.192 The authors prefer
the wedge fundectomy technique initially described by Hunter et al. In a series of 85 patients that had a
wedge fundectomy Collis gastroplasty and either a Nissen or Toupet fundoplication there were no staple
line leaks or abscesses in the perioperative period, and at a median follow-up of 12 months 93% were
free of heartburn. Dysphagia was significantly less common then preoperatively with new-onset
dysphagia in only two patients. On upper endoscopy in 54 patients at a median of 6 months
postoperatively esophagitis was only present in 11% of patients. These results suggest that a wedge
fundectomy can be added safely and with good results in patients where a shortened esophagus is found
intraoperatively.
INDICATIONS/CONTRAINDICATIONS
Table 42-9 Indications for Performing an Antireflux Procedure by a Transthoracic
Approach
Outcomes Following Antireflux Surgery. Any discussion regarding results following fundoplication
must consider:
1. Perioperative morbidity and mortality

2. Control of typical and atypical symptoms
3. Side effects
4. Objective relief from excessive esophageal acid exposure
5. Anatomic failure rates, such as recurrent hiatal herniation or slippage, and the need for reoperation
Complications of Antireflux Surgery. Carlson and Frantzides193 reported on complications and results
of primary minimally invasive antireflux operations based on a literature review. Included in their
analysis were 41 papers comprising 10,489 procedures. Postoperative complications were found to
occur in approximately 8% of patients, with the rate of conversion to an open procedure of about 4%.
The most common perioperative complication was early wrap herniation (1.3%), defined as occurring
within 48 hours of surgery. This is one complication that may be more common with the laparoscopic
than open approach. The explanation for this is unclear but may be related to the opening of tissue
planes by the pneumoperitoneum, the reduced tendency for adhesion formation after laparoscopic
compared to open surgery, and inadequate bites of crural tissue related to the magnified view with the
laparoscope. An adequate crural repair is critical in laparoscopic antireflux surgery (LARS).
Both pneumothorax and pneumomediastinum have been reported. The occurrence of pneumothorax is
related to breach of either pleural membrane, usually the left, during the hiatal dissection. Chest drain
insertion is usually not required because accumulated carbon dioxide rapidly dissipates following release
of pneumoperitoneum by a combination of positive pressure ventilation and absorption. Tension
1091
booksmedicos.org
pneumothorax intraoperatively is typically related to a ball-valve effect from a small opening in the
pleura. In this setting the laparoscopic capnoperitoneum gets into the pleural space with exhalation, but
cannot escape rapidly with inhalation. Creating a large pleural defect solves this issue, and since the
anesthesiologist can increase the ventilation pressure above the 15 mm used for laparoscopic
pneumoperitoneum there should be no difficulty ventilating the patient adequately.
As with any laparoscopic procedure, instrumental or trocar perforation of a hollow viscera may occur.
Esophageal perforation may arise intraoperatively during passage of the bougie, during the
retroesophageal dissection, or as a consequence of suture pull-through. Late esophageal perforation is
typically related to diathermy or dissection injury at the time of mobilization. Gastric perforations
usually result from excessive traction on the fundus particularly when reducing a PEH without first
mobilizing the hernia sac. Gastric perforation also occurs during reoperative fundoplication procedures.
The key is to recognize the injury and repair it appropriately since generally major complications are a
result of unrecognized injuries.
Hemorrhage during the course of laparoscopic fundoplication usually arises from the short gastric
vessels or spleen. Rarer causes include retractor trauma to the liver, injury to the left inferior phrenic
vein, an aberrant left hepatic vein, or the inferior vena cava. Cardiac tamponade as a result of right
ventricular trauma has also been reported. Major vascular injury mandates immediate conversion to an
open procedure to achieve hemostasis. One complication that has been virtually eliminated since the
advent of laparoscopic fundoplication is incidental splenic injury necessitating splenectomy (0.06%),
which occurred with a frequency of around 2% to 5% during the open era. The mortality rate for
primary minimally invasive antireflux surgery has fortunately been quite low, reported at 0.08%.
Symptomatic Outcomes Following Antireflux Surgery. Studies of long-term outcome following both
open and laparoscopic fundoplication document the ability of laparoscopic fundoplication to relieve
typical reflux symptoms (heartburn, regurgitation, and dysphagia) in more than 90% of patients at
follow-up intervals averaging 2 to 3 years and 80% to 90% of patients 5 years or more following
surgery.35,194–201 The data include evidence-based reviews of antireflux surgery,198 prospective
randomized trials comparing antireflux surgery to PPI therapy199 and open to laparoscopic
fundoplication,200 and analysis of U.S. national trends in utilization and outcomes.201 The results of
laparoscopic fundoplication compare favorably with those of the “modern” era of open fundoplication.
They also indicate the less predictable outcome of atypical reflux symptoms (cough, asthma, laryngitis)
after surgery being relieved in only two-thirds of patients.202
A few recent trials deserve emphasis. Results were updated on a prospective, randomized trial
comparing PPI therapy to antireflux surgery.203 The outcome of the study previously had been reported
at a follow-up of 5 years,199 while the latest update provided follow-up of at least 7 years. The
proportion of patients in whom treatment did not fail during the 7 years was significantly higher in the
surgical arm than in the medical arm. A smaller difference in outcomes was noted after dose
adjustments in the medical group. More patients in the surgical cohort, however, complained of side
effects such as dysphagia, inability to belch or vomit, and hyperflatulence. Disease control was
essentially stable between 5 and 7 years of follow-up. The authors concluded that surgery was more
effective in controlling overall GERD symptoms, though postfundoplication side effects were a concern.
Another prospective trial from the United Kingdom compared laparoscopic Nissen fundoplication to
PPI and reported follow-up at a median of 6.9 years.142 Some patients initially randomized to PPI
therapy were offered the opportunity to undergo surgery. While both the medical and surgical cohorts
reported an improvement in GERD-related symptoms after 12 months, further symptomatic
improvement was noted in those patients subsequently undergoing surgery despite optimal PPI therapy.
A multicenter, European, prospective randomized trial comparing LARS to medical therapy with
esomeprazole is ongoing (the LOTUS trial). Three-year outcomes in 288 patients assigned to LARS and
266 assigned to medical therapy were reported in 2008.204 The proportion of patients remaining in
symptomatic remission was similar between the two groups (90% for LARS, 93% for medical therapy in
an intention-to-treat analysis, p = 0.25). No major perioperative complications were noted and
esomeprazole appeared to be well tolerated.
Recent reports have called attention to the observation that many patients are prescribed acid
suppression medications after antireflux surgery. Spechler et al.205,206 reported on the long-term follow-
up of patients with complicated GERD enrolled in the Department of Veterans Affairs randomized trial
of medical versus surgical therapies. In the first report, almost half (46.9%) of the patients treated by
fundoplication had taken acid suppression medications at some point during the 11- to 13-year follow-up
period.205 In the second report, 62% of the surgically treated patients had used medications.206 The
1092
booksmedicos.org
reasons for and the necessity of acid suppression medication usage was not explored in this study. In
contrast, Lord et al.207 reported on 86 patients who had symptoms after Nissen fundoplication severe
enough to warrant evaluation with 24-hour ambulatory esophageal pH monitoring. Thirty-seven (43%)
of these patients were taking acid suppression medications, and only nine of them (24%) were found to
have abnormal pH scores. Heartburn and regurgitation were the only symptoms that were significantly
associated with an abnormal pH study. Multivariable logistic regression analysis showed that patients
with a disrupted or abnormally positioned fundoplication had a 52.6 times increased risk of abnormal
esophageal acid exposure. Based on these data, most patients using acid suppression medications after
antireflux surgery do not have abnormal esophageal acid exposure, and objective evidence of reflux
should be obtained prior to restarting acid suppression medications in patients with symptoms after a
fundoplication.
The goal of surgical treatment for GERD is to relieve abolish reflux by reestablishing the GE barrier.
This will alleviate symptoms related to reflux and protect the esophageal and laryngeal mucosa from
reflux-related injury. The challenge is to accomplish this without inducing dysphagia or other untoward
side effects. Dysphagia that existed prior to surgery usually improves following laparoscopic
fundoplication. Temporary dysphagia is common after surgery and generally resolves within 3 months.
Dysphagia persisting beyond 3 months has been reported in up to 10% of patients. In our experience,
dysphagia, manifested by occasional difficulty in swallowing solids, was present in 7% of patients at 3
months, 5% at 6 months, 2% at 12 months, and a single patient at 24 months following surgery.35
Others have observed a similar improvement in postoperative dysphagia with time. Induced dysphagia
is usually mild, does not require dilatation, and is temporary, often related to edema from the surgery.
Other side effects common to antireflux surgery include the inability to vomit and increased flatulence.
Most patients cannot vomit through an intact wrap, though this is rarely clinically relevant.
Hyperflatulence is a common and noticeable problem, likely related to increased air swallowing that is
present in most patients with reflux disease and the inability to belch.
Objective Outcomes Following Antireflux Surgery. Laparoscopic fundoplication results in a

significant increase in LES pressure and length, generally restoring these values to normal. The ability
of an antireflux operation to restore esophageal acid exposure to normal depends on the type of
fundoplication performed. Complete (Nissen) fundoplications generally are more reliable and durable
than partial (e.g., Toupet) fundoplications at preventing pathologic acid reflux. Objective studies have
shown that more than 90% of patients will have normal pH studies at 1 to 3 years following complete
fundoplication, whereas only 50% of patients will have normal esophageal acid exposure following a
partial fundic wrap.187
Quality-of-life analyses have become an important part of surgical outcome assessment, with both
generic and disease-specific questionnaires in use, in an attempt to quantitate quality of life before and
after surgical intervention. In general, these measures relate the effect of disease management to the
overall well-being of the patient.208 Most studies have utilized the Short Form 36 (SF-36) instrument,
because it is rapidly administered and well validated. This questionnaire measures 12 different health-
related quality-of-life parameters encompassing mental and physical well-being. Data from Los Angeles
indicate significant improvements in scores for the area of bodily pain and in a portion of the general
health index.35 Most other measures were improved but failed to achieve statistical significance. Trus et
al.209 have also analyzed SF-36 scores before and after LARS. In contrast to our data, scores in all fields
were significantly better after surgery. In this study, preoperative scores were dramatically lower than
were found in our study. Thus, the difference is likely to be secondary to the relatively high scores of
our patients prior to surgery (perhaps reflecting good disease control on medical therapy) and to our
small sample size.
Other investigators have also reported improvement in quality of life following antireflux surgery.
Glise et al.210 utilized two standardized and validated questionnaires, the Psychological General Well-
Being Index and the Gastrointestinal Symptom Rating Scale, to evaluate quality of life in a cohort of 40
patients following LARS. Scores with both instruments were improved following antireflux surgery and
better than in untreated patients. Of particular note was that scores were as good as or better than those
of patients receiving optimal medical therapy. Velonovich et al.,211 using a 10-item health-related
quality-of-life questionnaire specific for GERD, have also shown an improvement in quality of life
following antireflux surgery.
Fernando et al.212 reported on quality of life after antireflux surgery compared with nonoperative
management for severe GERD. Follow-up quality of life was measured using the SF-36, and heartburn
severity was measured using the Health-Related Quality-of-Life (QOL) scale. Detailed outcomes were
1093
booksmedicos.org
available for 101 surgical patients and 37 medical patients. Mean QOL scores were better in the surgical
group. More of the medical patients were dissatisfied with therapy. SF-36 scores were better in six of
eight domains for surgical patients. These data support the notion that antireflux surgery, performed on
properly selected patients, can significantly improve quality of life and may outperform medical therapy
in this regard.
Anatomic Failure Following Antireflux Surgery. An important and often underemphasized point is
that the rate of failure of fundoplication is largely dependent upon the size of the underlying hiatal
hernia. Repair of large sliding and PEHs is associated with a higher risk of recurrent hiatal herniation
compared to fundoplication for GERD in the setting of no or small hiatal hernias. Multiple potential
explanations exist to explain this differential, including the presence of a widened hiatus with weakened
or attenuated crural fibers that must be brought together under tension, the coexistence of esophageal
body shortening, the generally older and frailer nature of patients with a PEH, and underlying
anatomic, muscular, or connective tissue deficits that contributed to the pathogenesis of the hernia. In
particular, the association between kyphosis and intrathoracic stomach is becoming increasingly
recognized, as skeletal abnormalities likely are contributory to the pathogenesis of paraesophageal
hiatal herniation.213
The need for reoperation after fundoplication for GERD is only approximately 5% over the patient’s
lifetime, whereas the risk can run as high as 42% after repair of a giant PEH.214 In a trial from Finland,
objective outcomes were assessed by endoscopy and demonstrated a 40% disruption rate following open
Nissen fundoplication and a 13% disruption rate following a laparoscopic procedure.215 Despite these
relatively high rates of objective breakdown, only 8% of patients in the open group and 2% in the
laparoscopic group had undergone repeat operation for fundoplication failure.
A recent trial compared two techniques of laparoscopic PEH repair, with or without the use of a
biologic prosthesis placed at the esophageal hiatus.216 At 6 months, 9% of patients with the prosthesis
and 24% of patients without mesh reinforcement had developed a recurrent hiatal hernia as assessed by
a barium upper gastrointestinal examination, underscoring the potential for failure when operation is
undertaken for PEHs. However, at a median of 58 months follow-up the authors updated their results
and reported that greater than 50% of patients in both the mesh and nonmesh groups had objective
evidence of hernia recurrence.21 This has led to controversy about the role of mesh at the hiatus,
particularly in patients with large or paraesophageal-type hiatal hernias. It is likely that mesh use alone
is inadequate to prevent hernia recurrence if tension on the crural closure or related to esophageal
shortening is unaddressed. If mesh is to be used most experienced esophageal surgeons avoid the use of
large or esophageal-encircling permanent mesh to minimize the risk of erosion. A small strip of
synthetic mesh placed across the crural closure posterior to the esophagus may have less tendency to
erode and lead to a reduction in hernia recurrence. Bridging the crura with synthetic mesh should be
avoided since this leads to the highest risk for mesh erosion. An absorbable or biologic mesh bridge
should also be avoided since this will lead to hernia recurrence in essentially all patients. Instead, a
diaphragm relaxing incision should be used when the crura cannot be reapproximated or to do so
requires excessive tension. Increasingly biologic or bioresorbable mesh reinforcement of the primary
crural closure is being reported with good results.22 However, it is likely that mesh use increases the
complexity of a reoperation if necessary, and has been shown to lead to a higher risk for the need for
resection rather than redo fundoplication in the reoperative setting.23
Relaxing incisions have been used for hernia repairs at other sites in the abdomen, and logically
would be useful in patients with a widely splayed hiatus where the crura are unable to be approximated
without tension. A right-sided diaphragmatic relaxing incision is easiest and usually suffices, but in a
very large hiatus or in reoperations sometimes a left diaphragm relaxing incision is necessary. The
defect created in the diaphragm should be repaired with permanent mesh to avoid herniation of
abdomen contents into the thorax. The authors prefer a Gore Tex patch for this purpose and reinforce
the primary crural closure with an absorbable or biologic mesh.24
It is likely that efforts to reduce the high objective hernia recurrence rate after laparoscopic PEH
repair will require addressing crural tension, esophageal tension from a shortened esophagus, and mesh
reinforcement of the primary crural closure. When these adjunct techniques are added as necessary
during a laparoscopic PEH repair the authors have reported a very reasonable short-term objective
recurrence rate of 4%.25
FUTURE DIRECTIONS
1094
booksmedicos.org
Medical therapy for GERD and antireflux surgery both have inherent drawbacks. Major limitations of
acid suppressive medications include the inability to prevent regurgitation of weakly acidic or nonacidic
refluxate and the need for chronic, continual therapy, not to mention the cost, inconvenience, potential
side effects, and need for ongoing dietary and lifestyle modifications. In addition, current therapy does
not address the main pathophysiologic contributor to the presence of GERD, the mechanically defective
LES. Fundoplications, while intended to permanently restore the LES, suffer from the potential for
perioperative complications, a high initial cost, the risks inherent in general anesthesia, possible short-
and long-term side effects, and inconsistent reflux control across centers. In addition, proper patient
selection is critical and the operative technique is not well standardized, perhaps adversely affecting
outcomes, particularly in inexperienced hands.
For all of these reasons, an interest remains to create means of restoring LES competence by medical
or less invasive surgical or endoscopic techniques that are easily applied and highly reproducible.
Medications such as baclofen, a γ-aminobutyric acidB receptor agonist, have been utilized to decrease
TLESRs, thereby decreasing GERD.217 Similar investigational drugs are in the pipeline and likely will
reach clinical practice soon. A number of endoluminal therapies have been devised and tested to date,
the most promising of which are the transoral endoscopic fundoplication devices (EsophyX, EndoGastric
Solutions, Inc., Redmond, Washington and Medigus SRS, Medigus, Ltd., Omer, Israel). A recent
randomized control trial has shown that compared to PPI therapy a transoral fundoplication using the
EsophyX device was associated with improved regurgitation symptoms.26
Magnetic augmentation of the LES via a laparoscopically placed ring of small magnets (TORAX
Medical, Inc., Shoreview, Minnesota) has proven efficacy for control of reflux in appropriate patients.
The recently completed 5-year follow-up in 85 of an initial cohort of 100 patients showed no device
erosions, migrations, or malfunctions. The GERD quality of life scores, frequency of PPI use and
regurgitation symptoms were all improved compared to baseline. The ability to belch and vomit if
necessary was preserved in all patients, and bothersome gas-bloat symptoms were reduced from
baseline with a similar frequency of dysphagia symptoms.27
Lastly, a novel device that provides intermittent electrical current to the LES via implanted wires and
a pacer device (Endostim) has shown promising results in human trials from outside the United States.28
1095
booksmedicos.org
References
1. Gray SW, Rowe JS Jr, Skandalakis JE. Surgical anatomy of the gastroesophageal junction. Am Surg
1979;45(9):575–587.
2. Chandrasoma PT, Der R, Ma Y, et al. Histology of the gastroesophageal junction: an autopsy study.
Am J Surg Pathol 2000;24(3):402–409.
3. Chandrasoma PT, Der R, Dalton P, et al. Distribution and significance of epithelial types in
columnar-lined esophagus. Am J Surg Pathol 2001;25(9):1188–1193.
4. Abraham SC, Krasinskas AM, Correa AM, et al. Duplication of the muscularis mucosae in Barrett
esophagus: an underrecognized feature and its implication for staging of adenocarcinoma. Am J
Surg Pathol 2007;31(11):1719–1125.
5. Nigro JJ, Hagen JA, DeMeester TR, et al. Prevalence and location of nodal metastases in distal
esophageal adenocarcinoma confined to the wall: implications for therapy. J Thorac Cardiovasc Surg
1999;117(1):16–23; discussion 23–25.
6. Liebermann-Meffert DM, Luescher U, Neff U, et al. Esophagectomy without thoracotomy: is there a
risk of intramediastinal bleeding? A study on blood supply of the esophagus. Ann Surg
1987;206(2):184–192.
7. Liebermann-Meffert D. Human foregut anatomy, adjacent structures, and their relation to surgical
approaches. In: CJ Yeo, ed. Shackelford’s Surgery of the Alimentary Tract. Philadelphia, PA: Elsevier
Saunders: 2013;9–31.
8. Liebermann-Meffert DM, Walbrun B, Hiebert CA, et al. Recurrent and superior laryngeal nerves: a
new look with implications for the esophageal surgeon. Ann Thorac Surg. 1999;67(1):217–223.
9. Pouderoux P, Lin S, Kahrilas PJ. Timing, propagation, coordination, and effect of esophageal
shortening during peristalsis. Gastroenterology 1997; 112(4):1147–1154.
10. Pouderoux P, Shi G, Tatum RP, et al. Esophageal solid bolus transit: studies using concurrent
videofluoroscopy and manometry. Am J Gastroenterol 1999;94(6):1457–1463.
11. DeMeester TR, Peters JH, Bremner CG, et al. Biology of gastroesophageal reflux disease:
pathophysiology relating to medical and surgical treatment. Ann Rev Med 1999;50:469–506.
12. Bonavina L, Evander A, DeMeester TR, et al. Length of the distal esophageal sphincter and
competency of the cardia. Am J Surg 1986;151(1):25–34.
13. Mason RJ, DeMeester TR, Lund RJ, et al. Nissen fundoplication prevents shortening of the sphincter
during gastric distention. Archiv Surg 1997; 132(7):719–724; discussion 724–726.
14. Pettersson GB, Bombeck CT, Nyhus LM. The lower esophageal sphincter: mechanisms of opening
and closure. Surgery 1980;88(2):307–314.
15. Dent J. A new technique for continuous sphincter pressure measurement. Gastroenterology
1976;71(2):263–267.
16. Ismail T, Bancewicz J, Barlow J. Yield pressure, anatomy of the cardia and gastro-oesophageal
reflux. Br J Surg 1995;82(7):943–947.
17. Marchand P. The gastro-oesophageal sphincter and the mechanism of regurgitation. Br J Surg
1955;42(175):504–513.
18. Kahrilas PJ, Shi G, Manka M, et al. Increased frequency of transient lower esophageal sphincter
relaxation induced by gastric distention in reflux patients with hiatal hernia. Gastroenterology
2000;118(4):688–695.
19. DeMeester TR, Wernly JA, Bryant GH, et al. Clinical and in vitro analysis of determinants of
gastroesophageal competence. A study of the principles of antireflux surgery. Am J Surg
1979;137(1):39–46.
20. Johnson LF, Lin YC, Hong SK. Gastroesophageal dynamics during immersion in water to the neck. J
Appl Physiol 1975;38(3):449–454.
21. O’Sullivan GC, DeMeester TR, Joelsson BE, et al. Interaction of lower esophageal sphincter pressure
and length of sphincter in the abdomen as determinants of gastroesophageal competence. Am J Surg
1982;143(1):40–47.
22. Pellegrini CA, DeMeester TR, Skinner DB. Response of the distal esophageal sphincter to
respiratory and positional maneuvers in humans. Surg Forum 1976;27(62):380–382.
1096
booksmedicos.org
23. Stein HJ, Barlow AP, DeMeester TR, et al. Complications of gastroesophageal reflux disease. Role
of the lower esophageal sphincter, esophageal acid and acid/alkaline exposure, and duodenogastric
reflux. Ann Surg 1992;216(1):35–43.
24. Zaninotto G, DeMeester TR, Bremner CG, et al. Esophageal function in patients with reflux-induced
strictures and its relevance to surgical treatment. Ann Thorac Surg 1989;47(3):362–370.
25. Barham CP, Gotley DC, Mills A, et al. Precipitating causes of acid reflux episodes in ambulant
patients with gastro-oesophageal reflux disease. Gut 1995;36(4):505–510.
26. Bremner RM, Hoeft SF, Costantini M, et al. Pharyngeal swallowing. The major factor in clearance
of esophageal reflux episodes. Ann Surg 1993;218(3):364–369; discussion 369–370.
27. Iwakiri K, Kobayashi M, Kotoyori M, et al. Relationship between postprandial esophageal acid
exposure and meal volume and fat content. Dig Dis Sci 1996;41(5):926–930.
28. Fletcher J, Wirz A, Young J, et al. Unbuffered highly acidic gastric juice exists at the
gastroesophageal junction after a meal. Gastroenterology 2001;121(4):775–783.
29. Ayazi S, Tamhankar A, DeMeester SR, et al. The impact of gastric distension on the lower
esophageal sphincter and its exposure to acid gastric juice. Ann Surg 2010;252(1):57–62.
30. Oberg S, Peters JH, DeMeester TR, et al. Inflammation and specialized intestinal metaplasia of
cardiac mucosa is a manifestation of gastroesophageal reflux disease. Ann Surg 1997;226(4):522–
31. DeMeester TR, Wang CI, Wernly JA, et al. Technique, indications, and clinical use of 24 hour
esophageal pH monitoring. J Thorac Cardiovasc Surg 1980;79(5):656–670.
32. Theisen J, Oberg S, Peters JH, et al. Gastro-esophageal reflux disease confined to the sphincter. Dis
Esophagus 2001;14(3–4):235–238.
33. DeMeester TR, Ireland AP. Gastric pathology as an initiator and potentiator of gastroesophageal
reflux disease. Dis Esophagus 1997;10(1):1–8.
34. Kuster E, Ros E, Toledo-Pimentel V, et al. Predictive factors of the long term outcome in gastro-
oesophageal reflux disease: six year follow up of 107 patients. Gut 1994;35(1):8–14.
35. Peters JH, DeMeester TR, Crookes P, et al. The treatment of gastroesophageal reflux disease with
laparoscopic Nissen fundoplication: prospective evaluation of 100 patients with “typical” symptoms.
Ann Surg 1998;228(1):40–50.
36. Ganz RA, Peters JH, Horgan S. Esophageal sphincter device for gastroesophageal reflux disease. N
Engl J Med 2013;368(8):719–727.
37. Singh P, Adamopoulos A, Taylor RH, et al. Oesophageal motor function before and after healing of
oesophagitis. Gut 1992;33(12):1590–1596.
38. Tamhankar AP, Peters JH, Portale G, et al. Omeprazole does not reduce gastroesophageal reflux:
new insights using multichannel intraluminal impedance technology. J Gastrointest Surg,
2004;8(7):890–897; discussion 897–898.
39. Dodds WJ. 1976 Walter B. Cannon Lecture: current concepts of esophageal motor function: clinical
implications for radiology. AJR Am J Roentgenol 1977;128(4):549–561.
40. Ekberg O, Wahlgren L. Dysfunction of pharyngeal swallowing. A cineradiographic investigation in
854 dysphagia patients. Acta Radiol Diagn 1985;26(4):389–395.
41. Donner MW. Swallowing mechanism and neuromuscular disorders. Semin Roentgenol
1974;9(4):273–282.
42. Fuller L, Huprich JE, Theisen J, et al. Abnormal esophageal body function: radiographic-
manometric correlation. Am Surg 1999;65(10):911–914.
43. Schwizer W, Hinder RA, DeMeester TR. Does delayed gastric emptying contribute to
gastroesophageal reflux disease? Am J Surg 1989;157(1):74–81.
44. Genta RM, Spechler SJ, Kielhorn AF. The Los Angeles and Savary-Miller systems for grading
esophagitis: utilization and correlation with histology. Dis Esophagus 2011;24(1):10–17.
45. Theodorou D, Ayazi S, DeMeester SR, et al. Intraluminal pH and goblet cell density in Barrett’s
esophagus. J Gastrointest Surg 2012;16(3):469–474.
46. Oh D, Hagen JA, Chandrasoma PT, et al. Clinical biology and surgical therapy of intramucosal
adenocarcinoma of the esophagus. J Am Coll Surg 2006;203(2):152–161.
47. Oberg S, Peters JH, DeMeester TR, et al. Endoscopic grading of the gastroesophageal valve in
1097
booksmedicos.org
patients with symptoms of gastroesophageal reflux disease (GERD). Surg Endoscopy
1999;13(12):1184–1188.
48. Ayazi S, Hagen JA, Zehetner J, et al. The value of high-resolution manometry in the assessment of
the resting characteristics of the lower esophageal sphincter. J Gastrointest Surg, 2009;13(12):2113–
2120.
49. Johnson LF, Demeester TR. Twenty-four-hour pH monitoring of the distal esophagus. A quantitative
measure of gastroesophageal reflux. Am J Gastroenterology 1974;62(4):325–332.
50. Mason RJ, Oberg S, Bremner CG, et al. Postprandial gastroesophageal reflux in normal volunteers
and symptomatic patients. J Gastrointest Surg, 1998;2(4):342–349.
51. Ayazi S, Lipham JC, Portale G, et al. Bravo catheter-free pH monitoring: normal values,
concordance, optimal diagnostic thresholds, and accuracy. Clin Gastroenterol Hepatology
2009;7(1):60–67.
52. Ayazi S, Hagen JA, Zehetner J, et al. Proximal esophageal pH monitoring: improved definition of
normal values and determination of a composite pH score. J Am Coll Surg 2010;210(3):345–350.
53. Ayazi S, Lipham JC, Hagen JA, et al. A new technique for measurement of pharyngeal pH: normal
values and discriminating pH threshold. J Gastrointest Surg, 2009;13(8):1422–1429.
54. Vakil N, van Zanten SV, Kahrilas P, et al. The Montreal definition and classification of
gastroesophageal reflux disease; a global evidence-based consensus. Am J Gastroenterol
2006;101:1900–1920.
55. Locke GR, Talley NJ, Fett SL, et al. Prevalence and clinical spectrum of gastroesophageal reflux; a
population-based study in Olmsted County Minnesota. Gastroenterology 1997;112:1448.
56. Isolauri J, Laippala P. Prevalence of symptoms suggestive of gastroesophageal reflux disease in an
adult population. Ann Med 1995;27:67–70.
57. Sharma P, Wani S, Romero Y, et al. Racial and geographic issues in gastroesophageal reflux disease.
Am J Gastroenterol 2008;103:2669–2680.
58. El-Serag H. Time trends of gastroesophageal reflux disease: a systematic review. Clin Gastroenterol
Hepatol 2007;5:17–26.
59. Agency for Healthcare Research and Quality. Hospitalizations for problems caused by severe acid
reflux increase by 103 percent. AHRQ News and Numbers. Rockville, MD: Agency for Healthcare
Research and Quality; 2008. Available at: http://www.ahrq.gov/news/nn/nn010208.htm. Accessed
January, 2009.
60. El-Serag HB, Sonnenberg A. Opposing time trends of peptic ulcer and reflux disease. Gut
1998;43:327–333.
61. Panos MZ, Walt RP, Stevenson C, et al. Rising death rate from non-malignant disease of the
oesophagus (NMOD) in England and Wales. Gut 1995;36:488–491.
62. Jacobson BC, Somers SC, Fuchs CS, et al. Body-mass index and symptoms of gastroesophageal
reflux in women. N Eng J Med 2006;354:2340–2348.
63. Corely DA, Kubo A. Body mass index and gastroesophageal reflux disease: a systematic review and
meta-analysis. Am J Gastroenterol 2006;108: 2619–2628.
64. Pandolfino JE, El-Serag HB, Zhang Q, et al. Obesity: a challenge to esophagogastric junction
integrity. Gastroenterology 2006;130:639–649.
65. Edlestein ZR, Farrow DC, Bronner MP, et al. Central obesity and risk of Barrett’s esophagus.
Gastroenterology 2007;133:403–411.
66. Konturek JW. Discovery by Jaworski of Helicobacter pylori and its pathogenetic role in peptic
ulcer, gastritis and gastric cancer. J Physiol Pharmacol 2003;54(suppl 3):23–41.
67. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and
peptic ulceration. Lancet 1984;1:1311–1315.
68. Labenz J, Blum AL, Bayerdorffer E, et al. Curing Helicobacter pylori infection in patients with
duodenal ulcer may provoke reflux esophagitis. Gastroenterology 1997;112:1442–1447.
69. Bowrey DJ, Williams GT, Clark GW. Interactions between Helicobacter pylori and gastroesophageal
reflux disease. Dis Esophagus 1998;11: 203–209.
70. Werdmuller BF, Loffeld RJ. Helicobacter pylori infection has no role in the pathogenesis of reflux
esophagitis. Dig Dis Sci 1997;42:103–105.
1098
booksmedicos.org
71. Loffeld RJ, Ten Tije BJ, Arends JW. Prevalence and significance of Helicobacter pylori in patients
with Barrett’s esophagus. Am J Gastroenterol 1992;87:1598–1600.
72. Weel JF, Van Der Hulst RW, Gerrits Y, et al. The interrelationship between cytotoxin-associated
gene A, vacuolating cytotoxin, and Helicobacter pylori-related diseases. J Infect Dis 1996;173:1171–
1175.
73. Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence of cagA-positive Helicobacter pylori strains
in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998;115:50–57.
74. Chow WH, Blaser MJ, Blot WJ, et al. An inverse relation between cagA− strains of Helicobacter
pylori infection and risk of esophageal and gastric cardia adenocarcinoma. Cancer Res 1998;58:588–
590.
75. Labenz J, Nocon M, Lind T, et al. Prospective follow-up data for the ProGERD study suggest that
GERD is not a categorical disease. Am J Gastroenterol 2006;101:2457–2462.
76. Malfertheiner P, Nocon M, Vieth M, et al. Evolution of gastro-oesophageal reflux disease over 5
years under routine medical care – the ProGERD study. Aliment Pharmacol Ther 2012;35:154–164.
77. Monnier P, Ollyo JB, Fontolliet C, et al. Epidemiology and natural history of reflux esophagitis.
Semin Laparosc Surg 1995;2:2–9.
78. Costantini M, Crookes PF, Bremner RM, et al. The value of physiologic assessment of foregut
symptoms in a surgical practice. Surgery 1993; 114:780–786; discussion 786–787.
79. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux
esophagitis. N Engl J Med 1982;307: 1547–1552.
80. Mittal RK, Holloway R, Dent J. Effect of atropine on the frequency of reflux and transient lower
esophageal sphincter relaxation in normal subjects. Gastroenterology 1995;109:1547–1554.
81. Mittal RK, Hollaway RH, Penagini R, et al. Transient lower esophageal sphincter relaxation.
82. Van Herwaarden MA, Samson M, Smout AJ. Excess gastroesophageal reflux in patients with hiatal
hernia is caused by mechanisms other than transient LES relaxations. Gastroenterology
2000;119:1439–1446.
83. Zaninotto G, DeMeester TR, Schwizer W, et al. The lower esophageal sphincter in health and
disease. Am J Surg 1988;155:104–111.
84. Stein HJ, Eypasch EP, DeMeester TR, et al. Circadian esophageal motor function in patients with
gastroesophageal reflux disease. Surgery 1990; 108:769.
85. Cohen S, Harris LD. Does hiatus hernia affect competence of the gastroesophageal sphincter. N Engl
J Med 1971;284:1053–1056.
86. Mittal RK, Fisher MJ. Electrical and mechanical inhibition of the crural diaphragm during transient
relaxation of the lower esophageal sphincter. Gastroenterology 1990;99:1265–1268.
87. Hill LD, Kozarek RA, Kraemer SJM, et al. The gastroesophageal flap valve: in vitro and in vivo
observations. Gastrointest Endosc 1996;44:541–547.
88. Kahrilas PJ, Wu S, Shezhang L, et al. Attenuation of esophageal shortening during peristalsis with
hiatus hernia. Gastroenterology 1995;109:1818–1825.
89. Fletcher J, Wirz A, Henry E, et al. Studies of acid exposure immediately above the
gastroesophageal squamocolumnar junction: evidence of short segment reflux. Gut 2004;53:168–
173.
90. Iljima K, Henry E, Moriya A, et al. Dietary nitrate generates potentially mutagenic concentrations
of nitric oxide at the gastroesophageal junction. Gastroenterology 2002;122:1248–1257.
91. Lillimoe KD, Johnson LF, Harmon JW. Role of the components of the gastroduodenal contents in
experimental acid esophagitis. Surgery 1982;92:276–284.
92. Lillimoe KD, Johnson LF, Harmon JW. Alkaline esophagitis: a comparison of the ability of
components of gastroduodenal contents to injure the rabbit esophagus. Gastroenterology
1983;85:621–628.
93. Kauer WK, Peters JH, DeMeester TR, et al. Mixed reflux of gastric juice is more harmful to the
esophagus than gastric juice alone. The need for surgical therapy reemphasized. Ann Surg
1995;222:525–533.
94. El-Serag HB, Sonnenberg A. Comorbid occurrence of laryngeal or pulmonary disease with
esophagitis in United States Military Veterans. Gastroenterology 1997;113:755–760.
1099
booksmedicos.org
95. Havemann BD, Henderson CA, El-Serag HB. The association between gastro-oesophageal reflux
disease and asthma: a systematic review. Gut 2007;56:1654–1664.
96. Sontag SJ. The spectrum of pulmonary symptoms due to gastroesophageal reflux. Thorac Surg Clin
2005;15:353–368.
97. Blondeau K, Dupont L, Mertens V, et al. Gastroesophageal reflux and aspiration of gastric contents
in adult patients with cystic fibrosis. Gut 2008;57:1049–1055.
98. Rascon-Aguilar IE, Pamer M, Wludyka P, et al. Role of gastroesophageal reflux symptoms in
exacerbations of COPD. Chest 2006;130:1096–1101.
99. Hamelberg W, Bosomworth PP. Aspiration pneumonitis: experimental studies and clinical
observations. Anesth Analg Curr Res 1964;170:74–86.
100. Greenfield LJ, Singleton RP, McCaffree DR, et al. Pulmonary effects of experimental graded
aspiration of hydrochloric acid. Ann Surg 1969; 170:74–86.
101. Glauser FL, Millen JE, Falls R. Effects of acid aspiration on pulmonary alveolar epithelial
membrane permeability. Chest 1979;76:201–205.
102. Tuchman DN, Boyle JT, Pack AI, et al. Comparison of airway responses following tracheal or
esophageal acidification in the cat. Gastroenterology 1984;87:872–881.
103. Pearson JE, Wilson RS. Diffuse pulmonary fibrosis and hiatus hernia. Thorax 1971;26:300–305.
104. Mays EE, Dubois JJ, Hamilton GB. Pulmonary fibrosis associated with tracheobronchial aspiration:
a study of the frequency of hiatal hernia and gastroesophageal reflux in interstitial fibrosis of
obscure etiology. Chest 1976;69:512–515.
105. Raiha I, Manner R, Hietanen E. Radiographic pulmonary changes of gastro-oesophageal reflux
disease in elderly patients. Age Ageing 1992;21:250–255.
106. Tobin RW, Pope CE, Pellegrini CA. Increased prevalence of gastroesophageal reflux in patients with
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1988;158:1804–1808.
107. Kauer WK, Stein HJ, Möbius C, et al. Assessment of respiratory symptoms with dual pH monitoring
in patients with gastro-oesophageal reflux disease. Br J Surg 2004;91:867–871.
108. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal
reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136–142.
109. Crowell MD, Zayat EN, Lacy BE, et al. The effects of an inhaled beta(2)-adrenergic agonist on
lower esophageal function: a dose-response study. Chest 2001;120:1184–1189.
110. Mansfield LE, Hameister HH, Spaulding HS, et al. The role of the vagus nerve in airway narrowing
caused by intraesophageal hydrochloric acid provocation and esophageal distention. Ann Allergy
1981;47:431–434.
111. Wright RA, Miller SA, Corsello BF. Acid-induced esophagobronchial-cardiac reflexes in humans.
112. Schan CA, Harding SM, Haile JM, et al. Gastroesophageal reflux-induced bronchoconstriction. An
intraesophageal acid infusion study using state-of-the-art technology. Chest 1994;106:731–737.
113. Sweet MP, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary
fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007;133:1078–1084.
114. Sweet MP, Herbella FA, Leard L, et al. The prevalence of distal and proximal gastroesophageal
reflux in patients awaiting lung transplantation. Ann Surg 2006;244:491–497.
115. D’Ovidio F, Singer LG, Hadjiliadis D, et al. Prevalence of gastroesophageal reflux in end-stage lung
disease candidates for lung transplant. Ann Thoracic Surg 2005;80:1254–1261.
116. Ayazi S, Hagen JA, Zehetner J, et al. Loss of alkalization in proximal esophagus: a new diagnostic
paradigm for patients with laryngopharyngeal reflux. J Gastrointest Surg 2010;14(11):1653–1659
117. Worrell SG, DeMeester SR, Greene CL, et al. Pharyngeal pH monitoring better predicts a successful
outcome for extraesophageal reflux symptoms after antireflux surgery. Surg Endosc
2013;27(11):4113–4118.
118. Frank L, Kleinman L, Ganoczy D, et al. Upper gastrointestinal symptoms in North America:
prevalence and relationship to healthcare utilization and quality of life. Dig Dis Sci 2000;45:809–
818.
119. Jailawala JA, Shaker R. Oral and pharyngeal complications of gastroesophageal reflux disease:
globus, dental erosions, and chronic sinusitis. J Clin Gastroenterol 2000;30(3 suppl):S35–S38.
1100
booksmedicos.org
120. Hungin AP, Raghunath AS, Wiklund I. Beyond heartburn: a systematic review of the extra-
oesophageal spectrum of reflux-induced disease. Fam Pract 2005;22:591–603.
121. Levin TR, Sperling RM, McQuaid KR. Omeprazole improves peak expiratory flow rate and quality
of life in asthmatics with gastroesophageal reflux. Am J Gastroenterol 1998;93:1060–1063.
122. Boeree MJ, Peters FT, Postma DS, et al. No effects of high-dose omeprazole in patients with severe
airway hyperresponsiveness and symptomatic gastro-oesophageal reflux. Eur Respir J
1998;11:1070–1074.
123. Harding SM, Richter JE, Guzzo MR, et al. Asthma and gastroesophageal reflux: acid suppressive
therapy improves asthma outcome. Am J Med 1996;100:395–405.
124. Raghu G, Yang ST, Spada C, et al. Sole treatment of acid gastroesophageal reflux in idiopathic
pulmonary fibrosis: a case series. Chest 2006;129: 794–800.
125. Sontag SJ, O’Connell S, Khandelwal S, et al. Asthmatics with gastroesophageal reflux: long term
results of a randomized trial of medical and surgical antireflux therapies. Am J Gastroenterol
2003;98:987–999.
126. Lau CL, Palmer SM, Howell DN, et al. Laparoscopic antireflux surgery in the lung transplant
population. Surg Endosc 2002;16:1674–1678.
127. Linden PA, Gilbert RJ, Yeap BY, et al. Laparoscopic fundoplication in patients with end-stage lung
disease awaiting transplantation. J Thorac Cardiovasc Surg 2006;131:438–446.
128. Patti MG, Tedesco P, Golden J, et al. Idiopathic pulmonary fibrosis: how often is it really
idiopathic? J Gastrointest Surg 2005;9:1053–1056.
129. Fernando HC, El-Sherif A, Landreneau RJ, et al. Efficacy of laparoscopic fundoplication in
controlling pulmonary symptoms associated with gastroesophageal reflux disease. Surgery
2005;138:612–616.
130. Spechler SJ. The columnar lined esophagus: history, terminology and clinical issues. Gastroenterol
Clin North Am 1997;26:455–466.
131. Peters JH, Hagen JA, DeMeester SR. Barrett’s esophagus. J Gastrointest Surg 2004;8:1–17.
132. Chandrasoma P. Norman Barrett: so close, yet 50 years away from the truth. J Gastrointest Surg
1999;3:7–14.
133. Campos GM, DeMeester SR, Peters JH, et al. Predictive factors of Barrett’s esophagus: multivariate
analyses of 502 patients with GERD. Arch Surg 2001;136:1267–1273.
134. Kauer WK, Stein HJ. Bile reflux in the constellation of gastroesophageal reflux disease. Thorac Surg
Clin 2005;15:335–340.
135. Katzka DA, Castell DO. Successful elimination of reflux symptoms does not insure adequate control
of acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol 1994;89:989–991.
136. Ouatu-Lascar R, Triadafilopolous G. Complete elimination of reflux symptoms does not guarantee
normalization of intraesophageal acid reflux in patients with Barrett’s esophagus. Am J Gastroenterol
1998;93:711–716.
137. Sampliner RE, Fennerty B, Garewal HS. Reversal of Barrett’s esophagus with acid suppression and
multipolar electrocoagulation: preliminary results. Gastrointest Endos 1996;44:532–535.
138. Hofstetter WA, Peters JH, DeMeester TR, et al. Long term outcome of antireflux surgery in patients
with Barrett’s esophagus. Ann Surg 2001;234:532–539.
139. Lord RV, DeMeester SR, Peters JH, et al. Hiatal hernia, lower esophageal sphincter incompetence,
and effectiveness of Nissen fundoplication in the spectrum of gastroesophageal reflux disease. J
Gastrointest Surg 2009;13:602–610.
140. Farrell TM, Smith CD, Metreveli RE, et al. Fundoplication provides effective and durable symptom
relief in patients with Barrett’s esophagus. Am J Surg 1999;178:18–21.
141. Oelschlager BK, Barreca M, Chang L, et al. Clinical and pathologic response of Barrett’s esophagus
to laparoscopic antireflux surgery. Ann Surg 2003;238:458–466.
142. Mehta S, Bennett J, Mahon D, et al. Prospective trial of laparoscopic Nissen fundoplication versus
proton pump inhibitor therapy for gastroesophageal reflux disease: seven-year follow-up. J
143. Dallemagne B, Weerts J, Markiewicz S, et al. Clinical results of laparoscopic fundoplication at ten
years after surgery. Surg Endosc 2006;20:159–165.
1101
booksmedicos.org
144. Morgenthal CB, Shane MD, Stival A, et al. The durability of laparoscopic Nissen fundoplication: 11-
year outcomes. J Gastrointest Surg 2007;11:693–700.
145. Wijnhoven BP, Lally CJ, Kelly JJ, et al. Use of antireflux medication after antireflux surgery. J
146. Lurje G, Vallbohmer D, Collet PH, et al. COX-2 mRNA expression is significantly increased in acid-
exposed compared to nonexposed squamous epithelium in gastroesophageal reflux disease. J
147. Vallböhmer D, DeMeester SR, Oh DS, et al. Antireflux surgery normalizes cyclooxygenase-2
expression in squamous epithelium of the distal esophagus. Am J Gastroenterol 2006;101:1458–1466.
148. Oh DS, DeMeester SR, Vallböhmer D, et al. Reduction of interleukin 8 gene expression in reflux
esophagitis and Barrett’s esophagus with antireflux surgery. Arch Surg 2007;142:554–559.
149. Altorki NK, Sunagawa M, Little AG, et al. High-grade dysplasia in the columnar-lined esophagus.
Am J Surg 1991;161:99–100.
150. Pera M, Trastek VF, Carpenter HA, et al. Barrett’s esophagus with high grade dysplasia: an
indication for esophagectomy. Ann Thorac Surg 1992;54:199–204.
151. Ferguson MK, Naunheim KS. Resection for Barrett’s mucosa with high-grade dysplasia: implications
for prophylactic photodynamic therapy. J Thorac Cardiovasc Surg 1997;114:824–829.
152. www.drugs.com. Accessed September 12, 2006.
153. www.rxlist.com. Accessed September 12, 2006.
154. Sandmark S, Carlsson R, Fausa O, et al. Omeprazole or ranitidine in the treatment of reflux
esophagitis. Scand J Gastroenterol 1988;23:625–632.
155. Katzka DA, Paoletti V, Leite L, et al. Prolonged ambulatory pH monitoring in patients with
persistent gastroesophageal reflux disease symptoms: testing while on therapy identifies the need
for more aggressive anti-reflux therapy. Am J Gastroenterol 1996;91:2110–2113.
156. Peghini PL, Katz PO, Bracy NA, et al. Nocturnal recovery of gastric acid secretion with twice-daily
dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763–767.
157. Laheij RJ, Sturkenboom MC, Hassing R-J, et al. Risk of community-acquired pneumonia and use of
gastric acid-suppressive drugs. JAMA 2004; 292:1955–1960.
158. Yang Y-X, Lewis JD, Epstein S, et al. Long-term proton pump inhibitor therapy and the risk of hip
fracture. JAMA 2006;296:2947–2953.
159. Roux C, Briot K, Gossec L, et al. Increase in vertebral fracture risk in postmenopausal women using
omeprazole. Calcif Tissue Int 2009;84:13–19.
160. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-
related fractures. CMAJ 2008;179:319–326.
161. Campos GM, Peters JH, DeMeester TR, et al. The pattern of esophageal acid exposure in GERD
influences the severity of the disease. Arch Surg 1999;134:882–887; discussion 887–888.
162. Finks JF, Wei Y, Birkmeyer JD. The rise and fall of antireflux surgery in the United States. Surg
Endosc 2006;20:1698–1701.
163. Campos GM, Peters JH, DeMeester TR, et al. Multivariate analysis of the factors predicting
outcome after laparoscopic Nissen fundoplication. J Gastrointest Surg 1999;3:292–300.
164. Miller FA. Utilization of inlying pH-probe for evaluation of acid-peptic diathesis. Arch Surg
1964;89:199–203.
165. Johnson LF, DeMeester TR. Development of the 24-hour intraesophageal pH monitoring composite
scoring system. J Clin Gastroenterol 1986; 8(suppl 1):52–58.
166. Jamieson JR, Stein HJ, DeMeester TR, et al. Ambulatory 24-h esophageal pH monitoring: normal
values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol
1992;87:1102–1111.
167. Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal pH monitoring using a wireless
system. Am J Gastroenterol 2003;98:740–749.
168. Wenner J, Johansson J, Johnsson F, et al. Optimal thresholds and discriminatory power of 48-h
wireless esophageal pH monitoring in the diagnosis of GERD. Am J Gastroenterol 2007;102:1862–
1869.
169. Tutuian R, Vela MF, Shay SS, et al. Multichannel intraluminal impedance in esophageal function
1102
booksmedicos.org
testing and gastroesophageal reflux monitoring. J Clin Gastroenterol 2003;37:206–215.
170. Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simultaneous intraesophageal impedance and pH
measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology
2001;120:1599–1606.
171. Mainie I, Tutuian R, Agrawal A, et al. Combined multichannel intraluminal impedance-pH
monitoring to select patients with persistent gastro-oesophageal reflux for laparoscopic Nissen
fundoplication. Br J Surg 2006; 93:1483–1487.
172. Gruebel C, Linke G, Tutuian R, et al. Prospective study examining the impact of multichannel
intraluminal impedance on antireflux surgery. Surg Endosc 2008;22:1241–1247.
173. Gastal OL, Hagen JA, Peters JH, et al. Short esophagus: analysis of predictors and clinical
implications. Arch Surg 1999;134:633–636; discussion 637–638.
174. Ritter MP, Peters JH, DeMeester TR, et al. Treatment of advanced gastroesophageal reflux disease
with Collis gastroplasty and Belsey partial fundoplication. Arch Surg 1998;133:523.
175. DeMeester SR, Sillin LF, Lin HW, et al. Increasing esophageal length: a comparison of laparoscopic
versus transthoracic esophageal mobilization with and without vagal trunk division in pigs. J Am
Coll Surg 2003;197:558–564.
176. Stein HJ, Feussner H, Siewart JR. Failure of antireflux surgery: causes and management. Am J Surg
1996;171:36.
177. Johnson WE, Hagen JA, DeMeester TR, et al. Outcome of respiratory symptoms after antireflux
surgery on patients with gastroesophageal reflux disease. Arch Surg 1996;131:489–492.
178. Salvador R, Dubecz A, Polomsky M, et al. A new era in esophageal diagnostics: the image-based
paradigm of high-resolution manometry. J Am Coll Surg 2009;208:1034–1044.
179. Salvador R, Watson TJ, Herbella F, et al. Association of gastroesophageal reflux and O2
desaturation: a novel study of simultaneous 24-h MII-pH and continuous pulse oximetry. J
180. Potluri S, Friedenberg F, Parkman HP, et al. Comparison of a salivary/sputum pepsin assay with
24-hour esophageal pH monitoring for detection of gastric reflux into the proximal esophagus,
oropharynx, and lung. Dig Dis Sci 2003;48:1813–1817.
181. Johnston N, Knight J, Dettmar PW, et al. Pepsin and carbonic anhydrase isoenzyme III as
diagnostic markers for laryngopharyngeal reflux disease. Laryngoscope 2004;114:2129–2134.
182. Kim TH, Lee KJ, Yeo M, et al. Pepsin detection in the sputum/saliva for the diagnosis of
gastroesophageal reflux disease in patients with clinically suspected atypical gastroesophageal
reflux disease symptoms. Digestion 2008;77:201–206.
183. Watson DI, Jamieson GG, Pike GK, et al. Prospective randomized double-blind trial between
laparoscopic Nissen and anterior partial fundoplication. Br J Surg 1999;86:123–130.
184. Laws HL, Clements RH, Swillie CM. A randomized, prospective comparison of the Nissen
fundoplication versus the Toupet fundoplication for gastroesophageal reflux disease. Ann Surg
1997;225:647.
185. Hagedorn C, Lonroth H, Rydberg L, et al. Long-term efficacy of total (Nissen-Rossetti) and
posterior partial (Toupet) fundoplication: results of a randomized clinical trial. J Gastrointest Surg
2002;6:540–545.
186. Cai W, Watson DI, Lally CJ, et al. Ten-year clinical outcome of a prospective randomized clinical
trial of laparoscopic Nissen versus anterior 180° partial fundoplication. Br J Surg 2008;95:1501–
1505.
187. Jobe BA, Wallace J, Hansen PD, et al. Evaluation of laparoscopic Toupet fundoplication as a
primary repair for all patients with medically resistant gastroesophageal reflux. Surg Endosc
1997;11:1080–1083.
188. Bell RC, Hanna P, Mills MR, et al. Patterns of success and failure with laparoscopic partial
fundoplication. Surg Endosc 1999;13:1189–1194.
189. Patti MG, Robinson T, Galvani C, et al. Total fundoplication is superior to partial fundoplication
even when esophageal peristalsis is weak. J Am Coll Surg 2004;198:863.
190. Horvath KD, Jobe BA, Herron DM, et al. Laparoscopic Toupet is an inadequate procedure for
patients with severe reflux disease. J Gastrointest Surg 1999;3:583–591.
191. Watson DI, Jamieson GG, Devitt PG, et al. Paraoesophageal hiatus hernia: an important
1103
booksmedicos.org
complication of laparoscopic Nissen fundoplication. Br J Surg 1995;82:521–523.
192. Terry ML, Vernon A, Hunter JG. Stapled-wedge Collis gastroplasty for the shortened esophagus.
Am J Surg 2004;188:195–199.
193. Carlson MA, Frantzides CT. Complications and results of primary minimally invasive antireflux
procedures: a review of 10,735 reported cases. J Am Coll Surg 2001;193:429–439.
194. Hinder RA, Filipi CJ, Wetscher G, et al. Laparoscopic Nissen fundoplication is an effective
treatment for gastroesophageal reflux disease. Ann Surg 1994;220:472.
195. DeMeester TR, Bonavina L, Albertucci M. Nissen fundoplication for gastroesophageal reflux disease
– evaluation of primary repair in 100 consecutive patients. Ann Surg 1986;204:9–20.
196. Bammer T, Hinder RA, Klaus A, et al. Five- to eight-year outcome of the first laparoscopic Nissen
fundoplications. J Gastrointest Surg 2001;5:42–48.
197. Granderath FA, Kamolz T, Schweiger UM, et al. Long-term results of laparoscopic antireflux
surgery: surgical outcomes and analysis of failure after 500 laparoscopic antireflux procedures. Surg
Endosc 2002;16:753–757.
198. Catarci M, Gentileschi P, Papi C, et al. Evidence-based appraisal of antireflux fundoplication. Ann
Surg 2004;239:325–337.
199. Lundell L, Miettinen P, Myrvold HE, et al. Continued (5-year) follow-up of a randomized clinical
study comparing antireflux surgery and omeprazole in gastroesophageal reflux disease. J Am Coll
Surg 2001;192:172.
200. Nilsson G, Wenner J, Larsson S, et al. Randomized clinical trial of laparoscopic versus open
fundoplication for gastroesophageal reflux. Br J Surg 2004;91:552–559.
201. Finlayson SR, Laycock WS, Birkmeyer JD. National trends in utilization and outcomes of antireflux
surgery. Surg Endosc 2003;17:864–867.
202. So JB, Zeitels SM, Rattner DW. Outcomes of atypical symptoms attributed to gastroesophageal
reflux treated by laparoscopic fundoplication. Surgery 1998;124:28–32.
203. Lundell L, Miettinen P, Myrvold HE, et al. Seven-year follow-up of a randomized clinical trial
comparing proton-pump inhibition with surgical therapy for reflux oesophagitis. Br J Surg
2007;94:198–203.
204. Lundell L, Attwood SE, Ell C, et al. Comparing laparoscopic antireflux surgery with esomeprazole
in the management of patients with chronic gastro-oesophageal reflux disease: a 3-year interim
analysis of the LOTUS trial. Gut 2008;57:1207–1213.
205. Spechler SJ. Comparison of medical and surgical therapy for complicated gastroesophageal reflux
disease in veterans. The Department of Veterans Affairs Gastroesophageal Reflux Disease Study
Group. N Engl J Med 1992;326:786–792.
206. Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical and surgical therapies for
gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001;285:2331–
2338.
207. Lord RV, Kaminski A, Oberg S, et al. Absence of gastroesophageal reflux disease in a majority of
patients taking acid suppression medications after Nissen fundoplication. J Gastrointest Surg
2002;6:3.
208. Testa MA, Simonson DC. Assessment of quality-of-life outcomes. N Engl J Med 1996;334:835–840.
209. Trus TL, Laycock WS, Waring JP, et al. Improvement in quality of life measures following
laparoscopic antireflux surgery. Ann Surg 1999;229:331–336.
210. Glise H, Hallerbäck B, Johansson B. Quality-of-life assessments in evaluation of laparoscopic
Rossetti fundoplication. Surg Endosc 1995;9:183.
211. Velonovich V, Vallance SR, Gusz JR, et al. Quality of life scale for gastroesophageal reflux disease.
J Am Coll Surg 1996;183:217–224.
212. Fernando HC, Schauer PR, Rosenblatt M, et al. Quality of life after antireflux surgery compared
with nonoperative management for severe gastroesophageal reflux disease. J Am Coll Surg
2002;194:23–27.
213. Polomsky M, Siddall KA, Salvador R, et al. Association of kyphosis and spinal skeletal abnormalities
with intrathoracic stomach: a link toward understanding its pathogenesis. J Am Coll Surg
2009;208:562–569.
214. Hashemi M, Peters JH, DeMeester TR, et al. Laparoscopic repair of large type III hiatal hernia:
1104
booksmedicos.org
objective follow-up reveals high recurrence rate. J Am Coll Surg 2000;190:553–560.
215. Salminen PT, Hiekkanen HI, Rantala AP, et al. Comparison of long-term outcome of laparoscopic
and conventional Nissen fundoplication: a prospective randomized study with an 11-year follow-up.
Ann Surg 2007;246:201–206.
216. Oelschlager BK, Pellegrini CA, Hunter J, et al. Biologic prosthesis reduces recurrence after
laparoscopic paraesophageal hernia repair: a multicenter, prospective, randomized trial. Ann Surg
2006;244:481–490.
217. Rosen R, Nurko S, Furuta GT. Impeding gastroesophageal refluxate: a new application of an old
medication. Gastroenterology 2003;125:984–985.
1105
booksmedicos.org
Chapter 43
Esophageal Tumors and Injury

Jonathan D’Cunha and James D. Luketich
Key Points
1 The esophagus lacks a serosal layer. This is distinctive from other parts of the gastrointestinal tract.
It is a major factor as tumor growth radially is not limited as in other gastrointestinal cancers.
2 Esophageal perforation is a morbid clinical entity that has increasing incidence due to invasive
procedures where iatrogenic injury accounts for over 50% of cases.
3 The management of esophageal perforation is dictated by location of the perforation, the clinical
condition of the patient, and the presence of underlying pathology.
4 Esophageal stenting is a newer modality which has a role in esophageal perforation in well-selected
clinical cases.
5 The incidence of esophageal adenocarcinoma mirrors the rise in gastroesophageal reflux disease and
obesity at an epidemic rate.
6 In advanced stages, neoadjuvant therapy for esophageal adenocarcinoma suggests a survival
advantage when chemoradiation is given prior to surgery for advanced disease. Early stage disease
with minimal to no nodal involvement may go directly to surgery in selected cases.
7 Surgery remains the primary therapy for esophageal cancer and options include transhiatal
esophagectomy, Ivor Lewis esophagectomy, three-field esophagectomy, thoracoabdominal
esophagectomy, and minimally invasive esophagectomy.
8 Minimally invasive esophagectomy can be performed safely with excellent oncologic outcomes and
lower morbidity than the open procedure.
9 There are numerous palliative options for the patient with advanced esophageal cancer to maintain
comfort, afford oral intake, and manage the symptoms of the disease in the end-stage situation.
INTRODUCTION
The esophagus is an active conduit that assists in transfer of food and secretions from the pharynx to the
stomach. The esophagus is an organ of motility and provides no absorptive function. It also isolates the
food and secretions from the mediastinum during transit.
Although the esophageal anatomy has been reviewed in the previous chapter, there are several points
of consideration which need to be outlined as they are particularly relevant to surgical practice. First,
three indentations can be identified on esophagram (Fig. 43-1). The cricopharyngeus muscle is the most
proximal indentation and is a common location for iatrogenic perforation. The second indentation is the
aortic arch which is just to the left of the esophagus and a common location for foreign body or food
impaction. The third indentation is the left mainstem bronchus.
In the adult, the length of the esophagus is somewhat variable and certainly becomes relevant in the
presence of a perforation, injury, or any requirement for reconstruction. The average overall length of
the esophagus is 24 cm, with the esophagus beginning at the cricopharyngeus which is 14 to 16 cm from
the incisors in an average-sized adult and ends at the gastroesophageal sphincter which is located 38 to
40 cm from the incisors when measured endoscopically.
The blood supply to the esophagus is segmental. The esophagus is vascularized by numerous arteries
coursing through the lateral attachments and has an extensive submucosal collateral circulation. The
cervical esophagus receives blood from the superior and inferior thyroid arteries. Multiple
aortoesophageal arteries supply the intrathoracic esophagus and connect via collaterals with the inferior
thyroid, intercostal, bronchial, inferior phrenic, and left gastric arteries. This blood supply is especially
relevant during any operation on the esophagus and control of these segmental vessels is critical for a
smooth operative and postoperative course.
1106
booksmedicos.org
1 The esophagus is composed of an outer longitudinal muscle layer and an inner layer of circular
muscle. There is no serosal layer and this is a critical consideration when one thinks about disease
processes of the esophagus. The lack of serosal layer is a distinguishing feature of the esophagus when
compared with other parts of the gastrointestinal tract. The esophagus also has a unique submucosal
layer which has a high fat content. This leads to an overlying mobility of the mucosa and propensity for
proximal retraction such that care must be taken when placing sutures for reconstruction and
minimizing the potential for anastomotic leak. The intramural lymphatic network is predominantly
located within the submucosa of the organ. This is a rich lymphatic network which is especially relevant
when one considers oncologic spread of tumor. There are also lymphatic channels within the lamina
propria of the mucosa. All of this sets the stage for even superficial tumors to be associated with nodal
metastases.
The esophagus is innervated by the autonomic nervous system. The cervical esophagus receives
parasympathetic innervation through the recurrent laryngeal branches of the vagus nerve. Thus, injury
to the recurrent laryngeal nerve not only produces vocal cord dysfunction, but also upper esophageal
sphincter dysfunction.
ESOPHAGEAL INJURY
Perforation
Esophageal perforations are a major source of morbidity (10% to 60%) and mortality (4% to 50%);
furthermore, following a perforation, 10% to 50% of patients develop strictures requiring dilations.1–9
To date, no unified approach is available to treat these complex problems. Accurate diagnosis and early
treatment are essential to the successful management of these complicated and often significantly ill
patients. Some investigators suggest aggressive operative intervention (e.g., surgical exploration and
repair or gastric conduit takedown with diversion) for patients with postesophagectomy intrathoracic
anastomotic leak, while others recommend nonoperative management with stenting, jejunostomy feeds,
perianastomotic drainage, and broad-spectrum antibiotics.5,10–15 Guidelines for either approach may
work depending on the injury and thoracic surgeons must incorporate clinical judgment in the
therapeutic decision-making process. The decision is influenced by the location and size of the
perforation, the timing and mechanism, the degree of periesophageal soling and extravasation,
coexisting pathology of the esophagus, the patient’s overall clinical condition and perhaps most
importantly, the experience of the surgeon.
Figure 43-1. Barium contrast esophagography showing the constriction caused by the cricopharyngeal muscle, aortic arch, and the
left mainstem bronchus. Indentations of the esophagus made by external structures are important anatomic landmarks and are
often the sites of perforation due to instrumentation.
2 The incidence of perforation has risen in the modern era due to the rise in endoscopic interventions.
The causes of esophageal perforation are listed in Table 43-1. Generally speaking the incidence of
iatrogenic perforation (59%) far outweighs the incidence of spontaneous perforations (15%).12 Other
1107
booksmedicos.org
less common injuries include foreign-body ingestion (12%) and trauma (9%). Ingestion of foreign
bodies or caustic materials most commonly causes perforations in the anatomic areas just proximal or at
narrowing (cricopharyngeus, level of aortic arch, and the level of left mainstem bronchus). Also
included in the area at risk is the lower esophageal sphincter zone. External penetrating trauma can
occur at any level but is seen more commonly in the cervical esophagus as the mediastinal portion is
posterior and protected by the thorax. The morbidity and mortality of penetrating esophageal trauma is
usually related to associated injuries including major vascular and airway structures.16 Blunt traumatic
perforation of the esophagus is exceedingly rare.
The most commonly referenced and discussed perforation is the spontaneous one. This results from a
sudden increase in intraesophageal pressure and associated with hyperemesis, childbirth, seizure, or
prolonged coughing. Boerhaave syndrome is of special historical note, wherein patients develop
perforation of the distal esophagus following extensive ingestion of food or alcohol. What follows is
violent emesis resulting in a distal esophageal perforation, frequently into the left chest. The syndrome
was named after Herman Boerhaave, who provided a detailed account of this condition in 1723 through
a postmortem correlation of the perforation found in the High Admiral of the Dutch Navy, Baron Van
Wassenaer.17 Legend has it that the admiral attempted to relieve his postprandial discomfort by self-
induced vomiting after having feasted on roast duck and beer.
ETIOLOGY
Table 43-1 Causes of Esophageal Perforation
Clinical Features of Esophageal Perforation

The presenting features depend on the location of perforation and the time interval from perforation to
presentation. Underlying comorbidities may also have an influence on the presentation and the patient’s
physiologic reserve. Patients with cervical perforation present with dysphagia, neck pain, dysphonia,
and subcutaneous neck emphysema. Intrathoracic perforations present with signs and symptoms of
mediastinitis as follows: chest pain, tachycardia, tachypnea, fever, and leukocytosis. Perforations of the
intra-abdominal esophagus may present as an acute abdomen with signs and symptoms as follows: pain,
tachypnea, tachycardia, fever, and leukocytosis. More significant perforations and longer intervals to
presentation contribute to the features of systemic sepsis, shock, and rapid deterioration.
Diagnosis
The diagnosis of esophageal perforation needs to begin with the clinician and their index of suspicion.
Any patient who presents with pain following an endoscopic intervention needs to be carefully
evaluated for perforation. The initial workup involves careful history and physical examination,
laboratory studies including leukocyte count, and chemistry panel for acidosis. Chest x-ray is a good
screening test for other diagnoses in the differential. Contrast esophagography remains the gold
standard for diagnosis as the study will diagnose and localize the site of the perforation. This study also
gives important information about coexisting pathology of the esophagus and the degree of
1108
booksmedicos.org
extravasation and its trajectory. Water-soluble contrast (e.g., Gastrograffin) is the initial agent utilized,
followed by thin barium to enhance the sensitivity of the study. Water-soluble agents demonstrate 50%
of cervical perforations and 80% of intrathoracic perforations.18 Thin barium will identify 60% of
cervical and 90% of intrathoracic perforations.19 If there is a chance of aspiration or high concern of
tracheoesophageal fistula, thin barium should be used from the outset because the hyperosmolar water-
soluble contrast agents may cause rapid pulmonary edema and respiratory compromise.
Computerized tomography (CT) scan is very useful in the diagnostic evaluation of the patient with
concern for esophageal perforation. Often a CT scan is the first test obtained following a chest x-ray as
it affords the clinician the ability to narrow the differential diagnosis. CT may be useful for identifying
the site of perforation and any associated mediastinal or pleural fluid collections. It is very common for
a CT scan finding to prompt thoracic surgical consultation or transfer and there is much additional
information about the patient’s overall status which is routinely utilized in the management plan.
However, it should be emphasized that the barium swallow should be the procedure of choice unless
there is a significant risk of aspiration.
Flexible esophagoscopy should be utilized liberally in the diagnostic evaluation of the esophagus and
in the planning of treatment options, and in a significant number of cases it can also be used for
intervention. The scope is utilized to directly visualize the area of perforation and identify any potential
associated pathology. It has a sensitivity of over 95% and a specificity of 80% or even higher depending
on the experience of the physician.20 We routinely perform flexible endoscopy as the initial step in the
operating room when considering all options for patient management. Concern has been expressed by
some that the instrumentation of the esophagus and insufflation of air can worsen the extent of injury
and pathology and we would agree with that in inexperienced hands. With care and experience,
however, the flexible scope can be used safely and more effectively delineates the problem to aid in
surgical decision-making that follows. The vast majority of patients will require an endoscopic
evaluation at some point and the timing of this will depend on clinical presentation and findings on
radiologic imaging. For very small leaks present in stable and nontoxic patients, when the contrast
study shows little or no extravasation, we may opt to hold off on an endoscopy in select cases.
Management
3 The treatment of esophageal perforation is managed according to the clinical presentation which
includes the location of the perforation, the degree of soilage, and the clinical condition of the patient.
Generally speaking, the sooner diagnosis and a treatment plan is carried out, the better the outcome.
The goal of treatment is to stabilize the patient, stop ongoing soilage, control the infection, and
reestablish esophageal continuity. Algorithm 43-1 provides general guidelines to the management of
patients with esophageal perforations.
Nonoperative Treatment
For properly selected patients with esophageal perforation, nonoperative management may be
appropriate. Generally, as thoracic surgeons, we err on the side of operative exploration intervention
given the potential gravity of missing a clinically significant esophageal perforation with mediastinal
soilage. Reports of nonoperative management date back to the 1960s in which successful management
was accomplished in 18 highly selected patients with only one death.21 In the late 1970s, criteria were
published for nonoperative management.22 Current guidelines for patients that can be managed
nonoperatively include those with no transmural perforation or for whom transmural perforation
represents a contained process. There must also be no associated esophageal pathology such as
malignancy and no signs of systemic illness. The management of the nonoperative approach begins with
the administration of broad-spectrum antibiotics (including antifungals), the suspension of oral intake,
and vigilant clinical monitoring. The patient is followed clinically and reimaged as needed, generally
within 48 to 72 hours with an esophagram and CT scan. If the patient improves during that time and
testing is favorable, the diet may be advanced to clear liquids with the patient eventually being
discharged on oral antibiotics and full liquids until reevaluation with imaging in clinic in 2 weeks. Any
signs of sepsis such as fever, tachycardia, or leukocytosis suggest failure of this approach and further
intervention should be expeditiously considered.
1109
booksmedicos.org
Algorithm 43-1. Evaluation and treatment of esophageal perforation.
Esophageal Stents
4 Endoscopic placement of endoluminal stents for perforations has been a concept which has been
discussed for several decades.23 In the last 10 years, the technology of stents has improved such that
deployment is easier and our indications have expanded to include placement for perforations. Starting
with small limited series,24–30 their use has expanded dramatically to the point that they have become
one of the main tools in the management of select, contained perforations. Highly selected patients with
perforations are candidates for stenting in the context of a thoracic surgical practice according to the
principles outlined in this section. Our own investigations and use in our practice has found that
esophageal stent placement for perforations facilitates source control, may minimize stricture
formation, and frequently allows for early oral intake. However, success depends on a uniform
approach that focuses on appropriate patient selection, proper stent placement technique, thorough
drainage procedures which cannot be underemphasized, and meticulous postoperative care. Our
recommended uniform approach is presented here and this approach has yielded excellent results.31–33
DIAGNOSTIC EVALUATION
A computerized tomography (CT) scan, with or without oral and intravenous (IV) contrast, is a good
initial diagnostic test. The role of a CT scan is to help determine whether additional source-control
measures are needed (e.g., tube thoracostomy, decortication). We frequently perform the contrast
esophagram second as the barium may interfere with the CT scan and the only reason we omit this step
is in the case of aspiration risk. The barium esophagram is regarded as a real-time image, whereas the
contrast delivery of the CT scan does not provide the same functional and anatomic details of the site
and tracking of the leak, thus we prefer both when possible.
PATIENT SELECTION
For perforations proximal to the cricopharyngeus, stents have little or no role. For perforations 2 cm or
more distal to the cricopharyngeus, a stent may work if the proximal extent seats just below the
cricopharyngeus muscle. If the stent seats at or above the cricopharyngeus, patients experience
intolerable foreign-body sensations during deglutition and reflux and coughing are generally severe.
Also of note, stents placed in the proximal esophagus may cause pressure and compression of the
posterior membranous trachea leading to dyspnea and, in severe cases, critical airway compromise. If a
stent is considered in the proximal esophagus, the physician should strongly consider performing a
simultaneous bronchoscopy to assess airway patency. Perforations below this area may be good
1110
booksmedicos.org
candidates for stenting when there is limited perforation, and there is good purchase of esophagus
above and below the site of the perforation. This might include perforations associated with malignancy
and in benign diseases such as iatrogenic perforation, Boerhaave syndrome, and select cases of
achalasia. Patients with perforations from near-obstructing cancers can be ideal candidates for stents as
the stent will purchase well against the tumor, leading to sealing of the perforation and relieving any
coexisting blockage above or below the perforations. In addition, operating on perforated cancers can
be a significant clinical problem as this may occur at the initial diagnosis or the endoscopic ultrasound
(EUS), or may occur during chemo and radiation, thus making stenting our procedure of choice in the
setting of cancer.
Initial broad-spectrum antimicrobial therapy is directed to cover common gram-negative bacteria,
anaerobic bacteria, and fungi. We generally use a beta-lactam agent in combination with fluconazole,
which is usually sufficient. We adjust therapy to culture findings. Duration of therapy is patient
dependent, but it is typically continued for 10 to 14 days after resolution.
In addition to antimicrobial therapy, we tailor further source control in accordance with clinical, CT
scan, endoscopic, and intraoperative findings. We emphasize aggressive source control, and operative
drainage of any extraluminal material. Stent placement without drainage in the setting of mediastinal
soilage is a risky approach and if it is done, one may question whether the perforation was small
enough to need intervention and, if larger, we would typically perform a VATS or thoracotomy to
debride any soilage. If patients deteriorate clinically following any treatment, consideration of the
presence of undrained sepsis should always be considered. At times, a patient might require several
interventions to control the local and regional sepsis.
Source control measures vary depending on clinical and anatomical findings:
Mediastinal air (no fluid): antibiotics only without additional source control measures.
Mediastinal fluid collection or abscess: operative drainage; the approach varies by anatomical location:
Neck and superior mediastinum: lower neck incision with blunt mediastinal dissection, irrigation,
open packing, and, if deemed appropriate, drain placement.
Posterior mediastinum at any level: right thoracoscopy or thoracotomy with wide pleural incision,
drainage, irrigation, and large-bore chest tube(s) placement.
Lower posterior mediastinum only: left thoracoscopic or open drainage.
Free-flowing pleural effusion: large-bore tube thoracostomy.
Empyema: thoracoscopic or open decortication.
STENT SELECTION
Numerous stents are available for use. We prefer the Wallflex fully covered stent and find that the
longer stents (15 cm) work better to cover defects and minimize migration.
STENT PLACEMENT TECHNIQUE

We perform our procedures in the operating room and with the patients under general endotracheal
anesthesia. The key components of our stent placement technique are the following:
1. Position: supine position with the head of the bed elevated 30 degrees.
2. Intraoperative fluoroscopy:
Radiopaque skin markers: large-bore IV needles taped to the skin. Lock the fluoroscopy arm into
position once the desired image has been obtained and before skin marker placement; moving the
fluoroscopy arm after marker placement may lead to inaccurate marking.
At times, we will use intraoperative esophagram: if the leak is small, we will inject contrast through
the esophagoscope to clearly identify it; we always confirm leak sealing with contrast injection
after stent placement. We use isomolar and water-soluble contrast dye (iodixanol [Visipaque]; GE
Healthcare Inc, Princeton, NJ) to minimize respiratory complications in case of aspiration.
3. Wire of choice: superstiff, angled or straight tip, 0.035-in (0.8-mm) diameter, 260-cm length.
4. Stent position:
Minimum coverage: at least 3 to 4 cm above and below the leak or perforation.
Minimum distance from cricopharyngeus muscle (upper esophageal sphincter): 1 to 2 cm.
Distal end position: we avoid the distal end from crossing the GE junction.
1111
booksmedicos.org
5. Stent foreshortening or “jumping” on deployment: this varies by stent.
6. Intraoperative evaluation of stent position and proper sealing: every stent is placed and evaluated
with fluoroscopic guidance and endoscopy.
7. Tools and techniques for stent repositioning (if stent is too distal or too proximal): the “rattooth”
forceps is the best tool to pull the stent proximally if needed after deployment. If we need to advance
the stent in a patient with a gastric conduit, then we will advance the gastroscope into the distal
stomach, retroflex, lock the “rat-tooth” grasper on the distal end of the stent, and push the
gastroscope forward.
8. Indications for immediate stent removal: we never leave a stent in place if it is not in perfect
position, angulated too much, or obstructed.
POSTSTENT MANAGEMENT
1. Nutrition: enteral feeding access should be ensured as soon as possible, preferably at the time of
endoscopic and operative interventions. We place an operative jejunostomy tube or percutaneous
endoscopic jejunostomy tube in the occasional postesophagectomy patient who does not already have
enteral feeding access. In patients with perforations, we place a percutaneous endoscopic gastrostomy
(PEG) tube at the time of endoscopic or operative intervention but before stent placement. In our
experience, placing a PEG tube has no effect on the perforation; placing a PEG tube after stent
placement will likely displace the stent.
2. Aspiration and reflux precautions: these precautions are imperative in all postesophagectomy patients
and in patients with stents that cross the gastroesophageal junction.
3. Postprocedure follow-up:
a. Chest radiograph: we obtain chest radiography immediately after the procedure and daily
thereafter to monitor for migration.
b. Sepsis resolved: we wait until the patient is able to swallow appropriately; then we perform an
esophagram.
c. Ongoing sepsis: we thoroughly reassess the patient; ongoing sepsis is generally due to poor source
control and/or nonsealing of the leak or perforation. Reintervention is then tailored to the situation
but might require aggressive surgical intervention and stent removal and/or replacement.
d. Stent migration: mandates replacement unless leak has resolved. This is typically not an emergency
but should be addressed in a timely fashion.
4. Resumption of oral intake: this depends on the clinical scenario. A speech pathologist evaluates every
patient before an esophagram. Only patients who are safe to swallow undergo an esophagram. Oral
intake is then resumed.
5. Eventual stent removal or exchange: We generally repeat endoscopy at 3-week intervals and remove
the stent. If a small leak persists, we restent so that the distal end of the stent is slightly proximal or
distal to that of the previous stent to allow the area of inflamed gastric mucosa to heal.
6. Pain: pain appears to be less common in patients with leaks and perforations than in patients with
malignant strictures. Persistent pain should prompt reevaluation, because it might represent ongoing
mediastinal or pleural contamination.
Operative Treatment
The operative management of esophageal perforation is dictated by the location of the injury, extent of
injury, and underlying pathology. The operative approaches include the following options: drainage
alone, primary reinforced repair, esophagectomy with immediate/delayed reconstruction, and
esophageal exclusion.
Perforations of the upper third of the esophagus to the level of the carina and treated by cervical
drainage that is approached via a left neck incision as depicted in Figure 43-2. Traditionally it is not
necessary to find or close the perforation as this will seal during the process of healing. In order for this
to be successful, however, wide and complete drainage must be accomplished. The posterior
prevertebral fascia is opened completely to accomplish this. Preoperative imaging via CT scan will aid
in ensuring that the important areas of contamination are addressed surgically. In the operating room
we liberally use on-table flexible endoscopy to evaluate the defect and the location of the hole. If the
hole is identified and it is small, we advocate for closure of the hole. The neck incision is loosely closed
with staples over a drain. Postoperatively, broad-spectrum antibiotics are continued. One may consider
1112
booksmedicos.org
a gastrostomy or jejunostomy tube for nutritional access during the time the patient is NPO. Typically
at 5 to 7 days postoperatively a contrast esophagram is obtained, the patient’s diet is advanced, and the
drain is removed. If there is continued leak, the patient is left NPO or on clear liquids and restudied in 1
week. There should be no distal obstruction on the contrast study and if there is a stricture that prevents
normal contrast flow, we advocate for dilation to aid in eventual closure of the esophageal fistula. As
long as there is no underlying pathology and there is distal flow through the esophagus in the presence
of adequate drainage, the esophageal perforations will heal spontaneously.
Perforations of the middle third of the esophagus are best approached through the middle third of the
esophagus via a right 5th interspace posterolateral thoracotomy. After adequate IV access and arterial
line placement, a single-lumen tube is placed and bronchoscopy/esophagoscopy is performed. The
single-lumen endotracheal tube is changed to a double-lumen endotracheal tube and the patient is
positioned in the left lateral decubitus position. We routinely start thoracoscopically, but typically these
patients are very ill and thoracotomy is indicated early. At the time of entry into the chest, an
intercostal m. flap is routinely taken. We use papaverine solution to enhance blood flow and great care
is taken not to injure the flap when the retractors are placed. A Doppler is routinely used to confirm
blood flow in the flap. All pleural collections are drained, the lung is decorticated, and the site of
perforation identified after opening the posterior mediastinal pleura. Necrotic tissue at the site of the
perforation is debrided and the esophagus is mobilized. A vertical myotomy is performed to expose the
mucosa and the full extent of the tear (Fig. 43-3). The mucosa is repaired with interrupted or running
absorbable suture. The muscular layer is reapproximated with interrupted fine silk suture. On-table
endoscopy is performed to ensure the leak is repaired. The intercostal m. is then secured as an onlay
patch. Large chest tubes are placed and a 10-French Jackson–Pratt drain is left in the area of the repair
and placed to bulb suction. Typically nutritional access is not addressed at the time of the index
operation as the patients are quite ill, and this can be accomplished at a later date. On POD 7, a contrast
study is obtained and if there is no leak, the diet is advanced. Persistent leaks are treated with JP
drainage, provided CT imaging demonstrates that there are no undrained collections. Esophageal
dilation may be required to ensure proper forward flow. Reoperations for adequate drainage may be
required. Esophageal stenting may be used to exclude the leak provided that there is adequate drainage
and the principals described in the stenting portion of this chapter are followed. If the repair breaks
down or there are signs of clinical sepsis, esophageal exclusion may be required with cervical
esophagostomy, esophageal resection, and gastrostomy tube. When the patient recovers and walks into
clinic begging for reconstruction (this usually occurs at 6 to 12 months postexclusion), they may be
considered for reconstruction most commonly approached as a substernal gastric pull-up.
1113
booksmedicos.org
Figure 43-2. Approach for drainage of a cervical esophageal perforation. A: Skin incision parallel to the anterior border of the left
sternocleidomastoid muscle, extending from the level of the cricoid cartilage to the sternal notch. B: With the sternocleidomastoid
muscle and carotid sheath retracted laterally and the trachea and thyroid gland medially, blunt dissection along the prevertebral
fascia in the superior mediastinum is carried out. Injury to the recurrent laryngeal nerve in the tracheoesophageal groove must be
avoided. C: Schematic drawing of the prevertebral space drained by this cervical approach. D: Two 1-in rubber drains placed into
the superior mediastinum are brought out through the neck wound to allow establishment of an esophagocutaneous fistula, which
usually heals spontaneously.
Figure 43-3. Primary repair of esophageal perforation. The edematous mucosa pouting through the muscular defect (inset) is
grasped with Allis clamps and elevated. A 1-cm vertical esophagomyotomy is made at either end of the muscular defect to expose
the entire limits of the tear. This is facilitated by using a right-angle clamp to direct muscularis away from underlying submucosa
around the entire circumference of the tear. The result of this mobilization is exposure of a circumferential rim of normal
submucosa that can then be closed.
Perforations of the distal third of the esophagus are approached via a left 7th intercostal space
thoracotomy. Similar to the approach for middle-third perforations, after adequate IV access and arterial
line placement, a single-lumen tube is placed and bronchoscopy/esophagoscopy is performed. The
single-lumen endotracheal tube is changed to a double-lumen endotracheal tube and the patient is
positioned in the left lateral decubitus position. Thoracoscopy may be an option, but typically these
1114
booksmedicos.org
patients are very ill and thoracotomy is indicated. At the time of entry into the chest, an intercostal m.
flap is routinely taken and care is taken not to injure it as retractors are placed. The chest is drained,
lung decorticated, the perforation identified, and the repair performed as described above.
The operative treatment in the presence of underlying pathology deserves special attention and can
be quite challenging. If there is distal obstruction, this must be dealt with. Strictures can be dilated or
stented and often support the healing of a proximal perforation. Patients with achalasia who are
perforated during pneumatic dilation are especially challenging. Many are candidates for nonoperative
intervention as they have small perforations that are asymptomatic and the patients are clinically
nontoxic. This is acceptable provided the distal obstruction has been relieved. For those who fail
nonoperative management or are not candidates, operative management should be tailored to the
individual and their pathology. In patients with preserved motility, the perforation should be repaired
primarily and a vertical myotomy should be performed 180 degrees opposite the injury. These patients
should have a nonobstructive fundoplication performed. For stable patients with advanced achalasia,
esophagectomy should be considered. For unstable patients, esophageal exclusion should be performed.
Unstable patients with advanced pathology such as cancer should undergo esophageal exclusion. This
includes stapled esophageal diversion with resection of the diseased segment of the esophagus. A linear
stapler is deployed on the esophagus proximally and at the gastroesophageal junction. The esophagus is
resected. An end cervical esophagostomy is created saving as much esophageal length as possible.
Pleural drainage is accomplished. Subsequently the patient undergoes placement of gastrostomy (+/–
jejunostomy tube) with repair of the diaphragmatic defect from the abdominal side via laparoscopy or
laparotomy. The components of operation may be staged based on the severity of patient illness. If the
patient survives and is a candidate for reestablishment of continuity, this can be investigated at a later
date when they recover. In the current healthcare climate, the presentation of an advanced perforated
malignancy, stenting and drainage may have a role. Additionally, consideration should be given to end-
of-life discussions depending on the extent of the cancer.
Caustic Injury
Caustic burns of the esophagus result from ingestion of caustic substances. In children, ingestion is
typically accidental, but in adults, ingestion is often intentional as part of a suicide attempt. Although
prevention programs, consumer product safety commissions, lobbying by the medical profession, and
heightened consumer awareness have significantly diminished the devastating effects of caustic
ingestions, caustic injury of the esophagus remains a significant medical and social problem. The two
most common ingestion scenarios are accidental ingestions in children younger than 5 years old and
suicide attempts in individuals 15 to 40 years old. The most commonly ingested agent is an alkaline
household liquid cleaner. Although mortality from caustic ingestion is low, the morbidity associated
with caustic ingestions is significant. Acute morbidities include perforation and necrosis, and late
morbidities, which are more prevalent, include stricture formation and cancer.
The extent of injury to the esophagus caused by ingested caustic material is dependent on the volume
and nature of the ingestion. Injuries resulting from ingestion of liquids are much more severe than those
caused by ingestion of solids. The patient usually spits particulate matter out and, thus, it rarely moves
beyond the oropharynx. Liquid caustic agents contribute to pathology down the length of the
esophagus. Strong acid and alkali ingestions comprise the majority of caustic ingestions. These
substances are sold in various liquid and solid/particulate forms. The most commonly ingested strong
acids include industrial and swimming pool cleaning solutions, battery fluids, and antirust compounds.
Commonly ingested strong alkaline-containing substances include household cleaning products and
personal hygiene products. The most commonly ingested weak alkali is ammonia hydroxide, which is
found in most bleach solutions. Weak alkalis cause much less injury and require far less therapy.
The burns from acid ingestion cause coagulative necrosis and a superficial eschar that protects the
deeper layers of the esophagus from damage. Fortunately, acids tend to taste bitter and cause
immediate pain, thus the patient will usually spit the substance out well before it reaches the esophagus
and stomach. When acids are ingested in liquid form, they move quickly, typically spare the
oropharynx, and produce skip injuries to the esophagus. Acids in liquid form cause gastric and duodenal
injury more frequently than esophageal injury.
Alkaline burns are characterized by liquefactive necrosis, leading to far greater penetration at the
level of the oropharynx and esophagus. Solid alkali has a propensity to adhere to the oropharynx,
whereas liquid alkali is rapidly swallowed. Thus, liquid alkali results in more distal esophageal and
gastric injury. Frequently there is penetration of all layers of the esophagus causing substantial
1115
booksmedicos.org
secondary edema. Commensurate with this, the potential for perforation and circumferential scar
formation is greatest with an alkaline ingestion. In contrast to acid ingestion, alkali substances are
typically odorless and tasteless, which enhances the potential for deeper injury.
Management
The initial clinical presentation comprises oropharyngeal pain; irritability; and, in severe cases,
excessive salivation, dysphagia, and airway compromise. Ingestion of particulate caustic substances
results in signs of contact readily visible in the oropharynx. Hoarseness and stridor are signs of serious
airway injury that mandate intubation. Retrosternal pain, neck crepitus, and sudden onset of epigastric
pain imply full-thickness esophageal damage. Many patients present without symptoms and a significant
proportion have injuries that will require intervention. Thus, a 24-hour period of observation is
reasonable, even for asymptomatic patients, especially if there is any question about the circumstances
of the ingestion or extent of injury.
As with any acute situation, management should begin with the standard assessment of the ABCs
(airway, breathing, and circulation) (Algorithm 43-2). Most caustic ingestions involve the oropharynx,
lips, and gums. As with most foreign-body ingestions, the most common sites for pathology within the
esophagus are its three areas of narrowing: the cricopharyngeus, the level of the aortic arch, and the
gastroesophageal junction. A stable patient may undergo imaging via posteroanterior and lateral upright
chest and abdominal radiographs to evaluate for pleural effusion or free air. CT of the chest and
abdomen can provide important anatomical definition of injury. Patients with no visible symptoms or
only lip swelling or redness can be observed in the hospital or a short-stay unit for 24 hours to ensure
they can tolerate oral feedings. This is typically for pediatric patients. Patients with oral lesions should
undergo esophagoscopy and bronchoscopy. The bedside insertion of a nasogastric or orogastric tube is
discouraged when the extent and depth of injury have not been fully evaluated.
After radiographic imaging, rigid or flexible esophagoscopy to characterize the location and extent of
injury should be the next course of investigation. This instrumentation should be performed within the
first 24 hours as the risk of procedural complication increases with time. The indications for
esophagoscopy include stridor, vomiting, drooling, and intentional ingestion. Caution should be used
when moving beyond the first sign of pathology below the cricopharyngeus. If there are respiratory
symptoms, laryngoscopy and bronchoscopy should be performed. When injury is identified, the standard
grading of the esophageal burn should be reported (Table 43-2).
Patients with grade I injuries have superficial burns causing edema and hyperemia. These patients can
be observed, a normal diet can be advanced, and the patient ultimately can be followed in an outpatient
clinic. Superficial grade I injuries cause mucosal sloughing and should heal without a stricture. Grade II
injuries penetrate into the muscular layer of the esophagus and can result in either patchy (IIA) or
circumferential (IIB) injury. Ulcerations (superficial and deep) and pseudomembranes are found during
endoscopy. Once circumferential injury is identified, the risk of stricture formation increases
dramatically. Grade III injuries are full-thickness injuries, and mediastinitis or peritonitis occurs within
48 hours. Grade III findings are characterized by gray mucosal slough, thrombosed submucosal vessels,
and black eschar. All grade III burns and >75% of circumferential grade IIB burns cause esophageal
stricture and, as expected, are associated with a higher incidence of infection.
1116
booksmedicos.org
Algorithm 43-2. Proposed algorithm for evaluation and management of acute caustic ingestion.
Acute management of caustic ingestion should be dictated by the endoscopic grading of the esophagus
and the clinical status of the patient (Algorithm 43-2). Patients should be evaluated for using endoscopy
to grade the injury. If there is no evidence of perforation, patients with mild exposure (e.g., bleach or
detergent ingestion) can be observed for 24 to 72 hours (depending on the clinical presentation).
Generally, patients should be kept nil per os (NPO) until pain free. Enteral feedings can likely be
introduced within 48 hours for all patients with grade I or IIA burns.
CLASSIFICATION
Table 43-2 Endoscopic Grading of Acute Caustic Injury to the Esophagus
Patients with grade IIB or grade III esophageal burns without evidence of perforation should be
placed in a monitored setting, kept NPO, and given IV fluids and IV antibiotics (penicillin derivative or
clindamycin). Patients should also be maintained on proton pump inhibitors to reduce acid exposure of
the esophagus as this may decrease the stricture incidence. Steroid administration is controversial, does
not prevent stricture formation, and may mask findings in the serial abdominal examination. If
corticosteroids (2 to 2.5 mg/kg/d) are used, they should be instituted within the first 24 hours of
ingestion and for 3 weeks thereafter. Early introduction of parenteral nutrition is essential for all
patients with esophageal perforation and for patients with poor gastric motility. Open gastrostomy is
helpful for patients with grade IIB or III burns. Depending on the extent of injury, the patient may
require mechanical ventilation. Esophagram (or CT scan with oral contrast) may be used as an adjunct
evaluation. If free contrast extravasation into the mediastinum is visualized, drainage of the
1117
booksmedicos.org
mediastinum into the pleural space is indicated. Further, esophageal resection may be required with
findings of necrosis. On occasion, a contained mediastinal leak, which returns contrast material back
into the esophagus, may be observed without the need for immediate drainage. Pneumoperitoneum is
an absolute indication for laparotomy and resection of all dead tissues. Laparoscopic evaluation may be
useful to evaluate the abdomen if there is isolated mediastinal pathology.
Strictures of varying degrees occur in almost all patients and, thus, careful follow-up is recommended
after a caustic ingestion. The esophagus and stomach should be evaluated via barium swallow 3 weeks,
3 months, and 6 months after the ingestion to rule out stricture formation or gastric outlet obstruction.
Esophagogastroduodenoscopy (EGD) is typically performed 3 weeks after the ingestion for full
evaluation. Early endoscopy is warranted during the phase of cicatrix formation, and dilation is
repeated at varying intervals. The interval for intervention is patient dependent and clinically dictated
by the amount of dysphagia or interval to recurrence of dysphagia, the initial severity of burn, and
findings on radiographic studies.
Operative Considerations
Delay in the diagnosis of esophageal perforation from caustic ingestion is uniformly fatal. Isolated
mediastinal air can be managed with direct inspection of the thorax, open débridement of necrotic
tissue, and drainage of the mediastinum. Caustic esophageal perforations are best managed with urgent
esophagectomy. Removal of the entire esophagus is possible through a transhiatal approach followed by
a cervical esophagostomy, gastrostomy, and feeding jejunostomy. Patients with extensive full-thickness
esophageal and gastric necrosis should undergo total esophagogastrectomy with cervical esophagotomy
and feeding jejunostomy. Of course, any operative intervention should include assessment of other
organs involved and complete drainage/resection of necrotic tissue.
In most patients, management of esophageal strictures that develop as a result of caustic burns is the
primary operative consideration. Circumferential grade IIB burns can be managed with an open
gastrostomy and insertion of a string through the gastrostomy that exits transnasally. Four weeks after
the burn, serial dilations using progressive antegrade bougienage from the oropharynx or retrograde
stringing bougienage through the gastrostomy is effective. Retrograde string bougienage or antegrade
dilations should be performed at 2- to 3-week intervals for consecutive dilations. Optimal caliber
bougienage is 48 to 50 for adults and 34 to 36 for children. Esophageal stenting is a newer approach for
second-degree esophageal burns, which may be more palatable than string bougienage. A removable,
fully covered stent is placed endoscopically and left in place for 3 weeks. It can then be removed.
Recent reports have suggested that this is an appropriate intervention to prevent stricture formation in
some patients. Injection of the stricture with triamcinolone (30 mg/mL) also may be effective,
especially in those strictures that are focal.
Esophageal replacement is usually considered if a stricture fails to resolve after 1 year of dilations,
stricture injections, and antacid therapy. Malignant degeneration is possible at the area of the stricture,
and esophageal cancer occurs at a 1,000-fold greater frequency in individuals with a caustic injury to
the esophagus than in the general population. Any change in symptoms warrants radiographic and
endoscopic evaluation. Options for esophageal replacement include reverse gastric tube, gastric pull-up,
and colon or jejunal interposition. Most centers today use the gastric pull-up or colon interposition
(retrosternal). Short-term complications of replacement are those typical of esophagectomy;
anastomotic leak and poor conduit vascularity are the most feared complications. Long-term
complications depend on the type of replacement. Stomach conduits have the problem of continued
gastric acid secretion and the possibility of reflux and dysplasia. The colon (and the jejunum) can
become redundant and require revision. Overall, there is no optimal substitute for one’s own esophagus
and efforts should be made to preserve it at all costs.
Foreign Body
Foreign-body ingestion and food bolus impaction are common occurrences that physicians can encounter
when dealing with the esophagus. A majority of foreign bodies have been known to pass through the
gastrointestinal tract spontaneously. However, roughly 10% to 20% of cases may require nonoperative
intervention, with <1% requiring surgery.34–36 A large percentage of objects that do not pass
spontaneously remain in the cervical esophagus.
Foreign-body ingestion is most commonly seen in children between the ages of 6 months and 3 years,
with over 100,000 new cases occurring in the United States annually.37 Pediatric foreign-body ingestion
is typically accidental and most frequently involve coins, followed by toy parts, batteries, bones, and
1118
booksmedicos.org
food.37 Cases of foreign-body ingestion in adults are seen more commonly among the psychiatric
patients, patients with impaired cognition such as the elderly, and incarcerated individuals seeking
secondary gain.34–36
Endoscopy is the choice of management when nonoperative intervention is a viable option. Timing of
endoscopy is indicated by the risk of esophageal wall damage or aspiration, as well as the clinical status
of the patient. Urgent intervention using endoscopy may be required in patients with severe distress,
unable to swallow their own secretions, or with foreign bodies that are batteries or have sharp edges.
Patients who do not fit these criteria and have no evidence of severe obstruction can be handled less
urgently as most foreign objects will pass spontaneously.
Retrieval is the goal when dealing with foreign bodies that are not subjected to spontaneous passing.
General anesthesia is recommended during the entirety of this procedure. Flexible endoscopy is the
preferred method for most foreign bodies. A rigid endoscope is useful in the retrieval of foreign bodies
lodged in the proximal esophagus at the level of the cricopharyngeus muscle. Rigid esophagoscopy is a
rarer procedure and one should be familiar with the technique. Often senior surgical help should be
sought to accomplish the procedure safely and effectively because this technique is rarely used in
current training. Using either approach, the object should be reoriented with a grasper and removed
safely. When using the flexible esophagoscope, we have found the overtube to be a very useful tool for
removal of foreign bodies such that the esophagus is not injured proximally upon extrication of the
object. Esophagotomy may be required when the lodged foreign bodies are large, have sharp edges, are
embedded in the mucosa, or exceed the diameter of the rigid endoscope in all orientations. Following
removal of the foreign body, completion esophagoscopy and contrast esophagoscopy should be
performed to rule out injury. If there is a perforation, it should be managed according to the algorithm
in Algorithm 43-1.
BENIGN NEOPLASMS
Table 43-3 represents a list of all benign neoplasms of the esophagus. All of these lesions are rare, with
leiomyoma making up roughly 60% to 70% of all cases.38,39 Esophageal polyps are also seen frequently
in large referral centers and will be discussed. Other listed benign neoplasms of the esophagus will not
be discussed in this chapter, but the possibility of an occurrence should be noted, especially during the
formulation of a differential diagnosis.
Leiomyoma
As mentioned above, leiomyomas are by far the most common benign neoplasms of the esophagus,
accounting for roughly 60% to 70% of these cases.38,39 The incidence of leiomyoma of the esophagus
reported in autopsy range from 0.005% to 5.1%.40 Histologically, approximately 80% of leiomyoma
originates from the muscularis propria and are located intramurally. Upon visual inspection of the
esophagus, they are typically located in the middle and lower esophagus. They have been reported to
present as single lesions. Because leiomyomas are slow-growing tumors, the size of these lesions often
do not change for many years. Over 50% of these patients often are asymptomatic due to the nature of
the growth.39
CLASSIFICATION
Table 43-3 Classification of Benign Esophageal Tumors
1119
booksmedicos.org
Algorithm 43-3 depicts the process for evaluating and treating esophageal leiomyomas. Evaluation of
a patient suspected of having a leiomyoma should begin with a barium swallow, endoscopy, EUS, and
CT scan of the chest. Figure 43-4 depicts the typical appearance of an esophageal leiomyoma located in
the midthoracic of the esophagus. This smooth walled characteristic may indicate that mucosa is not
involved and that the lesion is contained in the submucosal layer. Figure 43-5 offers the endoscopic
appearance of a distal esophageal leiomyoma. The utility of the EUS also gives clinicians the ability to
ascertain the layer of origin of the mass. EUS in combination with fine-needle aspiration (FNA) may be
used to obtain tissue for histologic studies such as immunohistochemical (IHC) analysis. IHC analysis is
helpful in differentiating leiomyomas from other more aggressive pathology such as leiomyosarcomas
and gastrointestinal stromal tumors (GISTs) and should be incorporated into the surgical planning for
diagnosis.41 However, FNA should not be routinely performed due to the association between
preoperative biopsy and mucosal perforation at the time of surgical enucleation.42
Treatment in asymptomatic patients with tumors <3 cm is currently controversial. Nonoperative
surveillance or resection should be discussed with patients in this cohort. The surgical removal of an
esophageal leiomyoma is indicated with the development of symptoms of dysphagia, an increase in
tumor size, mucosal ulcerations, and to definitively rule out a malignant process such as a
leiomyosarcoma.
1120
booksmedicos.org
Figure 43-4. Esophagram of a leiomyoma. The acute angle at its junction with the esophageal wall is typical. (Reproduced with
permission from Orringer MB. Tumors of the esophagus. In: Sabiston DC Jr, ed. Textbook of Surgery. 13th ed. Philadelphia, PA: WB
Saunders; 1986:736.)
Figure 43-5. Endoscopic appearance of an esophageal leiomyoma at the level of the gastroesophageal junction. (Courtesy of
Michael L. Kochman, MD, Hospital of the University of Pennsylvania, Philadelphia.)
1121
booksmedicos.org
Algorithm 43-3. Evaluation and treatment of esophageal leiomyoma.
Like other lesions of the esophagus, the surgical approach is dependent on tumor location, size, and
characteristics. The typical approach to leiomyomas originating from the mid to distal esophagus is via
the right thorax. Surgical extramucosal enucleation is an approach that has shown excellent results with
patients with leiomyomas that are less than 8 cm without annular characteristics. Mortality was found
to be less than 1% for this approach with over 90% of patients symptom free at 5 years.43
Minimally, invasive approaches to enucleation have also been shown to be effective, particularly in
tumors smaller than 5 cm. Zaninotto and colleagues performed 11 video-assisted enucleations of
leiomyomas of the esophagus with no major morbidities, including death or postoperative leaks.44
Leiomyomas greater than 8 cm or annular in character usually require esophageal resection. Approaches
and techniques to esophageal resection will be covered later in this chapter.
Fibrolipomas and Fibrovascular Polyps

Fibrolipomas and fibrovascular polyps are rare tumors of the esophagus that often present as an
intraluminal mass originating from the cervical portion of the esophagus. Clinically, these tumors will
decrease intraluminal diameter and volume, and patients will present with dysphagia. The growth of
these tumors are influenced by the peristaltic action of the esophagus, causing these lesions to elongate
over time.45 The stalk-like nature of esophageal fibrolipomas can be seen endoscopically and
subsequently should be removed. Cervical esophagotomy or right thoracotomy approaches may be
required for resection if the size of the lesions restrict mobility. In rare instances, patients can present
with their polyp protruding from their mouth after an episode of coughing or emesis (Fig. 43-6). Polyps
may also flip and cause blockage of the airways and should be excised to avoid this occurrence.
MALIGNANT NEOPLASMS
Tumors of the esophagus include adenocarcinoma, squamous cell carcinoma, small cell carcinoma,
leiomyosarcoma, rhabdomyosarcoma, fibrosarcoma, liposarcoma, lymphomas, and metastatic lesions
from the other sites. Adenocarcinoma and squamous cell carcinoma are the most common, with
adenocarcinoma emerging in recent years in epidemic type rates of increase (Fig. 43-7). Recent analysis
of incidence has demonstrated that there are about 17,000 cases diagnosed each year in the United
States. About 14,000 will die annually. The lifetime risk of developing esophageal cancer is 0.5%, with
a slightly higher incidence in males. Risk factors include tobacco, alcohol, and obesity. Tylosis is the
only recognized family syndrome that predisposes patients to the development of esophageal cancer. It
is an autosomal dominant disorder that has been mapped to chromosome 17q25.40 These patients have a
95% risk of developing squamous cell carcinoma of the esophagus by age 70.
1122
booksmedicos.org
Figure 43-6. This patient presented with a large esophageal polyp protruding from her mouth following an episode of coughing.
This polyp was found to originate from a narrow stalk in her cervical esophagus and was removed endoscopically. Of note, she
had undergone operative resection of a cervical esophageal polyp earlier in life.
Figure 43-7. Relative change in incidence of esophageal adenocar-cinoma and other malignancies (1975–2001). Data from the
National Cancer Institute’s Surveillance, Epidemiology, and End Results program with age-adjustment using the 2000 U.S. standard
population. Baseline was the average incidence between 1973 and 1975. Blue line, esophageal adenocarcinoma; green line,
melanoma; orange line, prostate cancer; yellow line, breast cancer; purple line, lung cancer; red line, colorectal cancer. (Adapted with
permission from Pohl H, Welch G. The role of overdiagnosis and reclassification in the marked increase of esophageal
adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142–146.)

The vast majority of cases of esophageal cancer present late. The disease is largely asymptomatic due to
the location of the tumor and clinical symptoms do not drive patient presentation until there is a
significant degree of obstruction or bleeding. As a muscular conduit, the esophagus is quite
accommodating until it is narrowed significantly. Up to 80% of patients present with dysphagia and
20% present with odynophagia. More subtle signs of a problem are often elicited retrospectively when
questioning patients, where they admit to retrosternal discomfort and progressive symptoms that have
been overlooked. When one investigates further, it is often discovered that the patient has altered their
lifestyle or eating habits for a period of time. Typically patients have had difficulty with solids and then
liquids as the tumor progresses. The vast majority of patients have significant weight loss on
presentation and weight loss of more than 10% is a significant predictor of poor prognosis.46
Patients may also present with significant pulmonary symptoms when there is a more advanced
process leading to aspiration or there is direct airway invasion by a tumor. Direct airway invasion can
occur with midesophageal tumors as the esophagus courses directly posterior to the left mainstem
bronchus. New hoarseness is indicative of locally advanced tumor due to vocal cord paralysis. The
Virchow node, a palpable left supraclavicular node, may be present in some patients. These findings are
all indicators of poor prognosis and advanced disease.
The evaluation of a patient with suspected esophageal cancer involves a number of different tests
which are aimed at accurate diagnosis and staging. This is extremely important as therapy decisions are
made based on both of these findings. Barium swallow and esophagram are the mainstays of diagnosis
for assessment of patients. Barium swallow obtains both anatomic and functional information. Flexible
esophagoscopy is used to precisely locate the tumor, and biopsy can be performed to determine
histology. In patients with a known tumor, important additional information can be obtained by EUS
and this is considered the single most important test for determining T stage of the tumor. EUS
1123
booksmedicos.org
successfully predicts T stage in over 80% of cases when performed by an experienced endoscopist.
Regional lymph nodes can also be visualized and sampled by FNA. This aids in determining the N stage.
The sensitivity of EUS alone to predict N stage is 85% and increases to 95% when FNA is added.47
At present there are no serum markers that have been found in esophageal cancer patients that would
consistently yield meaningful clinical data. Standard serum cancer markers including CEA, CA19-9, and
CA-125 have no value in the preoperative evaluation of the patient with esophageal cancer. The most
useful laboratory parameters used clinically outside of a hemoglobin and electrolyte panel include
nutritional parameters (albumin, prealbumin).
A CT scan of the chest, abdomen, and pelvis with contrast is a valuable tool for assessing tumor,
lymph nodes, and the general anatomy related to the patient. Additionally, metastases to the liver and
lung are assessed via this method. Positron emission tomography (PET) with 18F-fluorodeoxyglucose
(FDG) is a physiologic unique test that detects metabolic activity within tissues. It is invaluable in the
assessment and clinical staging of patients with esophageal cancer as it provides information on N and
M stage to help guide clinical staging. PET scans are routinely obtained for the clinical staging of
esophageal cancer patients prior to and after treatment to evaluate for disease and disease progression,
respectively.
Additional staging modalities attempt to improve the accuracy of clinical staging. We use laparoscopic
staging quite liberally in our practice. This allows us to perform endoscopy and bronchoscopy on every
patient. In the laparoscopic staging procedure we can examine the extent of nodal involvement in the
celiac lymph nodes and evaluate for local tumor advancement and any diaphragmatic invasion.
Importantly, many patients present with significant dysphagia and weight loss, so nutritional needs can
be addressed at the time of this procedure either with an esophageal stent or feeding jejunostomy.
Finally, a chemotherapy port can be placed for easier access during treatment. We acknowledge that
staging laparoscopy is not absolutely required, however we feel there are many advantages that it has
to offer if planning further surgical intervention in the future.
Cervical Esophageal Cancer

Cancer of the cervical esophagus represents a very small subset of primary tumors. Direct extension into
the esophagus by tumors of the thyroid and trachea are much more common. These tumors are
challenging to treat and generally do not respond to surgical resection as a primary modality.
Traditionally, chemoradiotherapy has been the standard treatment for these tumors. Those who get
treated and have a good response may represent a small subset of patients that are referred
esophagectomy with laryngectomy and tracheostomy.
Adenocarcinoma
5 Adenocarcinoma of the esophagus is the most common esophageal tumor in the United States and
Western world, accounting for more than 50% of cases. The rise of this histologic subtype correlates
with the incidence of gastreoesophageal reflux disease (GERD) and obesity in the Western world, and
the overall prevalence of BE appears to be rising within the West. Whether this finding is related to a
true increased incidence or heightened surveillance is not clear. Although the overall incidence of BE is
unknown, autopsy series have estimated the prevalence to be 376 cases per 100,000 in Olmsted County,
MN, USA.48 Remarkably, this rate is five times the clinical prevalence in the same geographic area (82.6
per 100,000). As a result of findings such as these, it is generally well accepted that the subclinical
prevalence is underestimated. These cohort studies suggest that the majority of patients with BE are
undiagnosed because they experience minimal to no symptoms.
The sequence leading from chronic GERD to the development of Barrett esophagus, the precursor of
adenocarcinoma of the esophagus, is well defined. The esophagus is normally lined by squamous
mucosa, and repeated injury from chronic reflux leads to transformation of the normal squamous
mucosa into columnar epithelium. This is likely a two-step process, with the first step involving the
transformation of normal esophageal squamous mucosa to simple columnar epithelium. This initial step
takes place relatively quickly over the course of a few years, while the second step, the development of
intestinal metaplasia, proceeds over 5 to 10 years.49 Once present, Barrett can progress to low-grade
and high-grade dysplasia. With progression to dysplasia, the nuclei become more crowded and the
normal glandular architecture is lost. Patients with high-grade dysplasia carry a significant risk of the
development of adenocarcinoma, and at 5 years 10% to 30% of patients will develop invasive findings.
The annual rate of neoplastic transformation is 0.5%.50 Patients with recurring symptoms of reflux have
an eightfold increase in the risk of adenocarcinoma. Patients with nondysplastic Barrett’s have a 0.5%
per patient-year rate of progression to esophageal adenocarcinoma.51,52 At the time of espophagectomy
1124
booksmedicos.org
for high-grade dysplasia, invasive carcinoma is identified in as many as 30% to 40% of patients.53
Squamous Cell Carcinoma

Squamous cell carcinoma is more frequent world wide with the primary risk factor for development
being chronic irritation of the esophageal mucosa. This is hypothesized to be associated most frequently
with prolonged alcohol consumption which is believed to be enhanced with concomitant tobacco
exposure. Nitrosamines and other nitrosyl compounds found in smoked meats are especially important
carcinogens that the native populations rely on heavily. Hot beverages in Asian countries have been
theorized to be associated with a high incidence. Medical conditions such as achalasia, caustic strictures,
Plummer–Vinson syndrome, and tylosis also increase the risk of incidence. The risk with long-standing
achalasia is in the range of 5% to 7%, thus surveillance with biopsies is recommended in these
patients.54
Staging
In 2009, the American Joint Committee on Cancer (AJCC) published the seventh edition AJCC Cancer
Staging Manual. Table 43-4 summarizes the seventh edition AJCC TNM system for staging esophageal
cancers. This new staging system has significant revisions from the previous sixth edition which are
summarized in Table 43-5. Several stages and categories are redefined and subclassified. Tumors arising
in the stomach less or equal to 5 cm away from the esophagogastric (EG) junction and tumors arising
from or crossing the EG junction are all staged under this new system. The stage groupings have all
been reassigned, with the new pathologic stage relying all on the number of nodes containing
metastasis, tumor grade, tumor location, and histologic cell type in the seventh edition staging criteria.
The revised staging groupings and current recommended treatment strategies for each stage are
displayed in Table 43-6.
The importance of a cancer staging protocol lies in the strong association between stage of the disease
and outcomes. The seventh edition AJCC TNM staging system is data driven and harmonized. It will
allow physicians to clinical stage esophageal cancers accurately, which is of paramount importance
during the formulation of an appropriate treatment plan. Preoperative evaluation is necessary to
identify the extent of disease and help elicit the clinical stage. CT scans of the chest and abdomen are
crucial to preoperative evaluation and should be ordered in all patients. We also recommend PET
scanning in conjunction with CT imaging to detect distant metastatic disease. In the absence of liver,
lung, or other distant metastatic disease, esophageal ultrasound should be used to assess regional lymph
nodes and define the depth of tumor invasion. Patients with stage-appropriate disease should be
optimized from a medical standpoint prior to undergoing resection.
Table 43-4 T, N, and M Status and Histologic Grade Definitions for Esophagus
and Esophagogastric Junction Cancer in the Seventh Edition of the
American Joint Committee on Cancer (AJCC) Cancer Staging Manual
1125
booksmedicos.org
Neoadjuvant Therapy
The current information on neoadjuvant treatment can be divided into studies evaluating preoperative
radiation, preoperative chemotherapy, and combined preoperative chemoradiation therapy. In operable
patients with resectable tumors, the results of any preoperative therapy followed by resection must be
compared with the results of primary resection alone. It is important that this analysis takes into
account the toxicities associated with multimodality therapy and the impact on the intended resection
and quality of life. Several randomized trials have failed to show any benefit from preoperative
radiation therapy alone. Proponents of preoperative radiotherapy argue that the trials are too small to
demonstrate the advantages of this approach. A meta-analysis of available randomized trials comprising
1,147 patients, however, found no improvement in survival with preoperative radiotherapy alone in
patients with resectable esophageal cancer.55 At this time, there is no indication for preoperative
radiation therapy alone followed by resection.
Table 43-5 Summary of Changes from AJCC Sixth to Seventh Edition Esophagus
and Esophagogastric Junction Cancers Staging System
Table 43-6 American Joint Committee on Cancer (AJCC) Stage Groupings with
Recommended Treatment and 5-Year Survival
1126
booksmedicos.org
The utility of preoperative chemotherapy alone is much more poorly defined. A large multicenter
randomized trial in the United States (Intergroup Trial) of 440 patients failed to show any improvement
in survival after three cycles of combined cisplatin and fluorouracil followed by surgery and two
postoperative cycles when compared to surgery alone.56 This is in contrast to a large randomized
European study (Medical Research Council), which suggested that neoadjuvant chemotherapy resulted
in nearly a 10% improvement in survival at 2 years.57 Unfortunately, the preoperative staging
techniques and duration of treatments were quite different, making the two studies difficult to compare.
More recently, another European neoadjuvant chemotherapy trial (MAGIC trial) demonstrated
improved survival with perioperative chemotherapy versus surgery alone (36% vs. 23% at 5 years).58
Of note, 75% of the MAGIC trial participants had gastric cancer. Also, only 41.6% of patients
randomized to perioperative chemotherapy were able to complete all six prescribed cycles of therapy.
In a recent Cochrane review of the topic, 11 randomized controlled trials with 2,051 patients suggested
that preoperative chemotherapy plus surgery may offer a survival advantage compared to surgery alone
for resectable esophageal cancer.59 There was no demonstrable difference in the rate of resection, tumor
recurrence, or postoperative morbidity. There was some chemotherapy-related morbidity. Presumably
based on the relative success of the MRC and MAGIC trials, chemotherapy alone is used quite commonly
as neoadjuvant therapy in Europe, whereas combined chemotherapy and radiation is used more
commonly in the United States. Several small randomized trials have evaluated combined preoperative
chemoradiation followed by surgical resection. The most widely cited trial to justify the use of
combined treatment followed by surgery was published by Walsh et al. in 1996.60 This study projected a
3-year survival of 32% in the neoadjuvant treatment group as compared to 6% in the surgery alone
group for patients with adenocarcinoma. Critics were quick to point out the lack of appropriate staging,
the poor survival in the surgical group as compared with other surgical series, and the small study size.
A more recent study found equivalent median and 3-year survival in patients with squamous cell
carcinoma of the esophagus randomized to either preoperative chemoradiation followed by surgery or
surgery alone.61 An increased complication rate was noted in the patients undergoing preoperative
chemoradiation therapy. A recent metaanalysis of 10 randomized controlled trials of neoadjuvant
chemoradiotherapy versus surgery alone demonstrated an absolute survival advantage of 13% at 2 years
favoring neoadjuvant therapy.62 Despite a paucity of conclusive data, there seems to be an evolving
consensus at most centers that patients with T3 and/or N1 disease should receive neoadjuvant
chemoradiation. This issue remains unresolved, and operation remains the standard treatment for
localized esophageal cancer outside of a clinical trial. At this time we consider neoadjuvant
chemoradiotherapy to be investigational. Unfortunately, a large intergroup trial designed to answer this
question was closed because of poor accrual.
More recently, the CROSS Trial enrolled 363 patients from the Netherlands, of which 75% had GE
junction adenocarcinoma.63 They were randomized to chemotherapy with concurrent XRT (41.4 Gy)
then surgery versus upfront surgery. Improved survival was seen in the neoadjuvant group at 5 years
suggesting that chemoradiotherapy followed by surgery provided a survival advantage. Both arms in
the trial were noted to have an unusually high leak rate related to surgery (CRT 22% vs. surgery 30%).
This called into question the validity of the surgical standardization in the operative approach as this
leak rate is quite high. The long-term results (minimum 5-year follow-up) were recently reported and
confirmed the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery (43
1127
booksmedicos.org
months vs. 27 months, p < 0.03) in patients with resectable esophageal or EG junctional cancer.64
6 Recently the Society of Thoracic Surgeons released a consensus statement on neoadjuvant therapy
for the treatment of esophageal cancer stating the following class IIA recommendations based on level A
evidence65:
1. “Neoadjuvant platinum-based doublet chemotherapy alone is beneficial before resection for patients
with locally advanced esophageal adenocarcinoma.”
2. “Neoadjuvant chemoradiotherapy should be used for locally advanced squamous cell cancer and
either neoadjuvant chemotherapy or chemoradiotherapy for locally advanced adenocarcinoma as
multimodality therapy has advantages over operation alone.”
SURGICAL CONSIDERATIONS IN APPROACHING THE ESOPHAGUS

The esophagus is generally considered one of the most problematic organs to manage when it comes to
the indication for operation, patient fitness, operative approach, and the postoperative consequences of
complications. There is no doubt that surgical experience and expertise play a critical role in all phases
of esophageal disease ending up in the operating room.
A complete working knowledge of the anatomical relationships between the esophagus and adjacent
structures is vital. We feel it is a requirement and marked advantage for those formally trained in
general thoracic surgery to be the ones performing these operations. The upper esophagus is in contact
with the posterior membranous trachea, the left mainstem bronchus, and the aortic arch. Patients with
cancers involving the upper thoracic esophagus must undergo preoperative bronchoscopy to rule out
involvement of the airway as this generally precludes safe resection.
From a surgical perspective the esophagus is divided into thirds. The upper third can be reached
through a cervical incision. The middle third is best approached through the right chest as access
through the left chest is limited by the aortic arch. The distal third of the esophagus is best approached
through the left chest. The short segment of intra-abdominal esophagus may be approached through the
upper abdomen.
7 When esophagectomy is required, several surgical approaches have been described. Generally
speaking, no one surgical approach fits all. These approaches include the transhiatal approach,66
transabdominal transthoracic approach (Ivor Lewis),67 the three-stage or “three-field” approach
(McKeown),68 and the thoracoabdominal approach.69,70 In the current era, both minimally invasive and
robotic approaches have been championed and our group has led pioneering efforts in this regard. Each
approach has its own set of risks and benefits as well as clear opinions on those merits. Our belief is that
selection of the approach should be coupled with surgical expertise and patient pathology. Generally
speaking, several studies have shown equivalent outcomes when it comes to removal of the esophagus
and one trades one variable for another when critically evaluating the results. Careful review of the
literature draws on two important variables: surgeon experience and volume.71 Failures in technique
that occur during the performance of esophagectomy are associated with increased length of stay, in-
hospital mortality, and poorer overall long-term survival.72
OPERATIVE MANAGEMENT
Approaches to Esophagectomy
There are several surgical approaches to esophagectomy and the master esophageal surgeon should be
familiar with all approaches as they have different indications depending on the individual patient, the
location of the tumor, and surgeon experience. Options for reconstruction include a gastric tube, colonic
interposition, and in selected small cases an intestinal free graft. We opt for the use of colon or small
bowel in patients where the stomach is not usable because of the morbidity associated with these
conduits. The highlights of the main approaches will be presented along with an in-depth description of
the approach to minimally invasive esophagectomy (MIE) to help outline the critical considerations for
the steps of the operation.
Transhiatal Esophagectomy
Mark Orringer has championed this approach for esophagectomy with outstanding results and leak rates
1128
booksmedicos.org
in the 3% to 5% range.73 The procedure starts with an upper midline laparotomy and left cervical
incision as shown in Figure 43-8. A gastric conduit based on the right gastroepiploic artery is used to
establish gastrointestinal continuity. A modified stapled anastomosis is performed to complete the EG
anastomosis (Fig. 43-9).
Many surgeons prefer THE in the current era, as historically it has been compared to open Ivor Lewis
esophagectomy. Debate continues over the effectiveness of it as a cancer operation, as thoracic
lymphadenectomy is not a part of the procedure as seen in the Ivor Lewis Approach. Proponents for the
operation argue that the approach has lower morbidity and mortality than the Ivor Lewis approach.
Should a leak occur in the neck, it can be treated by simple bedside cervical drainage. A leak in the
chest following the Ivor Lewis approach is far more likely to result in severe mediastinitis and other
significant complications. The arguments and debates are certainly quite different in the current era
with the excitement surrounding MIE.
Ivor Lewis Esophagectomy

The transabdominal transthoracic approach to esophagectomy as initially described is more commonly
referred to as the Ivor Lewis esophagectomy. The specific steps are covered in the section on MIE as we
perform this operation through minimal access surgery. Following laparotomy and creation of the
gastric conduit, the stomach is mobilized and a posterolateral thoracotomy is performed through the 5th
interspace. The intrathoracic esophagus is mobilized under direct vision and the EG anastomosis is
performed at the level of the azygos vein. This approach is especially useful for bulky tumors or where
there are concerns regarding airway injury. As discussed above, critics of this approach point out the
increased morbidity of the operation and the potential perils of a chest anastomosis. The
lymphadenectomy is clearly superior with this approach and the risk of local recurrence, in theory,
reduced.
Three-Field Esophagectomy
This approach is carried out through a separate laparotomy, thoracotomy, and left cervical incision.68
The anastomosis is performed in the neck. This approach is appropriate for mid-esophageal tumors
where there is concern of airway injury during the dissection. Another potential advantage is a three-
field lymphadenectomy. In summary, the operation has the potential to provide the patient with a more
complete resection and thus improves long-term survival. This claim has not been overtly substantiated
in the literature.
Thoracoabdominal Approach
The left thoracoabdominal approach is the least frequently used of all the approaches to the esophagus.
It is performed by making an oblique incision from the midpoint between the xiphoid and the umbilicus
across the costal arch to the tip of the scapula. The abdomen is opened and the diaphragm divided along
the chest wall to spare any phrenic nerve branches. This approach is sometimes useful in those patients
who have had hiatal work done previously. For patients with distal tumors and inadequate conduit for
esophageal replacement, the anastomosis can be made in the left chest just below the inferior
pulmonary vein. For those with adequate conduit, the esophagus can be mobilized and a left cervical
anastomosis can be performed. The morbidity of this approach is quite high, however the largest series
of 64 patients reported no anastomotic leaks and 2% mortality.74
1129
booksmedicos.org
Figure 43-8. A: Transhiatal mobilization of the thoracic esophagus from the posterior mediastinum with the use of blunt dissection
and traction on rubber drains placed around the esophagogastric junction and cervical esophagus. The volar aspects of the fingers
are kept against the esophagus to reduce the risk for injury to adjacent structures. B: Lateral view showing transhiatal mobilization
of the esophagus away from the prevertebral fascia. Half of a sponge on a stick is inserted through the cervical incision and
advanced until it makes contact with the hand inserted from below through the diaphragmatic hiatus. Arterial pressure is
monitored as the heart is displaced forward by the hand in the posterior mediastinum.
Figure 43-9. The stapled technique for cervical esophageal anastomosis. This technique results in lower anastomotic leak rates and
fewer postoperative strictures.
Minimally Invasive Esophagectomy

Some surgeons have combined a thoracoscopic approach with a laparotomy, while others reported a
laparoscopic abdominal component with an open thoracotomy for the chest. While these hybrid
operations do fall under the umbrella of minimally invasive esophageal resection, a strict definition of
minimally invasive esophageal resection avoids both a thoracotomy and a laparotomy completely. In
our experience, we initially started with a laparoscopic transhiatal approach (in 15 patients) and
attempted to reach our finger dissection from the neck incision. We found this to be quite difficult in
most patients. We then converted to a combined thoracoscopic/laparoscopic approach with a neck
1130
booksmedicos.org
anastomosis, as it afforded better visualization of the periesophageal structures especially near the main
airways and subcarinal areas, was less affected by patient height and body habitus, improved our ability
to do a more complete nodal dissection, and greatly improved overall visualization compared with the
totally laparoscopic method. This minimally invasive three-field (McKeown approach) operation was
our procedure of choice for 6 to 8 years (approximately 500 cases). Following this extensive minimally
invasive experience, we moved to a minimally invasive Ivor Lewis approach in which we start
laparoscopically and complete using a right thoracoscopic approach and a high thoracic anastomosis. We
prefer this approach because the avoidance of a neck dissection essentially eliminates recurrent
laryngeal nerve injury. Additionally, minimally invasive Ivor Lewis resection allows a more aggressive
gastric resection margin; amputation of the most proximal tip of the newly constructed gastric conduit,
which is the most susceptible to ischemia and potential leak; and performance of the anastomosis with a
wide view within the chest cavity.75,76
8 In 2000, Nguyen et al. compared MIE with open transthoracic esophagectomy and transhiatal
esophagectomy (THE). Shorter operative times, less blood loss, and shorter stays in the ICU with no
increase in morbidity were documented with the minimally invasive approach as compared with the
open approach. Over the past several years, several series have been published on minimally invasive
resections that demonstrate comparable survival outcomes compared with large open series.77
Indications for the minimally invasive approach for esophagectomy include Barrett esophagus with
high-grade dysplasia, end-stage achalasia, esophageal strictures, and esophageal cancer. While most T4
esophageal cancers are generally not amenable to open or minimally invasive surgical approaches,
cancers of all other T stages are potentially amenable to MIE in experienced hands. Esophageal cancer
that has been downstaged after neoadjuvant chemoradiation is also potentially resectable by a
minimally invasive approach but, as with open operations in this setting, can be technically more
difficult than nonirradiated fields. Previous thoracic and abdominal surgery is not necessarily a
contraindication to MIE depending on the extent of the previous surgery and the experience of the
surgeon. The minimally invasive Ivor Lewis esophagectomy works well for most distal esophageal
cancers, short-to-moderate length Barrett with high-grade dysplasia, and gastroesophageal junction
tumors extending onto the gastric cardia. Total laparoscopic and thoracoscopic Ivor Lewis resections
should not be performed for upper third esophageal cancers with significant proximal extension due to
concern for adequate margins of resection. Some midesophageal tumors can be approached with the
Ivor Lewis technique, but a very high intrathoracic anastomosis may be needed to gain a negative
margin.
Anesthetic Considerations
Anesthetic management during MIE poses specific challenges. Whereas all patients receive an arterial
blood pressure monitoring line, central venous catheter placement is not routine. A double-lumen
endotracheal tube is placed initially in anticipation of the thoracoscopic phase. In patients with
midthoracic or upper thoracic tumors, a single-lumen endotracheal tube is initially placed for
preoperative bronchoscopy to evaluate airway involvement.
Patients generally require significant volume loading during the laparoscopic phase secondary to the
pneumoperitoneum and steep reverse Trendelenburg positioning. Given the high flow of CO2 required,
the patient can develop significant hypercarbia and acidosis. The surgeon must also be mindful of
vasopressors administered by the anesthesiologist because these agents directly affect the viability of
the newly created gastric conduit. Simple measures can be undertaken to help correct these problems.
Maneuvers to increase preload include lowering the insufflation pressure, decreasing the degree of the
reverse Trendelenburg position, and increasing volume loading. In addition to changes in the ventilator
settings, hypercarbia can often be corrected by reversing the pneumoperitoneum, allowing the patient
time to compensate and clear the excess CO2. There must be clear and ongoing communication
throughout the procedure between the surgeon and the anesthesiologist.
Endoscopic Evaluation
The operation begins with a careful EGD. The location of the tumor is confirmed along with precise
measurements of the proximal and distal extent of the lesion. The surrounding esophagus is examined
for evidence of Barrett changes proximal to the intended resection margin, with four-quadrant biopsies
taken in areas of clinical concern. Careful endoscopic examination of the stomach is also imperative to
assess its suitability for use as a conduit in esophageal reconstruction. Air insufflation should be kept to
a minimum during the examination to reduce the degree of small bowel distention which may
1131
booksmedicos.org
significantly decrease domain and heighten the difficulty of laparoscopy.
Laparoscopic Phase
Positioning and Laparoscopic Port Placement
The patient is positioned supine with the arms out at 60 degrees. A foot board is placed to allow steep
reverse Trendelenburg positioning during the hiatal dissection. The costal margin is identified and a line
is drawn from the xiphoid to the umbilicus. This line is then divided into thirds. The first port is placed
using a direct Hassan cutdown approach in the right paramedian position roughly 2 cm lateral to the
midline at the junction of the lower and middle thirds of the described line. A total of five abdominal
ports are used for gastric mobilization (12-mm right and left paramedian, 5-mm right and left subcostal,
and a second 5-mm right lateral subcostal port for liver retraction (Fig. 43-10) with the remaining ports
placed under direct laparoscopic vision. A sixth port is placed in the right paraumbilical region to assist
in placement of the feeding jejunostomy tube. All ports should be a hand’s breadth apart so as to avoid
interference between instruments. In addition, it is important to keep skin and fascial incisions small so
as to avoid subcutaneous emphysema.
While working at the hiatus, the camera is placed in the left paramedian port position. The surgeon
works from the right side of the table using the right paramedian and subcostal ports. The assistant, on
the left of the table, controls the camera as well as a second grasper for retraction (through the left
subcostal port). The liver retractor is brought in through the right lateral subcostal port and positioned
to elevate the left lobe of the liver and expose the hiatus.
Figure 43-10. Laparoscopic port placement. The 10-mm port is placed first in the right midabdomen using open Hasson trocar
insertion technique. An additional 5/11-mm port is placed in the right lower quadrant that is helpful for retraction during
pyloroplasty and gastric tube creation.
Gastric Mobilization
Thorough inspection of the abdomen is performed to ensure that no injuries were caused during the
process of port placement and to evaluate for intraperitoneal metastasis. The peritoneal lining,
omentum, and liver are visually inspected for abnormalities with biopsies taken of any suspicious
lesions for frozen-section evaluation. The gastrohepatic ligament is opened and the left gastric vascular
pedicle identified (Fig. 43-11). A complete lymph node dissection is then performed, leaving the left
gastric and celiac lymph nodes with the specimen. This dissection is continued laterally along the splenic
artery and the superior border of the pancreas and superiorly toward the crura along the preaortic
plane. If there is a question of potential malignant involvement, these nodes are sent for frozen-section
evaluation to aid in determination of resectability. Once ensured that no nodal disease is present, the
right crus is dissected, allowing lateral mobilization of the esophagus. This dissection is continued
anterior to the esophagus, transecting the phrenoesophageal ligaments and exposing the anterior hiatus.
The left crus may be exposed either by the continuation of this anterior dissection along the medial
crural border or by first mobilizing the fundus of the stomach by division of the short gastric vessels.
Dissection of the left crus is continued posteriorly until the decussation of the right and left crural fibers
is noted. This exposes the retroesophageal window and ensures complete mobilization of the superior
1132
booksmedicos.org
portion of the lesser curvature and gastroesophageal junction.
After identifying the gastrocolic omentum, the antrum of the stomach is retracted, and a window is
created in the greater omentum, thus allowing access to the lesser sac. The remaining short gastric
vessels are divided, taking care to preserve the right gastroepiploic arcade. The fundus is retracted to
the right and this dissection is continued posteriorly, eventually exposing the left gastric artery and vein
and joining the lesser curve dissection plane to complete mobilization of the stomach. Gastric
mobilization is carried inferiorly to the pyloroantral region. Meticulous attention must be paid during
this phase of the dissection because any injury to the gastroepiploic arcade at this level may render the
gastric conduit unusable. This dissection may be especially difficult in patients who have had
pancreatitis or a history of prior biliary surgery. Adequate mobilization has been achieved when the
pylorus is able to reach the level of the caudate lobe of the liver, which may require either a partial or a
complete Kocher maneuver. The left gastric artery and vein are then divided using an endovascular GIA
stapler. Care should be taken to ensure that all nodes are swept toward the specimen side and to avoid
narrowing of the splenic or hepatic arteries.
Creation of the Gastric Tube

The gastric tube is created prior to the completion of the pyloroplasty and placement of the feeding
jejunostomy tube to allow for an assessment of the viability of the gastric conduit. The gastric tube
follows the arc of the greater curve of the stomach and is based on the right gastroepiploic artery (Fig.
43-12). An endovascular stapling technique allows for a controlled creation of the gastric tube conduit.
The first staple load is placed across the adipose tissue and vessels along the lesser curve, above the
level of the right gastric artery. No stomach is divided in this initial staple firing, which is intended to
provide hemostasis. The subsequent staple firings divide the stomach. We prefer 45-mm staple loads for
this process (purple loads; Endo GIA Reloads with Tri-staple Technology, Covidien, Mansfield, MA)
because the course of the greater curvature can be followed more precisely, resulting in improved
conduit length. An additional grasper is brought through the right paraumbilical port at this time to
assist in the retraction of the stomach during creation of the gastric tube. It is important to keep the
stomach on stretch during this process so as to create a straight conduit. The first assistant grasps the tip
of the fundus along the greater curve and gently stretches it toward the spleen. A second instrument
from the paraumbilical port grasps the antral area with a slight downward retraction. The stomach is
first horizontally divided across the antrum. The staple line is then directed superiorly, toward the
fundus, parallel to the line of the greater curve. A conduit width of 4 to 5 cm is preserved (Fig. 43-13).
The length of the conduit is shortened if there is concern for extension of the tumor onto the gastric
cardia. Sutures may be placed to reinforce the staple line if there is concern about its integrity, although
this practice is not routinely necessary.
Figure 43-11. Laparoscopic staging, with opening of the gastrohepatic ligament and evaluation of left gastric/celiac lymph nodes.
1133
booksmedicos.org
Figure 43-12. Creation of gastric conduit. The first stapler along the lesser curve is a vascular endo GIA stapler after which the
thick antrum is divided with the 4.8 mm (green) loads that are 45 mm long fired sequentially. The antrum and the fundus are
pulled in opposite direction to provide adequate tension during the gastric conduit creation.
Pyloroplasty
The pylorus is visually identified and 2-0 Surgidac (Covidien, Mansfield, MA) stay sutures are placed on
the superior and inferior aspects using the Endostitch device (U.S. Surgical, Norwalk, CT) to place it on
stretch (Fig. 43-14). The anterior wall of the pylorus is then transected with ultrasonic shears. The
pyloromyotomy is then closed transversely in a Heineke–Mikulicz fashion using simple, interrupted 2-0
Surgidac sutures. An omental patch (with a vascular pedicle if the patient received neoadjuvant
treatment) is placed over the pyloroplasty prior to termination of the abdominal portion of the
operation.
Figure 43-13. Completed gastric conduit with an intact right gastroepiploic arcade and an intact right gastric artery.
Figure 43-14. Creation of pyloroplasty (A) and vertical closure (B) in a Heineke–Mikulicz fashion.
Feeding Jejunostomy Tube Placement
1134
booksmedicos.org
A 10-French jejunostomy catheter is placed in the left lower quadrant using a percutaneous technique
(Fig. 43-15). The transverse colon is retracted superiorly to expose the ligament of Treitz and a position
in the jejunum is identified 30 to 40 cm from this location. The antimesenteric border of the bowel is
sutured to the abdominal wall with a 2-0 Surgidac suture. The 12-mm right paraumbilical port is used
by the surgeon with the camera positioned in the right paramedian location. A Seldinger technique is
then used to introduce the catheter into the jejunum under direct laparoscopic vision. Air insufflation
via the catheter can be used to verify luminal placement. The jejunum is then tacked to the abdominal
wall anterior to the catheter entry site to prevent leakage, and an additional suture to the abdominal
wall is placed in the distal limb of jejunum to prevent rotation and obstruction.
Preparation for Thoracoscopic Phase
The gastric conduit is again assessed for viability and, if needed, resection of the nonviable portion and
further mobilization with extension of the Kocher maneuver are performed at this time. Once viability
of the conduit is ensured, the most superior portion of the gastric tube is stitched to the specimen (Fig.
43-16). It is imperative to maintain the alignment of the conduit so that twisting is avoided as the
stomach is brought into the chest. We ensure this by suturing the greater curvature along the short
gastric vessels to the staple line of the proximal gastric remnant. If an omental flap has been created,
the distal end is sutured to the conduit tip. Clips are applied to the staple line as needed for hemostasis.
The specimen and gastric conduit are then placed in the lower mediastinum, again taking care to
preserve the proper orientation of the gastric conduit (Fig. 43-17). If the hiatal opening appears large,
the crura are reapproximated with a stitch to prevent delayed thoracic herniation of the conduit. A
nasogastric tube is then placed in the esophagus for decompression in preparation for the thoracic phase
of the operation.
Thoracoscopic Phase
Positioning and Port Placement
Turn the patient to the left lateral decubitus position and reconfirm placement of the double-lumen
endotracheal tube. The operating surgeon stands on the right side of the table (facing the patient’s back)
while the assistant stands on the left side of the table. A total of five thoracoscopic ports are used (Fig.
43-18). A 10-mm camera port is placed in the eighth or ninth intercostal space, just anterior to the
midaxillary line. The working port is a 10-mm port placed in the eighth or ninth intercostal space,
posterior to the posterior axillary line. Another 10-mm port is placed in the anterior axillary line at the
fourth intercostal space, through which a fan-shaped retractor aids in retracting the lung to expose the
esophagus. A 5-mm port is placed just inferior to the tip of the scapula for the surgeon’s left hand. A
final 5-mm port is placed at the sixth rib, at the anterior axillary line for suction by the assistant.
Thoracoscopic Dissection and Resection of the Esophagogastric Specimen

Adequate retraction of the diaphragm is essential to the thoracoscopic phase of the dissection. A 48-in, 0
Surgidac suture is placed through the central tendon of the diaphragm using the Endostitch. The suture
is brought out through the lateral chest wall at the level of the insertion of the diaphragm through a
small stab incision, retracting the diaphragm inferiorly and exposing the distal esophagus. The inferior
pulmonary ligament is divided to the level of the inferior pulmonary vein to allow for maximal
retraction to the lung. This dissection is carried onto the avascular plane along the surface of the
pericardium, which becomes the medial border of the dissection. This dissection is carried superiorly to
the subcarinal space, with the lymph nodes kept en bloc with the esophagus (Fig. 43-19). Care must be
taken to identify the membranous wall of the right mainstem bronchus because it is easily injured
during this phase of the dissection. Removing any suction from the right lung during this dissection will
prevent the membranous wall from collapsing and can aid in visualization. The lung is then retracted
anteriorly and the pleura incised along the anterior border of the esophagus to the level of the azygos
vein. The azygos vein and vagus nerve are divided to facilitate the dissection and prevent traction
injuries to the recurrent laryngeal nerve during esophageal mobilization. Above the level of the azygos
vein, dissection is kept close to the esophagus to avoid injury to the recurrent nerves. The extent of
superior dissection and mobilization depends upon the location of the tumor and the intended site of
resection. To facilitate lateral mobilization, the pleura is divided in the groove posterior to the
esophagus. This dissection is kept superficial to avoid injury to the thoracic duct and underlying thoracic
aorta. Bridging lymphatics and aortoesophageal vessels are controlled with endoclips and subsequently
divided with the ultrasonic shears. A careful thoracic duct ligation should be considered if there is
1135
booksmedicos.org
concern for trauma to the duct. This lateral dissection is carried along the length of the esophagus from
above the azygos vein to the level of the gastroesophageal junction. The contralateral pleura marks the
deep margin of the dissection. The left pleural space may be entered if needed to remove a bulky
tumor. The insertion of a Penrose drain to encircle the esophagus can also be useful to provide traction
and elevate the esophagus from the mediastinal bed.
Figure 43-15. Placement of a 10-French needle jejunostomy catheter and an antitorsion stitch 3 to 4 cm distally along the
antimesenteric border.
Figure 43-16. The gastric conduit is secured to the specimen along the lesser curve staple line for proper orientation during the
thoracoscopic portion with a horizontal U stitch.
Figure 43-17. Proper orientation of the gastric conduit during the thoracoscopic part.
Once the esophagus has been completely mobilized, the specimen and attached gastric conduit are
delivered into the chest, preserving the orientation of the gastric tube. The conduit staple line should be
directly facing the lateral chest wall. The stitch between the specimen and the conduit is cut and the tip
1136
booksmedicos.org
of the conduit secured to the diaphragm with an Endostitch to prevent it from retracting into the
abdomen. The specimen is then retracted anteriorly and superiorly, away from the esophageal bed, and
the dissection completed along the contralateral pleural surface. Above the level of the azygos vein, this
dissection again moves to the plane along the wall of the esophagus itself to avoid recurrent laryngeal
nerve injury. Lymph node sampling is not routinely performed at this level.
Once mobilization of the esophagus is complete, a 4- to 5-cm minithoracotomy is made between the
surgeon’s working port and the tip of the scapula. A wound retractor (Applied Medical, Rancho Santa
Margarita, CA) is placed to protect the skin and chest wall. The esophagus is then sharply transected
using laparoscopic scissors at or above the level of the azygos vein as determined by the proximal
extent of tumor. The nasogastric tube is pulled back into the proximal esophagus under direct vision as
this is done. The esophagogastrectomy specimen is then withdrawn through the wound protector and
sent for frozen section evaluation of the resection margins.
Creation of the Gastroesophageal Anastomosis

Attention is next turned to construction of the EG anastomosis. Our preferred technique utilizes an end-
to-end anastomosis (EEA) stapling device (Fig. 43-20). The anvil of the stapler is placed in the cut
proximal end of the esophagus and secured in place with two pursestring sutures of 2-0 Surgidac. All
layers of the esophagus must be included in the suture to ensure a competent anastomosis. Typically, a
28-mm EEA stapler can be used without difficulty. This size will help to minimize stricture formation
and potentially decreases the need for postoperative dilation. If the proximal esophagus does not appear
large enough to accommodate the 28-mm anvil, a Foley catheter can be used to gently dilate the
esophageal lumen in an attempt to facilitate placement of the anvil before electing a smaller stapler
size. The gastric conduit is pulled further into the chest and the tip of the gastric conduit is opened using
ultrasonic shears to the right side of the staple line. The EEA stapler is placed through the wound
protector and positioned through the gastrotomy inside the conduit. The stapler spike is brought out
along the greater curve of the gastric conduit to dock with the anvil. Prior to creating the anastomosis,
we carefully estimate the amount of conduit that will lie in the chest. It is a common mistake to bring
an excess stomach into the chest with the intent of minimizing tension on the anastomosis. A redundant
conduit above the diaphragm can lead to significant problems with conduit emptying. In addition,
ensuring proper orientation of the stomach is critical to prevent twisting. The stapler is then opened two
complete turns and withdrawn. The tissue rings are inspected to ensure that they are complete prior to
proceeding further.
Figure 43-18. Thoracoscopic port placement.
After stapling, the remaining excess gastric tip, including the gastrotomy through which the stapler
was introduced, is resected with two or three loads of the endovascular GIA stapler (Fig. 43-21). If an
omental flap was created during the abdominal dissection, it is wrapped around the anastomosis and
secured in place with two or three sutures. The chest is then thoroughly irrigated and inspected for
hemostasis. Final anatomy of the reconstruction is demonstrated in Figure 43-22.
1137
booksmedicos.org
Figure 43-19. Thoracoscopic esophageal mobilization. The lung is retracted anteriorly and the pleura along the esophagus is
excised. The subcarinal lymph nodes are excised en bloc along with the specimen.
Drain Placement and Closure

Adequate drainage of the mediastinum and the area surrounding the anastomosis is imperative to
mitigate complications related to anastomotic leak. A 10-mm Jackson–Pratt drain is placed posteriorly
along the anastomosis and a 28-French chest tube is directed posteriorly toward the apex. The
previously placed nasogastric tube is advanced past the anastomosis under thoracoscopic visualization.
The gastric conduit is sutured to the right crus with a single 2-0 Endostitch to prevent torsion or delayed
herniation of the conduit. A long aspirating needle is used to instill a multilevel intercostal nerve block
to aid in postoperative pain control. The minithoracotomy is closed using pericostal sutures with a
multilayer soft tissue closure. The Jackson–Pratt drain is secured with multiple sutures to prevent it
from becoming dislodged. Once the patient is turned to the supine position, the oropharynx and
nasopharynx are suctioned free of all secretions. The double-lumen endotracheal tube is withdrawn and
the patient reintubated with a single-lumen endotracheal tube. Use of a tube exchange catheter should
be discouraged because this device is placed blindly and may cause injury to the right mainstem
bronchus, which is potentially vulnerable owing to the dissection of the thoracic esophagus. A toilet
bronchoscopy is then performed using an adult bronchoscope. At this time, both right and left mainstem
bronchi are examined for any evidence of airway injury.
Postoperative Care
Patients are taken to the intensive care unit postoperatively and typically remain there for the first
postoperative day before transferring to the surgical floor. The typical hospital stay is 7 days in patients
with an uncomplicated postoperative course. The nasogastric tube may be removed on day 2 and
“trickle” (20 to 30 mL/hr) jejunostomy tube feeds are started. A contrast esophagram is obtained on day
3 to 4 if the patient has adequate pulmonary toilet and a good cough. If there is no evidence of leak,
oral intake is initiated in the form of 1 to 2 oz of clear liquids per hour. This is advanced over 2 days to
full liquids, no more than 3 to 4 oz/hr along with cycled tube feeds. The chest tube is removed when
output low (<150 cc/d) and the clinical course negative for leak. The Jackson–Pratt drain is pulled
back 3 to 5 cm on postoperative day 5 and resecured. The drain is removed at the first postoperative
clinic visit in 2 weeks’ time.
1138
booksmedicos.org
Figure 43-20. Creation of the esophago-gastric anastomosis. The anvil is secured in the proximal esophagus with two purse-string
sutures. The EEA stapler is introduced into the conduit via a gastrostomy and is docked with the anvil keeping the conduit aligned
with the lesser curve staple line facing the camera.
Figure 43-21. The gastrotomy is closed with an Endo GIA stapler and this part of the stomach is sent as final gastric margin. Care
is taken not to encroach this staple line too close to the circular EEA staple line. A JP drain is left in the esophageal bed posterior
to the anastomosis.
PALLIATIVE OPTIONS IN ADVANCED ESOPHAGEAL CANCER

9 In the event that patients have unresectable disease, metastatic disease, or are medically unfit for
surgery, numerous palliative therapies are available. The goal of these therapies is to maintain comfort
by restoring as much swallowing function as possible and support nutrition.
Figure 43-22. Completed reconstruction.
Nutrition support and hydration can be provided through alternative enteral access. PEG or surgical
jejunostomy tube should be placed whenever possible under endoscopic guidance. Open gastrostomy or
jejunostomy tubes are an alternative in patients with bulky obstructive lesions who cannot receive a
PEG.
Chemotherapy
Chemotherapy can also provide palliation in patients with esophageal cancer. Many regimens are
available that have been extensively studied. Agents such as fluorouracil and taxanes may be used either
alone or in combination with platin-based agents to provide symptomatic relief. Palliative
chemotherapy typically requires time to effectively reduce dysphagia. Special attention is needed while
implementing these chemotherapeutic agents in usually debilitated, malnourished patients.
Radiation
Radiotherapy can be used for palliative reasons in patients with dysphagia. The typical dosage used is
4,000 to 5,000 cGy delivered over 4 weeks. The goal for this treatment is to allow patients with
1139
booksmedicos.org
advanced disease and severe obstructive symptoms to handle secretions and swallow liquids such as
dietary supplements. Like with palliative chemotherapy, radiotherapy does not offer immediate relief
and will require time in order to reach maximal palliative effect. Patients with life expectancies greater
than 3 months can be offered a combination of chemotherapy and radiation to achieve palliation. Side
effects of radiation therapy include skin irritation and erythema. Patients may also experience
esophagitis with painful swallow, stricture formation, radiation pneumonitis, and fistulization to the
airway.
Stenting
Stenting technology has advanced significantly since its initial introduction in the 1970s as a palliative
option for inoperable malignant esophageal strictures.23 Currently, many stents are available on the
market included self-expanding coated and uncoated nitinol types. Patients have the option of either
inserting them endoscopically or radiologically. Stenting can be done in conjunction with other
palliative treatment options including balloon dilation, neodymium; yttrium-aluminum-garnet (Nd:YAG)
laser fulguration, and photodynamic therapy (PDT), which we will discuss next.
Neodymium:Yttrium-Aluminum-Garnet Laser Fulguration

In patients with unresectable obstructive tumors, endoscopic Nd:YAG laser fulguration is a surgical
option that can provide temporary relief of esophageal obstruction. First, an esophagoscope is used to
identify the lesion. The YAG laser energy is delivered through a flexible quartz fiber that is passed
through the working channel of the scope. Multiple YAG laser sessions will be required to debulk the
lumen of the esophagus to the point where patients may function relatively normally. As with many
palliative treatments, laser fulguration is often performed in conjuncture with endoluminal stenting and
radiation therapy to achieve better functional success. It can be particularly useful in patients who have
undergone prior stenting and are experiencing an ingrowth of tumor through the stent. Tumor ingrowth
is less of a problem with many of the current stents because we prefer to use the fully covered stents.
Photodynamic Therapy
Another form of palliative therapy is intraluminal PDT. It is a nonthermal ablative technique that
requires the systemic administration of a photosensitizing substance such as hematoporphyrin. Over the
course of 48 hours, this photosensitizing substance becomes highly concentrated in malignant cells.
Patients will then undergo endoscopic evaluation with application of an argon-pump dye-laser
introduced endoluminally in the esophagus to deliver light at a wavelength of 630 nm. This endoluminal
light source will cause a chain reaction that generates an overwhelming concentration of oxygen
radicals, quickly leading to tumor necrosis and patent luminal area. Perforation is of little concern with
PDT because the risk of full-thickness necrosis of the esophagus is rare due to the limited depth of
penetration of the light. Unfortunately, photosensitizing agents such as hematoporphyrin are frequently
retained by the reticuloendothelial system of the skin. This retention will cause patients to be sensitive
to infrared wavelength light, including sunlight, radiant heat, fluorescent light, and strong incandescent
light. Patients should be informed of these side effects as they may persist for up to 3 months depending
on what agent was used as well as the individual. Because of these long-lasting postoperative effects,
endoluminal PDT may not be a favored option for patients with shorter life expectancies.
In a recent series of 215 patients who underwent endoluminal PDT for palliation, investigators
reported a procedure-related mortality rate of 1.8%. With a median survival of 4.8 months, this series
found this technique to be an effective palliative treatment in 85% of patients with obstructive
esophageal tumors.78 Of note, some of these patients also required stenting for palliation, suggesting
that PDT may have a role in a multimodal palliative treatment plan for patients with obstructing
esophageal cancers.
References
1. Briel JW, Tamhankar AP, Hagen JA, et al. Prevalence and risk factors for ischemia, leak, and
stricture of esophageal anastomosis: gastric pull-up versus colon interposition. J Am Coll Surg
2004;198(4):536–541; discussion 541–542.
2. Young MM, Deschamps C, Trastek VF, et al. Esophageal reconstruction for benign disease: early
morbidity, mortality, and functional results. Ann Thorac Surg 2000;70(5):1651–1655.
1140
booksmedicos.org
3. Vigneswaran WT, Trastek VF, Pairolero PC, et al. Transhiatal esophagectomy for carcinoma of the
esophagus. Ann Thorac Surg 1993;56(4):838–844; discussion 844–846.
4. Young MM, Deschamps C, Allen MS, et al. Esophageal reconstruction for benign disease: self-
assessment of functional outcome and quality of life. Ann Thorac Surg 2000;70(6):1799–1802.
5. Crestanello JA, Deschamps C, Cassivi SD, et al. Selective management of intrathoracic anastomotic
leak after esophagectomy. J Thorac Cardiovasc Surg 2005;129(2):254–260.
6. Parekh K, Iannettoni MD. Complications of esophageal resection and reconstruction. Semin Thorac
Cardiovasc Surg 2007;19(1):79–88.
7. Kent MS, Schuchert M, Fernando H, et al. Minimally invasive esophagectomy: state of the art. Dis
Esophagus 2006;19(3):137–145.
8. Alanezi K, Urschel JD. Mortality secondary to esophageal anastomotic leak. Ann Thorac Cardiovasc
Surg 2004;10(2):71–75.
9. Eroglu A, Turkyilmaz A, Aydin Y, et al. Current management of esophageal perforation: 20 years
experience. Dis Esophagus 2009;22(4):374–380.
10. Wehrmann T, Stergiou N, Vogel B, et al. Endoscopic debridement of paraesophageal, mediastinal
abscesses: a prospective case series. Gastrointest Endosc 2005;62(3):344–349.
11. Amir AI, van Dullemen H, Plukker JT. Selective approach in the treatment of esophageal
perforations. Scand J Gastroenterol 2004;39(5):418–422.
12. Brinster CJ, Singhal S, Lee L, et al. Evolving options in the management of esophageal perforation.
Ann Thorac Surg 2004;77(4):1475–1483.
13. Muir AD, White J, McGuigan JA, et al. Treatment and outcomes of oesophageal perforation in a
tertiary referral centre. Eur J Cardiothorac Surg 2003;23(5):799–804; discussion 804.
14. Page RD, Shackcloth MJ, Russell GN, et al. Surgical treatment of anastomotic leaks after
oesophagectomy. Eur J Cardiothorac Surg 2005;27(2):337–343.
15. Sauvanet A, Baltar J, Le Mee J, et al. Diagnosis and conservative management of intrathoracic
leakage after oesophagectomy. Br J Surg 1998;85(10):1446–1449.
16. Weiman DS, Walker WA, Brosnan KM, et al. Noniatrogenic esophageal trauma. Ann Thorac Surg
1995;59(4):845–849; discussion 849–850.
17. Barrett NR. Spontaneous perforation of the oesophagus; review of the literature and report of three
new cases. Thorax 1946;1:48–70.
18. Foley MJ, Ghahremani GG, Rogers LF. Reappraisal of contrast media used to detect upper
gastrointestinal perforations: comparison of ionic water-soluble media with barium sulfate.
Radiology 1982;144(2):231–237.
19. Gollub MJ, Bains MS. Barium sulfate: a new (old) contrast agent for diagnosis of postoperative
esophageal leaks. Radiology 1997;202(2):360–362.
20. Horwitz B, Krevsky B, Buckman RF Jr, et al. Endoscopic evaluation of penetrating esophageal
injuries. Am J Gastroenterol 1993;88(8):1249–1253.
21. Mengold L KK, Conservative management of esophageal perforation. Arch Surg 1965;91:232.
22. Cameron JL, Kieffer RF, Hendrix TR, et al. Selective nonoperative management of contained
intrathoracic esophageal disruptions. Ann Thorac Surg 1979;27(5):404–408.
23. Atkinson M, Ferguson R. Fibreoptic endoscopic palliative intubation of inoperable oesophagogastric
neoplasms. Br Med J 1977;1(6056):266–267.
24. Tuebergen D, Rijcken E, Mennigen R, et al. Treatment of thoracic esophageal anastomotic leaks and
esophageal perforations with endoluminal stents: efficacy and current limitations. J Gastrointest Surg
2008;12(7):1168–1176.
25. Blackmon SH, Santora R, Schwarz P, et al. Utility of removable esophageal covered self-expanding
metal stents for leak and fistula management. Ann Thorac Surg 2010;89(3):931–936; discussion
936–937.
26. Fischer A, Thomusch O, Benz S, et al. Nonoperative treatment of 15 benign esophageal perforations
with self-expandable covered metal stents. Ann Thorac Surg 2006;81(2):467–472.
27. Freeman RK, Ascioti AJ, Wozniak TC. Postoperative esophageal leak management with the Polyflex
esophageal stent. J Thorac Cardiovasc Surg 2007;133(2):333–338.
28. Freeman RK, Van Woerkom JM, Ascioti AJ. Esophageal stent placement for the treatment of
1141
booksmedicos.org
iatrogenic intrathoracic esophageal perforation. Ann Thorac Surg 2007;83(6):2003–2007; discussion
2007–2008.
29. Karbowski M, Schembre D, Kozarek R, et al. Polyflex self-expanding, removable plastic stents:
assessment of treatment efficacy and safety in a variety of benign and malignant conditions of the
esophagus. Surg Endosc 2008;22(5):1326–1333.
30. Schubert D, Scheidbach H, Kuhn R, et al. Endoscopic treatment of thoracic esophageal anastomotic
leaks by using silicone-covered, self-expanding polyester stents. Gastrointest Endosc 2005;61(7):891–
896.
31. Rueth NM, Shaw D, D’Cunha J, et al. Esophageal stenting and radiotherapy: a multimodal approach
for the palliation of symptomatic malignant dysphagia. Ann Surg Oncol 2012;19(13):4223–4228.
32. D’Cunha J, Rueth NM, Groth SS, et al. Esophageal stents for anastomotic leaks and perforations. J
Thorac Cardiovasc Surg 2011;142(1):39–46.e1.
33. D’Cunha J. Esophageal stents for leaks and perforations. Semin Thorac Cardiovasc Surg
2011;23(2):163–167.
34. Eisen GM, Baron TH, Dominitz JA, et al. Guideline for the management of ingested foreign bodies.
Gastrointest Endosc 2002;55(7):802–806.
35. Longstreth GF, Longstreth KJ, Yao JF. Esophageal food impaction: epidemiology and therapy. A
retrospective, observational study. Gastrointest Endosc 2001;53(2):193–198.
36. Smith MT, Wong RK. Foreign bodies. Gastrointest Endosc Clin N Am 2007;17(2):361–382, vii.
37. Kay M, Wyllie R. Pediatric foreign bodies and their management. Curr Gastroenterol Rep
2005;7(3):212–218.
38. Hatch GF 3rd, Wertheimer-Hatch L, Hatch KF, et al. Tumors of the esophagus. World J Surg
2000;24(4):401–411.
39. Seremetis MG, Lyons WS, deGuzman VC, et al. Leiomyomata of the esophagus. An analysis of 838
cases. Cancer 1976;38(5):2166–2177.
40. Postlethwait RW, Musser AW. Changes in the esophagus in 1,000 autopsy specimens. J Thorac
41. Stelow EB, Jones DR, Shami VM.. Esophageal leiomyosarcoma diagnosed by endoscopic ultrasound-
guided fine-needle aspiration. Diagn Cytopathol 2007;35(3):167–170.
42. Bonavina L, Segalin A, Rosati R, et al. Surgical therapy of esophageal leiomyoma. J Am Coll Surg
1995;181(3):257–262.
43. Lee LS, Singhal S, Brinster CJ, et al. Current management of esophageal leiomyoma. J Am Coll Surg
2004;198(1):136–146.
44. Zaninotto G, Portale G, Costantini M, et al. Minimally invasive enucleation of esophageal
leiomyoma. Surg Endosc 2006;20(12):1904–1908.
45. Schuhmacher C, Becker K, Dittler HJ, et al. Fibrovascular esophageal polyp as a diagnostic
challenge. Dis Esophagus 2000;13(4):324–327.
46. Fein R, Kelsen DP, Geller N, et al. Adenocarcinoma of the esophagus and gastroesophageal junction.
Prognostic factors and results of therapy. Cancer 1985;56(10):2512–2518.
47. Puli SR, Reddy JB, Bechtold ML, et al. Staging accuracy of esophageal cancer by endoscopic
ultrasound: a meta-analysis and systematic review. World J Gastroenterol 2008;14(10):1479–1490.
48. Cameron AJ, Zinsmeister AR, Ballard DJ, et al. Prevalence of columnar-lined (Barrett’s) esophagus.
Comparison of population-based clinical and autopsy findings. Gastroenterology 1990;99(4):918–922.
49. Öberg S, Johansson J, Wenner J, et al. Metaplastic columnar mucosa in the cervical esophagus after
esophagectomy. Ann Surg 2002;235(3):338–345.
50. Shaheen N, Ransohoff DF. Gastroesophageal reflux, barrett esophagus, and esophageal cancer:
Scientific review. JAMA 2002;287(15):1972–1981.
51. Sikkema M, de Jonge PJ, Steyerberg EW, et al. Risk of esophageal adenocarcinoma and mortality
in patients with Barrett’s esophagus: a systematic review and meta-analysis. Clin Gastroenterol
Hepatol 2010;8(3):235–244; quiz e32.
52. Wani S, Puli SR, Shaheen NJ, et al. Esophageal adenocarcinoma in Barrett’s esophagus after
endoscopic ablative therapy: a meta-analysis and systematic review. Am J Gastroenterol
2009;104(2):502–513.
1142
booksmedicos.org
53. Spechler SJ. Dysplasia in Barrett’s esophagus: limitations of current management strategies. Am J
Gastroenterol 2005;100(4):927–935.
54. Aggestrup S, Holm JC, Sorensen HR. Does achalasia predispose to cancer of the esophagus? Chest
1992;102(4):1013–1016.
55. Arnott SJ, Duncan W, Gignoux M, et al. Preoperative radiotherapy for esophageal carcinoma.
Cochrane Database Syst Rev 2005;(4):Cd001799.
56. Kelsen DP, Ginsberg R, Pajak TF, et al. Chemotherapy followed by surgery compared with surgery
alone for localized esophageal cancer. N Engl J Med 1998;339(27):1979–1984.
57. Medical Research Council Oesophageal Cancer Working Group. Surgical resection with or without
preoperative chemotherapy in oesophageal cancer: a randomised controlled trial. Lancet
2002;359(9319):1727–1733.
resectable gastroesophageal cancer. N Engl J Med 2006;355(1):11–20.
59. Malthaner RA, Collin S, Fenlon D Preoperative chemotherapy for resectable thoracic esophageal
cancer. Cochrane Database Syst Rev 2006;(3):Cd001556.
60. Walsh TN, Noonan N, Hollywood D, et al. A comparison of multimodal therapy and surgery for
esophageal adenocarcinoma. N Engl J Med 1996; 335(7):462–467.
61. Bosset JF, Gignoux M, Triboulet JP, et al. Chemoradiotherapy followed by surgery compared with
surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337(3):161–167.
62. Gebski V, Burmeister B, Smithers BM, et al. Survival benefits from neoadjuvant chemoradiotherapy
or chemotherapy in oesophageal carcinoma: a meta-analysis. Lancet Oncol 2007;8(3):226–234.
63. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal
or junctional cancer. N Engl J Med 2012;366(22):2074–2084.
64. Shapiro J, van Lanschot JJ, Hulshof MC, et al. Neoadjuvant chemoradiotherapy plus surgery versus
surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised
controlled trial. Lancet Oncol 16(9):1090–1098.
65. Little AG, Lerut AE, Harpole DH, et al. The Society of Thoracic Surgeons practice guidelines on the
role of multimodality treatment for cancer of the esophagus and gastroesophageal junction. Ann
Thorac Surg 2014;98(5):1880–1885.
66. Orringer MB, Sloan H. Esophagectomy without thoracotomy. J Thorac Cardiovasc Surg
1978;76(5):643–654.
67. Lewis I. The surgical treatment of carcinoma of the oesophagus; with special reference to a new
operation for growths of the middle third. Br J Surg 1946;34:18–31.
68. McKeown KC. Total three-stage oesophagectomy for cancer of the oesophagus. Br J Surg
1976;63(4):259–262.
69. Forshaw MJ, Gossage JA, Ockrim J, et al. Left thoracoabdominal esophagogastrectomy: still a valid
operation for carcinoma of the distal esophagus and esophagogastric junction. Dis Esophagus
2006;19(5):340–345.
70. Linden PA, Sugarbaker DJ. Section V: Techniques of esophageal resection. Semin Thorac Cardiovasc
Surg 2003;15(2):197–209.
71. Dimick JB, Pronovost PJ, Cowan JA, et al. Surgical volume and quality of care for esophageal
resection: do high-volume hospitals have fewer complications? Ann Thorac Surg 2003;75(2):337–
341.
72. Rizk NP, Bach PB, Schrag D, et al. The impact of complications on outcomes after resection for
esophageal and gastroesophageal junction carcinoma. J Am Coll Surg 2004;198(1):42–50.
73. Orringer MB, Marshall B, Iannettoni MD. Eliminating the cervical esophagogastric anastomotic leak
with a side-to-side stapled anastomosis. J Thorac Cardiovasc Surg 2000;119(2):277–288.
74. Heitmiller RF. Results of standard left thoracoabdominal esophagogastrectomy. Semin Thorac
75. Luketich JD, Pennathur A, Awais O, et al. Outcomes after minimally invasive esophagectomy:
review of over 1000 patients. Ann Surg 2012;256(1):95–103.
76. Luketich JD, Pennathur A, Franchetti Y, et al. Minimally invasive esophagectomy: results of a
prospective phase II multicenter trial-the eastern cooperative oncology group (E2202) study. Ann
Surg 2015;261(4):702–707.
1143
booksmedicos.org
77. Nguyen NT, Follette DM, Wolfe BM, et al. Comparison of minimally invasive esophagectomy with
transthoracic and transhiatal esophagectomy. Arch Surg 2000;135(8):920–925.
78. Litle VR, Luketich JD, Christie NA, et al. Photodynamic therapy as palliation for esophageal cancer:
Experience in 215 patients. Ann Thorac Surg 2003;76(5):1687–1692; discussion 1692–1693.
1144
booksmedicos.org
SECTION E: STOMACH AND DUODENUM
1145
booksmedicos.org
Chapter 44
Gastric Anatomy and Physiology

Key Points
1 The stomach is an extremely well-vascularized organ, supplied by a number of major arteries and
protected by a large number of extramural and intramural collaterals.
2 Oxyntic glands occupy the fundus and body of the stomach and contain the oxyntic or parietal cells,
which are the sites of acid production. Oxyntic glands also contain chief cells, the site of gastric
pepsinogen synthesis.
3 The most important stimulant of gastrin release is a meal. Postprandial luminal pH also strongly
affects gastrin secretion.
4 The basolateral membrane of the parietal cell contains specific receptors for histamine, gastrin, and
acetylcholine, the three major stimulants of acid production.
5 Pepsins are a heterogeneous group of proteolytic enzymes that are secreted by the gastric chief cells.
6 The gastric mucosa is the site of production of intrinsic factor, which is necessary for the absorption
of cobalamin from the ileal mucosa. Total gastrectomy is regularly followed by cobalamin
malabsorption, as is resection of the proximal stomach or atrophic gastritis that involves the oxyntic
mucosa.
GROSS ANATOMY
The stomach and duodenum, along with the esophagus, liver, bile ducts, and pancreas, are derived from
the embryonic foregut. During the fifth week of gestation, the future stomach is marked as a dilation in
the caudal portion of the foregut. Cranial to this dilation, the trachea forms as a bud from the future
esophagus. At this time, the primitive stomach is invested with both ventral and dorsal mesenteries. The
embryonic ventral mesentery is represented in postnatal life by the falciform ligament and by the
gastrohepatic and hepatoduodenal mesenteries that form the lesser omentum. The celiac artery, the
major blood supply to the foregut, passes within the dorsal mesentery. The primitive dorsal mesentery
ultimately forms three structures: the gastrocolic ligament, the gastrosplenic ligament, and the
gastrophrenic ligament.
During the sixth and seventh weeks of gestation, the typical morphology of the stomach is
established. Accelerated growth of the left gastric wall, relative to the right, establishes the greater and
lesser curvatures. This unequal growth also rotates the stomach and causes the left vagal nerve trunk to
assume its anterior position, whereas the right vagal trunk is located posteriorly. The growth of
structures cephalad to the stomach causes the organ to descend. During the sixth week, the primitive
stomach lies between the T10 and T12 vertebral segments. By the eighth week, the stomach is located
between the T11 and the L4 segments. In adult life, the stomach is most commonly located between the
T10 and the L3 vertebral segments.
The stomach can be divided into anatomic regions based on external landmarks (Fig. 44-1). Although
this division is commonly referred to in surgical texts and is useful in discussing gastric resective
procedures, it does not necessarily reflect the secretory or motor functions of the mucosal and muscular
layers of the stomach. The gastric cardia is the region of the stomach just distal to the gastroesophageal
junction. The fundus is the portion of the stomach above and to the left of the gastroesophageal
junction. The corpus constitutes the region between the fundus and the antrum. The margin between the
corpus and antrum is not distinct externally but can be defined arbitrarily by a line from the incisura
angularis on the lesser curvature to a point one-fourth the distance from the pylorus to the esophagus
along the greater curvature. The gastric antrum is bounded distally by the pylorus, which can be
appreciated by palpation as a thickened ring of smooth muscle.
The stomach is mobile in most people and is fixed at only two points, proximally by the
1146
booksmedicos.org
gastroesophageal junction and distally by the retroperitoneal duodenum. Therefore, the position of the
stomach varies and depends on the habitus of the person, the degree of gastric distention, and the
position of the other abdominal organs. Anteriorly, the stomach is in contact with the left
hemidiaphragm, the left lobe and the anterior segment of the right lobe of the liver, and the anterior
parietal surface of the abdominal wall. The posterior surface of the stomach is related to the left
diaphragm; the left kidney and left adrenal gland; the neck, tail, and body of the pancreas; the aorta and
celiac trunk; and the periaortic nerve plexuses. The greater curvature of the stomach is near the
transverse colon and the transverse colonic mesentery. The concavity of the spleen contacts the left
lateral portion of the stomach.
1 The stomach is an extremely well-vascularized organ, supplied by a number of major arteries and
protected by a large number of extramural and intramural collaterals. Gastric viability can be preserved
after ligation of all but one primary artery, an advantage that can be exploited during gastric
reconstructive procedures. Also, the rich network of anastomosing vessels means that gastric
hemorrhage cannot be controlled by the extramural ligation of gastric arteries. Most gastric blood flow
is ordinarily derived from the celiac trunk (Fig. 44-2). The lesser curvature is supplied by the left gastric
artery, which is the first major branch of the celiac trunk, and by the right gastric artery, which is
derived from the hepatic artery. Branches of the left gastric artery also supply the lowermost portion of
the esophagus. The greater curvature is supplied by the short gastric and left gastroepiploic arteries,
which are branches of the splenic artery, and by the right gastroepiploic artery, a branch of the
gastroduodenal artery. In instances of celiac trunk occlusion, gastric blood flow is usually maintained
from the superior mesenteric artery collaterally by way of the pancreaticoduodenal arcade. In general,
venous effluent from the stomach parallels the arterial supply. The venous equivalent of the left gastric
artery is the coronary vein.
Figure 44-1. Topographic relations of the stomach.
As a first approximation, the lymphatic drainage of the stomach parallels gastric venous return (Fig.
44-3). Lymph from the proximal portion of the stomach along the lesser curvature first drains into
superior gastric lymph nodes surrounding the left gastric artery. The distal portion of the lesser
curvature drains through suprapyloric nodes. The proximal portion of the greater curvature is supplied
by lymphatic vessels that traverse pancreaticosplenic nodes, whereas the antral portion of the greater
curvature drains into the subpyloric and omental nodal groups. Secondary drainage from each of these
systems eventually traverses nodes at the base of the celiac axis. These discrete anatomic groupings are
misleading. The lymphatic drainage of the human stomach, like its blood supply, exhibits extensive
intramural ramifications and a number of extramural communications. As a consequence, disease
processes that involve the gastric lymphatics often spread intramurally beyond the region of origin and
to nodal groups at a distance from the primary lymphatic zone.
The left and right vagal nerves descend parallel to the esophagus within the thorax before forming a
periesophageal plexus between the tracheal bifurcation and the diaphragm. From this plexus, two vagal
trunks coalesce before passing through the esophageal hiatus of the diaphragm (Fig. 44-4). The left
vagal trunk is usually closely applied to the anterior surface of the esophagus, whereas the posterior
vagal trunk is often midway between the esophagus and the aorta. The anterior vagus supplies a hepatic
1147
booksmedicos.org
division, which passes to the right in the lesser omentum before innervating the liver and biliary tract.
The remainder of the anterior vagal fibers parallels the lesser curvature of the stomach, branching to
the anterior gastric wall. The posterior vagus nerve branches into the celiac division, which passes to
the celiac plexus, and a posterior gastric division, which innervates the posterior gastric wall.
Figure 44-2. Arterial blood supply of the stomach.
Figure 44-3. Lymphatic drainage of the stomach.
Approximately 90% of the fibers in the vagal trunks are afferent, transmitting information from the
gastrointestinal tract to the central nervous system (CNS). Parasympathetic afferent fibers are not
responsible for the sensation of gastric pain. Only 10% of vagal nerve fibers are motor or secretory
efferents. Parasympathetic efferent fibers contained in the vagus originate in the dorsal nucleus of the
medulla. Vagal efferent fibers pass without synapse to contact postsynaptic neurons in the gastric wall
in the myenteric and submucous plexuses. Secondary neurons directly innervate gastric smooth muscle
or epithelial cells. Acetylcholine is the neurotransmitter of primary vagal efferent neurons.
The gastric sympathetic innervation is derived from spinal segments T5 through T10. Sympathetic
fibers leave the corresponding spinal nerve roots by way of gray rami communicantes and enter a series
of bilateral prevertebral ganglia (Fig. 44-5). From these ganglia, presynaptic fibers pass through the
greater splanchnic nerves to the celiac plexus, where they synapse with secondary sympathetic neurons.
Postsynaptic sympathetic nerve fibers enter the stomach in association with blood vessels. Afferent
sympathetic fibers pass without synapse from the stomach to dorsal spinal roots. Pain of gastroduodenal
origin is sensed through afferent fibers of sympathetic origin.
1148
booksmedicos.org
Figure 44-4. Vagal innervation of the stomach.
Figure 44-5. Derivation of gastric sympathetic innervation.
MICROSCOPIC ANATOMY
The glandular portions of the stomach are lined by a simple columnar epithelium composed of surface
mucous cells. The luminal surface, visualized by scanning electron microscopy, appears cobblestoned,
interrupted at intervals by gastric pits. Opening into the gastric pits are one or more gastric glands that
impart functional significance to the gastric mucosa. The mucosa of the human stomach is composed of
three distinct types of gastric glands – cardiac, oxyntic, and antral.
In humans, cardiac glands occupy a narrow zone adjacent to the esophagus and mark a transition
from the stratified squamous epithelium of the esophagus to the simple columnar epithelium of the
stomach. The surface and gastric pit mucous cells of the cardia are not distinguishable from those in
other areas of the stomach. Cardiac glands contain mucous and undifferentiated and endocrine cells but
not the parietal or chief cells that are prominent in the adjacent oxyntic mucosa. Cardiac glands are
usually branched and connect with relatively short gastric pits. The functional properties of cardiac
glands include the secretion of mucus.
2 Oxyntic glands are the most distinctive feature of the human stomach. They occupy the fundus and
body of the stomach and contain the oxyntic or parietal cells, which are the sites of acid production.
Oxyntic glands also contain chief cells, the site of gastric pepsinogen synthesis. The tubular oxyntic
1149
booksmedicos.org
glands are usually relatively straight but sometimes branch; several glands may empty into a single
gastric pit. The glands are divided into three regions: (a) the isthmus, containing surface mucous cells
and a few scattered parietal cells; (b) the neck, with a heavy concentration of parietal cells and a few
neck mucous cells; and (c) the base of the gland, containing chief cells, undifferentiated cells, a few
parietal cells, and some mucous neck cells. Endocrine cells are scattered throughout all three regions of
oxyntic glands.
The most distinctive cell of the gastric mucosa is the acid-secreting parietal cell. Parietal cells have an
unusual ultrastructural specialization in the form of intracellular canaliculi, a network of clefts
extending to the basal cytoplasm and often encircling the nucleus, which is continuous with the gland
lumen (Fig. 44-6). The surface area provided by the intracellular secretory canaliculi is large and is
further magnified by microvilli lining the canaliculi. In parietal cells that are not stimulated to secrete
acid, the secretory canaliculi are collapsed and inconspicuous. On stimulation, a severalfold increase in
canalicular surface area occurs, the intracellular clefts become prominent, and the communication with
the luminal surface is readily identified. These changes create an intracellular space in communication
with the gastric lumen into which hydrogen ions are secreted at high concentration.
The cytoplasm of the parietal cell also contains an abundance of large mitochondria. Mitochondria are
estimated to occupy 30% to 40% of the cytoplasmic volume of unstimulated parietal cells, reflecting the
extremely high oxidative activity of these cells. The oxygen consumption rate of isolated parietal cells is
approximately five times higher than that of gastric mucous cells. The cytoplasm also contains a limited
amount of rough endoplasmic reticulum, presumed to be the production site of intrinsic factor, which is
also secreted by parietal cells.
Figure 44-6. Resting and stimulated parietal cell, emphasizing morphologic transformation with increase in secretory canalicular
membrane surface area that occurs with acid secretion.
1150
booksmedicos.org
Figure 44-7. Contrasting morphology of antral gastrin cell (left) with basally oriented secretory granules, and gastric mucous cell
(right) with apical mucous granules.
In addition to parietal cells, the oxyntic glands contain the gastric chief cells, which synthesize and
secrete pepsinogen. Chief cells are most abundant in the basal region of the oxyntic glands. The cells
have a morphology typical of protein-secreting exocrine cells and are similar in ultrastructural
appearance to pancreatic acinar cells. Rough endoplasmic reticulum is abundant in the cytoplasm and
extends between secretory granules. Zymogen granules containing pepsinogen are most concentrated in
the apical cytoplasm. Pepsinogen is released by exocytosis from secretory granules at the apical surface
of chief cells.
Antral glands occupy the mucosa of the distal stomach and pyloric channel. Antral glands are
relatively straight and often empty through deep gastric pits. Although most cells in the antral glands
are mucus secreting, gastrin cells are the distinctive feature of this mucosa. Gastrin cells are pyramid
shaped, with a narrow area of luminal contact apically and a broad surface overlying the lamina propria
basally (Fig. 44-7). Gastrin cells are identified immunocytochemically by the presence of the peptide.
Granules ranging from 150 to 400 nm in diameter are the sites of gastrin storage and are most
numerous in the basal cytoplasm. Gastrin is released by exocytotic fusion of the secretory granule with
the plasma membrane. In contrast to secretion from chief cells, emptying of gastrin-containing granules
occurs at the basal membrane rather than at the apical region of the cell. Gastrin thus released diffuses
to and enters submucosal capillaries in close apposition to the lamina propria.
GASTRIC PEPTIDES
The stomach contains a number of biologically active peptides in nerves and mucosal endocrine cells,
including gastrin, somatostatin, ghrelin, gastrin-releasing peptide, vasoactive intestinal polypeptide
(VIP), substance P, glucagon, and calcitonin gene–related peptide. The peptides with the greatest
importance to human disease and clinical surgery are gastrin, somatostatin, and ghrelin.
Gastrin
The synthesis, secretion, and action of gastrin have been extensively studied, and many aspects of the
biology of gastrin appear to be shared by other gastrointestinal peptide hormones.1 The gene that
encodes for gastrin was isolated using a human DNA library. The human gastrin gene contains three
exons; two exons consist of coding sequences. The major active product is encoded by a single exon. In
adults, the gastrin gene is expressed primarily in mucosa cells of the gastric antrum, with lower levels
of expression in the duodenum, pituitary, and testis. During embryonic development, the gastrin gene is
transiently active in pancreatic islets and colonic mucosa.
The human gene encompasses approximately 4,100 base pairs and directs the synthesis of a peptide of
101 amino acids (Fig. 44-8). The resulting peptide, preprogastrin, contains the sequence of gastrin
1151
booksmedicos.org
within its amino acid sequence. Preprogastrin consists of a signal peptide of 21 amino acids, an
intervening peptide of 37 amino acids, the 34-residue region of the gastrin molecule, and a carboxyl-
terminal extension of nine amino acids. Gastrin is derived from its preprohormone by the sequential
enzymatic cleavage of the signal peptide, the intervening peptide, and the carboxyl-terminal extension.
The signal peptide region of preprogastrin consists of a series of hydrophobic amino acids that direct
the nascent peptide into the endoplasmic reticulum as it is translated from messenger RNA. After
directing the preprogastrin molecule into the rough endoplasmic reticulum, the signal peptide is
removed. The remaining peptide is termed progastrin. Progastrin is further processed as it traverses the
endoplasmic reticulum to mature secretory vesicles. Enzymatic cleavage at a pair of basic amino acid
residues proximal to the gastrin 34 (G34) sequence removes the intervening peptide. A similar cleavage
removes a six-amino-acid fragment at the carboxyl-terminal end. The peptide that remains has a Gly-
Arg-Arg sequence at the carboxyl terminus. Carboxypeptidase cleaves the Arg residues, and the peptide
that results is termed glycine-extended gastrin. G34 is formed by cleavage of the Gly-Arg-Arg sequence
and amidation of the carboxyl-terminal phenylalanine. Gastrin, like most gastrointestinal peptide
hormones, requires terminal amidation for biologic activity. Gastrin 17 (G17), the most abundant form
of gastrin in the human antrum, is formed by further processing that removes the first 17 amino acids at
the amino terminus of G34. G34 is the predominate molecular form of gastrin in the duodenum.
Figure 44-8. Sequential processing of preprogastrin molecule.
3 The most important stimulant of gastrin release is a meal. Small peptide fragments and amino acids
that result from intragastric proteolysis are the most important food components that stimulate gastrin
release. The most potent gastrin-releasing activities are demonstrated by the amino acids tryptophan
and phenylalanine. Ingested fat and glucose do not cause gastrin release. Gastric distention by a meal
activates cholinergic neurons and stimulates gastrin release. As the meal empties and distention
diminishes, VIP-containing neurons are activated, which stimulate somatostatin secretion and thus
attenuate gastrin secretion.
Postprandial luminal pH also strongly affects gastrin secretion. Gastrin release is inhibited when
acidification of an ingested meal causes the intraluminal pH to fall below 3.0. Conversely, maintaining
intragastric pH above 3.0 potentiates gastrin secretion after ingestion of protein or amino acids.2
Pernicious anemia and atrophic gastritis, which produce chronic achlorhydria, are associated with
fasting hypergastrinemia and an exaggerated gastrin meal response. Release of mucosal somatostatin
occurs with gastric acidification and this peptide has been implicated in the inhibition of gastrin release
that occurs when luminal pH falls.
The vagus nerve appears to both stimulate and inhibit gastrin release.3 In humans, vagally mediated
1152
booksmedicos.org
stimulation of gastrin release can be demonstrated by sham feeding, insulin-induced hypoglycemia, and
administration of the vagal stimulant gamma-aminobutyric acid. In contrast to these stimulatory vagal
effects, hypergastrinemia, observed after vagotomy, suggests that inhibitory vagal effects on gastrin
release may also exist. Cholinergic neurons stimulate gastrin secretion directly by actions on gastrin
cells. By decreasing somatostatin secretion, cholinergic neurons also indirectly stimulate gastrin release.
Evidence suggests that vagal stimulation of gastrin release is mediated by bombesin or its mammalian
equivalent, gastrin-releasing peptide, acting as a neurotransmitter in the gastric wall. Adrenergic
stimulation has also been noted to increase gastrin release.
Chronic gastric infection with Helicobacter pylori causes increased acid secretion by altering gastrin
release.4,5 H. pylori has been observed to upregulate proinflammatory cytokines, including interleukin
(IL)-6, IL-8, and tumor necrosis factor-α (TNF-α). Several inflammatory mediators have been
demonstrated to stimulate gastrin release from isolated gastrin cells. The putative gastrin secretagogues
include IL-1, IL-8, TNF-α, interferon-gamma, and leukotrienes C4 and D4. The same factors that affect
gastrin release also influence gastrin mRNA expression. Food ingestion increases gastrin mRNA
abundance, whereas fasting and somatostatin decrease gastrin mRNA production. Chronic achlorhydria,
as seen in pernicious anemia, increases gastrin mRNA production.
In addition to stimulating acid secretion from gastric parietal cells (detailed later in this chapter),
gastrin has important physiologic actions in the control of gastrointestinal mucosal growth. The acid-
secreting oxyntic mucosa is particularly sensitive to the trophic actions of gastrin, but the mucous
membranes of the duodenum, colon, and pancreatic parenchyma are also affected. Stimulation of
mucosal growth by gastrin is enhanced by the presence of solid food in the diet. The 17- and 34-amino-
acid forms of gastrin are equipotent in stimulating mucosal growth. Prolonged stimulation by high
levels of gastrin, as seen in the Zollinger–Ellison syndrome, is associated with hypertrophy of the gastric
mucosa. Smaller increases in circulating gastrin, such as those that follow vagotomy, do not cause
mucosal hypertrophy.
Figure 44-9. Derivation of somatostatin 14 from preprosomatostatin precursor.
Somatostatin
Somatostatin, like gastrin, is very significant in gastric physiology. Somatostatin was first isolated from
hypothalamic tissues and was named for its ability to inhibit the release of growth hormone. The
peptide was subsequently localized in neurons in central and peripheral nervous systems, and in
endocrine cells in the pancreas, stomach, and intestine.6 The wide tissue distribution of somatostatin
suggested important regulatory functions, a concept validated by many investigations.
The human somatostatin gene is located on chromosome 3 and encodes for a precursor of 116 amino
acids (Fig. 44-9). The somatostatin molecule is contained in the carboxyl-terminal sequence of this
preprohormone. The first 24 amino acids of the amino terminus of preprosomatostatin constitute a
signal peptide; cleavage of this signal peptide leaves prosomatostatin. Enzymatic cleavage of an
additional 64-amino-acid segment from prosomatostatin forms somatostatin 28. Further processing of
somatostatin 28 to somatostatin 14 is tissue-specifically regulated. In the stomach, most somatostatin
exists as the shorter peptide.
Gastric somatostatin release responds to luminal, hormonal, and neural signals. Luminal acidification
is associated with increased somatostatin release, whereas somatostatin release decreases when luminal
pH is increased. A number of peptides have been demonstrated experimentally to release somatostatin
from the stomach, including gastrin, cholecystokinin, and secretin. β-Adrenergic agonists have also been
1153
booksmedicos.org
shown to release somatostatin. In contrast, electrical stimulation of vagal nerves inhibits somatostatin
release, as does the cholinergic agonist methacholine.
The most important gastric function of somatostatin appears to be regulation of acid secretion and
gastrin release. Circulating somatostatin appears to be important in modulating gastric acid secretion;
locally released somatostatin functions to regulate gastrin release. In each instance, somatostatin serves
an inhibitory function, decreasing acid secretion and diminishing the release of gastrin. In animals,
antral or duodenal acidification has been associated with an increase in circulating somatostatin.
Increases in circulating somatostatin are followed, in turn, by decreased gastric acid secretion. Infusion
of exogenous somatostatin in doses that produce somatostatin levels similar to those observed
postprandially has also been shown to inhibit acid secretion. In humans, concentrations of somatostatin
capable of inhibiting acid secretion can do so without altering serum gastrin levels, indicating a direct
action on the acid-secreting fundic mucosa.
Somatostatin is believed to influence gastrin secretion through a locally active intramucosal
mechanism. Local actions of somatostatin are supported by ultrastructural studies of antral somatostatin
cells, which demonstrate long cytoplasmic processes that make intimate cell-to-cell contact with antral
gastrin cells. The presence of somatostatin at these sites of cellular contact implies that somatostatin
cells influence the function of gastrin cells through local release of the peptide. Somatostatin can also
reach neighboring gastrin cells through diffusion or local blood flow. A number of experiments have
suggested that release of somatostatin and gastrin is functionally, although reciprocally, linked. For
example, in anesthetized animals, an increase in gastric pH or ingestion of a meal is associated with
increases in gastrin and decreases in somatostatin in antral venous blood. Cholinergic agents stimulate
gastrin release while inhibiting somatostatin release. Prostaglandin E2, in contrast, inhibits gastrin
release and stimulates somatostatin secretion. These and similar observations suggest that increases in
somatostatin release are often associated with decreased gastrin secretion. A family of five somatostatin
receptors has been cloned. Inhibition of gastrin-stimulated gastric acid secretion is mediated by
somatostatin receptor subtype 2.7
GASTRIC ACID SECRETION

Cellular Events
4 An appreciation of the mechanisms that control gastric acid formation is essential to a discussion of
gastric disease. An understanding of the cellular basis of acid secretion by the gastric parietal cell also
provides a foundation for discussing the pharmacologic treatment of acid–peptic diseases. The
basolateral membrane of the parietal cell contains specific receptors for histamine, gastrin, and
acetylcholine, the three major stimulants of acid production.8 Each stimulant reaches the parietal cell by
a different route. Histamine is released from mastlike cells within the lamina propria and diffuses to the
mucosa, acetylcholine is released in close proximity to the parietal cells from cholinergic nerve
terminals, and gastrin is delivered by the systemic circulation to the fundic mucosa from its source in
the antrum and proximal duodenum (Fig. 44-10), activating protein kinase A, which in turn catalyzes
protein phosphorylation. The target protein molecules for this phosphorylation, in turn, stimulate acid
production.
1154
booksmedicos.org
Figure 44-10. Interactions of cell types that affect parietal cell acid secretion.
Acetylcholine and related cholinergic agonists activate parietal cells after binding to muscarinic
receptors. The stimulatory effects of acetylcholine and its congeners can be abolished by atropine. The
action of acetylcholine is mediated by muscarinic receptor subtype 3 (M3). Studies suggest that
cholinergic stimulation of parietal cell function is coupled to enhanced mobilization of intracellular
calcium. The resultant transient increases in intracellular calcium activate mechanisms that stimulate
acid secretion (Fig. 44-11). Evidence also indicates that occupation of acetylcholine receptors increases
turnover of specific membrane phospholipids termed phosphatidylinositides. Acetylcholine–receptor
binding is followed by activation of membrane-associated phospholipase C. Phospholipase C acts on
phosphatidylinositol-4,5-bisphosphate (PIP2) within the plasma membrane to liberate water-soluble
inositol triphosphate (IP3) and diacylglycerol. A major action of IP3 is to increase intracellular calcium,
mainly from intracellular stores in the endoplasmic reticulum. The resulting increased cytosolic calcium
interacts with calmodulin or other calcium-binding proteins. Calmodulin kinase type II is involved in
parietal cell activation by acetylcholine. Intracellular calcium in this form is postulated to modulate
parietal cell function through protein phosphorylation or enzyme activation. Diacylglycerol, the second
product released by hydrolysis of PIP2, activates a class of protein kinases that are phospholipid
dependent and Ca2+ activated, protein kinase C. Protein kinase C in turn acts to phosphorylate a set of
proteins that are distinct from those affected by the calmodulin-dependent system. The ultimate result
of this protein phosphorylation is parietal cell activation and hydrogen ion secretion.
Parietal cells can also be activated by occupation of specific gastrin receptors. As with cholinergic
stimulation, gastrin exposure increases membrane PIP2 turnover (Fig. 44-11). Like acetylcholine, the
actions of gastrin depend highly on increases in intracellular calcium and activation of protein kinase C.
Although histamine, acetylcholine, and gastrin occupy separate receptors on the parietal cell and
activate differing second-messenger systems, each secretagogue ultimately acts by means of a
specialized ion transport system called the parietal cell proton pump. This membrane-bound protein is
located in the secretory canaliculus of the parietal cell; the peptide has not been identified in other
gastric cells or in significant amounts in other organs. The proton pump is an H+-K+-adenosine
triphosphatase (ATPase) that electroneutrally exchanges cytosolic H+ for luminal K+. Hydrogen ions
are concentrated 2.5-million-fold within the secretory canaliculus, and the hydrolysis of ATP is the
energy source for transport against the steep electrochemical gradient generated. For each H+ ion
transported to the luminal surface of the canalicular membrane, one K+ ion is transported to the
cytosolic surface (Fig. 44-12). This cotransport requires that K+ be continuously supplied to the luminal
surface of the secretory membrane. This requirement is satisfied by conductance of K+ across the
canalicular membrane from intracellular stores. Chloride ions also enter the secretory canaliculus by
diffusion.
Activation of the H+-K+-ATPase significantly increases intracellular OH− generation, with potential
cellular toxicity. Carbonic anhydrase, which is associated with the canalicular membrane, converts OH−
to HCO3−. The HCO3− produced is disposed of by exchange for Cl− at the basolateral membrane.
1155
booksmedicos.org
Intracellular Cl− thus acquired supplies the necessary Cl− on a one-to-one basis for each H+ secreted.
The transcellular exchange of H+ for HCO3− ensures that the voluminous secretion of hydrochloride at
the luminal surface of the gastric mucosa is matched by an equivalent delivery of base to submucosal
capillaries. Parietal cell ionic transport pathways are shown in Figure 44-13.
Figure 44-11. Cellular mechanisms controlling parietal cell acid secretion. ADP, adenosine diphosphate; ATP, adenosine
triphosphate; cAMP, cyclic adenosine monophosphate; PI, phosphatidylinositol; PIP, phosphatidylinositol-4,5-phosphate; PIP2,
phosphatidylinositol-4,5-bisphosphate; RER, rough endoplasmic reticulum.
The function of the proton pump is highly regulated. In the unstimulated state, the enzyme is
sequestered in cytoplasmic structures termed tubulovesicles that are not connected to the gastric lumen.
Tubulovesicle membranes in this state have a low permeability to KCl. Stimulation of acid secretion
causes tubulovesicles to fuse with apical secretory membranes and increases membrane permeability to
KCl. In this way, the fusion of tubulovesicle membrane exposes the H+-K+ pump to the gastric lumen
and simultaneously provides the K+ substrate necessary for acid secretion.
Parietal cells also contain membrane receptors that inhibit acid secretion. Specific receptors for
somatostatin have been identified using isolated gastric cells. Activation of isolated parietal cells by
histamine, pentagastrin, or the cholinergic agonist carbachol can be blocked by somatostatin 28. In the
case of histamine activation, the inhibitory effects appear to be mediated by the ability of somatostatin
to block the production of cyclic adenosine monophosphate (cAMP). Somatostatin appears to inhibit the
actions of these agonists at a point distal to second-messenger generation. Gastric parietal cells also
contain receptors for prostaglandins, notably prostaglandin E2 and its derivatives. Prostaglandin E2 is a
potent inhibitor of histamine-stimulated parietal cell activation, probably by a mechanism that inhibits
formation of cAMP. Prostaglandin inhibition is specific for histamine; the actions of gastrin or carbachol
are not affected. Epidermal growth factor and transforming growth factor-α also inhibit histamine-
stimulated acid secretion through effects on cAMP production.
1156
booksmedicos.org
Figure 44-12. Gastric H+-K+-adenosine triphosphatase (ATPase). ADP, adenosine diphosphate; ATP, adenosine triphosphate; Pi,
phosphate ion.
Figure 44-13. Ionic fluxes associated with acid secretion by the parietal cell.
These considerations of the cellular basis of acid production demonstrate how parietal cell function
can be altered pharmacologically. Gastric acid production can be blocked by receptor antagonists for
each of the three primary stimulants – gastrin, acetylcholine, and histamine. Direct inhibition of acid
production can be effected by derivatives of somatostatin or prostaglandin E2. All forms of stimulated
acid production can be blocked by agents that act as inhibitors of the parietal cell proton pump. Agents
that act at each of these points have been developed, and their appropriate clinical applications are
discussed in subsequent chapters.
Regulation of Acid Secretion

Given the multiple receptors on parietal cells, it is not surprising that a great deal of secretagogue
interdependence, both stimulatory and inhibitory, exists in humans. Parietal cell activation, and the
resultant acid secretion, is greater in response to a combination of agonists than it is in response to the
total effect of agents used singly. This increase in responsiveness is defined as potentiation. Potentiating
interactions are most apparent when agents are used that act by way of different second-messenger
systems. Thus, histamine strongly potentiates the acid-secretory response to pentagastrin or to carbachol
in humans. Conversely, blockade of receptors to one stimulant also decreases responsiveness to the
other agonists. For example, blocking histamine receptors with agents such as cimetidine decreases
responsiveness to pentagastrin, even though gastrin receptors are not directly affected. These inhibitory
interactions are exploited therapeutically in the treatment of acid–peptic diseases.
Humans normally secrete 2 to 5 mEq/hr of hydrochloride in the fasting state, constituting basal acid
secretion. Both vagal tone and ambient histamine secretion are presumed to be important in
determining the rate of basal acid secretion. In humans, truncal vagotomy decreases basal secretion by
approximately 85%. Similarly, H2-receptor antagonists also inhibit basal acid secretion by
approximately 80%. Gastrin does not have an important role in determining basal acid secretion in
normal people.
Stimulated acid secretion begins with the thought, sight, or smell of food (Fig. 44-14). This cephalic
phase of gastric acid secretion is mediated by the vagus nerve. Vagal discharge directs a cholinergic
mechanism, and the cephalic phase of acid secretion can be inhibited by administering atropine. Vagal
discharge secondary to cephalic stimulation also inhibits the release of somatostatin. Diminished
secretion of somatostatin further augments stimulatory vagal effects, presumably by eliminating tonic
inhibition of acid secretion exerted by somatostatin. The cephalic component of acid secretion can be
measured in normal people by sham feeding and is approximately 10 mEq/hr. The cephalic phase
approximates 40% of the maximal acid-secretory response to gastrin infusion.
The gastric phase of acid secretion begins when food enters the stomach. The presence of partially
hydrolyzed food constituents, gastric distention, and the buffering capacity of food all stimulate acid
secretion. Gastrin is the most important mediator of the gastric phase of acid secretion. In normal
humans, acid-secretory rates after a mixed meal average 15 to 25 mEq/hr, approximately 75% of the
maximal response achieved with infusion of exogenous gastrin or histamine. The meal response is less
than the maximal response to exogenous stimulants because food also causes the release of somatostatin
1157
booksmedicos.org
and initiates other inhibitory responses. In humans, 90% of meal-stimulated acid secretion is mediated
by gastrin release.9
The inhibitory regulation of gastric acid secretion is accomplished by CNS, gastric, and intestinal
mechanisms. Stimulated acid secretion can be inhibited experimentally by administering various
neuropeptides into the lateral cerebral ventricles, including gastrin-releasing peptide (bombesin),
corticotropin-releasing factor, and calcitonin gene–related peptide. Although the relevance of these
observations to human physiology remains to be determined, it is likely that CNS inhibition of acid
secretion exists in humans. In this regard, the vagus nerve has both a stimulatory and an inhibitory role
in acid secretion and gastrin release. Vagotomy causes fasting and postprandial hypergastrinemia,
indicating that an inhibitory regulation of gastrin release normally exists. Hypergastrinemia is sustained
long term after vagotomy by hyperplasia of antral gastrin cells. The vagal fibers to the oxyntic region of
the stomach appear to mediate this inhibitory effect.
Figure 44-14. Regulation of acid secretion in vivo. TRH, thyroid-releasing hormone.
In humans, the most important and clearly established gastric inhibitory influence is the suppression
of gastrin release when the antral mucosa is exposed to acid. When luminal pH falls to 2.0, gastrin
release stops. Antral acidification also suppresses the gastrin response to an ingested meal. Somatostatin
acting locally in the gastric mucosa as a paracrine agent may mediate this important inhibitory
response. Release of gastric somatostatin is reciprocally linked to that of gastrin; acidification of the
antrum causes increases in somatostatin release and decreases in gastrin secretion. Antral distention also
inhibits stimulated acid secretion.
The entry of digestive products into the intestine begins intestinal-phase inhibition of gastric acid
secretion. Acidification of the duodenal bulb inhibits acid secretion, and although exogenous secretin
also can inhibit acid secretion, this effect appears to be independent of the release of secretin from the
duodenal mucosa. Hyperosmolar solutions and those containing fat also potently inhibit acid secretion.
Several peptides, including secretin, somatostatin, peptide YY, gastric inhibitory peptide, and
neurotensin, have been proposed as mediators of the intestinal phase effects.
PEPSIN
5 Pepsins are a heterogeneous group of proteolytic enzymes that are secreted by the gastric chief cells.
Pepsin is derived under acidic conditions from pepsinogen by the autocatalytic loss of a variable amino-
terminal sequence of the parent compound. This conversion occurs slowly at pH values of 5.0 to 6.0 and
occurs rapidly when luminal pH approximates 2.0. Pepsin catalyzes the hydrolysis of a wide variety of
peptide bonds that contain acidic residues, with a pH optimum for hydrolysis between 1.5 and 2.5. Once
activated, pepsin is sensitive to ambient pH values; it is irreversibly denatured at pH 7.0 or greater.
The most important stimulus for pepsinogen secretion is cholinergic stimulation. Acetylcholine and its
1158
booksmedicos.org
derivatives stimulate pepsinogen secretion by a mechanism that can be antagonized by atropine,
indicating a muscarinic receptor. The receptor is an M1 type. Endogenous cholinergic stimulation
through the vagal nerve results in the formation of a gastric secretion that is rich in pepsin. Although
both exogenous histamine and gastrin can stimulate pepsin secretion, their actions appear to be
indirectly due to the concomitant secretion of gastric acid rather than to direct stimulation of chief cells.
Chief cells have also been shown to possess cholecystokinin receptors, and cholecystokinin-like peptides
appear to have a direct stimulatory action on chief cells. The oxyntic mucosa contains somatostatin cells
near chief cells. Pepsinogen secretion in response to a variety of stimuli has been demonstrated to be
inhibited by somatostatin.
The major physiologic function of pepsin is to initiate protein digestion. Pepsin is highly active
against collagen and may be important in the digestion of animal protein. Intragastric protein hydrolysis
by pepsin is incomplete, and relatively large peptides enter the intestine, although amino acids and
small peptide fragments are released. These products of partial hydrolysis are important signals for
gastrin and cholecystokinin release, which in turn regulate digestive processes. In this way, pepsin also
contributes to the overall coordination of the digestive process.
INTRINSIC FACTOR
6 The gastric mucosa is the site of production of intrinsic factor, which is necessary for the absorption of
cobalamin from the ileal mucosa. Total gastrectomy is regularly followed by cobalamin malabsorption,
as is resection of the proximal stomach or atrophic gastritis that involves the oxyntic mucosa.
Autoradiographic and immunocytochemical techniques have confirmed the parietal cell as the site of
intrinsic factor synthesis and storage in humans. Intrinsic factor secretion, like acid secretion, is
stimulated by histamine, acetylcholine, and gastrin. Unlike acid production, intrinsic factor secretion
peaks rapidly after stimulation and then returns to baseline. The amount of intrinsic factor secreted
usually greatly exceeds the amount needed to bind and absorb available dietary cobalamin.
GASTRIC BICARBONATE PRODUCTION

It is generally agreed that the gastric mucosa secretes HCO3− in addition to acid. The cells responsible
for HCO3− production are presumed to be the surface mucous cells facing the gastric lumen, and
HCO3− transport has been postulated to protect against damage from luminal acid. In theory, H+ ions
diffusing from luminal bulk fluids toward the gastric mucosa could be neutralized by secreted HCO3−
near the surface (Fig. 44-15). In this way, nearly neutral pH can be maintained at the mucosal surface,
even if the total amount of hydrochloride secreted greatly exceeds gastric HCO3− production. The
occurrence of pH gradients at the surface of the gastric mucosa have been demonstrated in humans
using microelectrodes. Drugs or chemicals that inhibit bicarbonate secretion result in acidification of the
mucosal surface.
The degree of luminal acidity, reflected by pH, required to stimulate bicarbonate secretion is greater
in the stomach than in the duodenum. Direct exposure of the gastric mucosa to pH levels of 2.0 or more
increases bicarbonate secretion. In the duodenum, exposure of the mucosa to pH 5.0 doubles
bicarbonate secretion, whereas exposure to pH 2.0 increases alkaline secretion 10-fold.
Cholinergic agonists, vagal nerve stimulation, and sham feeding have all been shown to increase
gastric HCO3− production. The effects of cholinergic stimulation can be blocked by atropine. In the
human stomach, exposure to luminal perfusates at pH 2.0 has been associated with increased release of
prostaglandin E2. Prostaglandin E2 and its synthetic derivatives are also potent stimulants of gastric
bicarbonate secretion. Because mucosal bicarbonate production can be decreased in experimental
models by indomethacin, endogenous prostaglandins are thought to be important in the mucosal
alkaline response.
GASTRIC BLOOD FLOW

Because the gastric mucosa is metabolically highly active, control of mucosal blood flow is of great
physiologic importance. In addition, studies have implicated perfusion abnormalities in the development
of mucosal lesions during periods of stress. Mucosal blood flow is regulated by neural, hormonal, and
1159
booksmedicos.org
locally active influences.
Postganglionic sympathetic nerve fibers reach the stomach in association with its blood supply and
richly innervate small mucosal arteries. Mucosal capillaries do not receive adrenergic innervation.
Electrical stimulation of sympathetic nerves supplying the stomach is followed by decreased total
gastric blood flow, decreased flow in celiac and gastroepiploic vessels, and diminished blood flow to the
mucosa. Studies in animals demonstrate that vasoconstriction of the gastric vascular bed is mediated by
α-adrenergic receptors and that vasodilation is mediated by β-adrenergic receptors.
Figure 44-15. Schematic representation of mucosal bicarbonate secretion showing neutralization of luminal hydrogen ions
immediately above the mucosal surface.
Stimulation of the vagus nerve is followed by a prompt increase in blood flow, suggesting a dilatory
effect of parasympathetic nerves. The effects of vagal stimulation on mucosal blood flow are
complicated by accompanying increases in acid secretion. Almost all stimuli that increase acid
production also increase blood flow secondarily.
A number of gastrointestinal peptide hormones affect gastric blood flow, most because of their ability
to increase or decrease acid secretion. Thus, gastrin, because it is a potent stimulant of acid secretion,
also increases mucosal blood flow. Cholecystokinin appears to have direct vasodilatory effects on the
gastric vasculature. Vasopressin has been well demonstrated to have direct vasoconstrictor activity.
Nitric oxide modulates basal gastric vascular tone and controls gastric vasodilation and hyperemia.
Nitric oxide mediates the hyperemic response that accompanies increases in acid secretion, although the
molecule has no direct stimulatory role in acid production.
Prostaglandins are important mucosally produced compounds that have clear effects on the gastric
vasculature. Prostaglandins of the E class have been shown in animals and humans to increase gastric
blood flow at doses that decrease acid secretion. Indomethacin, in doses sufficient to inhibit
prostaglandin formation, decreases the diameter of submucosal blood vessels and reduces basal blood
flow. Complete inhibition of cyclooxygenase activity causes an approximate 50% reduction in resting
blood flow. These studies suggest that endogenous, locally produced prostaglandins are crucial to
maintaining basal gastric blood flow in humans and probably act in concert with endogenous nitric
oxide.
GASTRIC MOTILITY
Gastric Smooth Muscle
Consideration of gastric motility requires that the stomach be viewed in functional terms as two
different regions, the proximal one-third and the distal two-thirds. These areas are distinct in terms of
smooth muscle anatomy, electrical activity, and contractile function. The regions do not correspond to
the traditional anatomic divisions of fundus, corpus, and antrum.
In the proximal stomach, three layers of gastric smooth muscle can be distinguished: an outer
longitudinal layer, a middle circular layer, and an inner oblique layer. In the distal two-thirds of the
stomach, the longitudinal layer is most clearly defined, and the inner oblique layer is usually not
distinct. The gastric smooth muscle ends at the pylorus.
The smooth muscle of the proximal stomach is electrically stable, whereas the smooth muscle of the
distal stomach demonstrates spontaneous, repeated electrical discharges. Gastric smooth muscle exhibits
myoelectric activity that is based on a highly regular pattern called the slow wave.10 In the stomach,
1160
booksmedicos.org
slow waves occur with a frequency of three cycles per minute. Slow waves do not, by themselves, lead
to gastric contractions, but they do set the maximum rate of contractions at three per minute. Gastric
contractions occur when action potentials are phase locked with the crest of the slow wave.
Extracellular electrical recording from the serosal surface of the stomach also demonstrates the
intrinsic electrical activity of the distal stomach in the form of pacesetter potentials. Pacesetter
potentials reflect partial depolarization of the gastric smooth muscle cell and are recorded during
relatively long periods (2 or 3 seconds). Pacesetters originate along the greater curvature at a point in
the proximal third of the stomach. Pacesetter potentials, discharging at a rate of three times per minute
in humans, drive cells located distally. Spread of the pacesetter potentials is faster along the greater
curvature, so that a ring of electrical activity reaches the pylorus simultaneously along both curvatures.
The pacesetter potentials do not result in smooth muscle contraction unless an additional depolarization
is superimposed in the form of an action potential. When action potentials occur, a ring of smooth
muscle contraction moves peristaltically along the distal stomach toward the pylorus.
Duodenal slow-wave frequency and maximum rate of phasic contractions are higher than those
observed in the stomach. The duodenal rate is approximately 12 cycles per minute; the contraction rate
declines progressively to nine cycles per minute in the distal ileum.
The smooth muscle activity of the proximal stomach is fundamentally different from that of the distal
stomach. There are no pacesetters or action potentials in the proximal stomach. As a result, peristalsis
does not occur. Proximal gastric contraction is tonic and prolonged, and increases in luminal pressure
are often sustained for several minutes.
Coordination of Contraction
Important vagally mediated reflexes influence intragastric pressure, presumably by affecting contractile
activity of smooth muscle in the proximal stomach. The most important reflex is termed receptive
relaxation and occurs with ingestion of a meal. Increasing gastric volumes are accommodated with little
increase in intragastric pressure by relaxation of the proximal stomach. This receptive relaxation allows
the proximal stomach to act as a storage site for ingested food in the immediate postprandial period.
Afferent impulses, presumed to originate from stretch receptors in the gastric wall, are carried along
vagal fibers; efferent vagal discharges are inhibitory. Receptive gastric accommodation is lost after
either truncal or proximal gastric vagotomy. After the meal has been ingested, proximal contractile
activity increases; alterations in proximal gastric tone cause the compressive movement of gastric
content from the fundus to the antrum.
Food that enters the antrum from the proximal stomach is propelled peristaltically toward the
pylorus. A number of observations indicate that the pylorus closes 2 or 3 seconds before the arrival of
the antral contraction ring. This coordinate closing of the pylorus allows a small bolus of liquid and
suspended food particles to pass while retropulsing the main mass of gastric contents back into the
proximal antrum. The churning action that results, mixes ingested food particles, gastric acid, and
pepsin, and contributes to the grinding function of the stomach. Solid food particles do not ordinarily
pass the pylorus unless they are no larger than 1 mm.
A consistent finding in humans ingesting a mixed solid–liquid meal is that liquids empty more quickly
than solids. Characteristically, solid food empties only after a lag period, whereas liquid emptying
begins almost immediately. A traditional interpretation of these human observations has been that the
proximal stomach is the dominant force in determining how quickly a liquid meal empties by the
gastroduodenal pressure gradient generated by proximal gastric contractions. The actions of the
proximal stomach in liquid emptying are also regulated by the sieving actions of the antropyloric
segment and are modified by the nutrient composition of the ingested meal. The distal gastric segment
has been postulated to control solid emptying through its grinding and peristaltic actions. This
traditional concept of the two-component stomach is useful in considering observations in patients who
have undergone gastric operative procedures. Patients who have undergone proximal gastric vagotomy
exhibit accelerated emptying of liquids but have normal solid emptying. Because of loss of receptive
relaxation, the denervation of the proximal stomach is presumed to increase intragastric pressure and
accelerate liquid emptying while leaving the distal gastric segment unaffected. Conversely, vagal
denervation of the antrum interrupts gastric emptying of solids to a greater degree than liquids.
Although this model of gastric emptying oversimplifies the many mechanisms (gastric, pyloric, and
intestinal) that work in concert to control gastric emptying, it provides a useful framework for
considering the effects of gastric surgical procedures.
1161
booksmedicos.org
References
1. Von Rosenvinge EC, Raufman J-P. Gastrointestinal peptides and regulation of gastric acid secretion.
Curr Opin Endocrinol Diabetes Obes 2010;17(1):40–44.
2. Schubert M, Peura D. Control of gastric acid secretion in health and disease. Gastroenterology
2008;134(7):1842–1860.
3. Schubert ML. Gastric secretion. Curr Opin Gastroenterol 2008;24:(6)659–664.
4. Debas HT, Carvajal SH. Vagal regulation of acid secretion and gastrin release. Yale J Biol Med
1994;67:145–151.
5. Cover TL. Role of Heliocobacter pylori CagL in modulating gastrin expression. Gut 2012;61:965–
966.
6. Corleto VD. Somatostatin and the gastrointestinal tract. Curr Opin Endocrinol Diabetes Obes
2010;17:63–68.
7. Theodoropoulou M, Stalla GK. Somatostatin receptors: from signaling to clinical practice. Front
Neuroendocrinol 2013;34:228–252.
8. Urushidani T, Forte JG. Signal transduction and activation of acid secretion in the parietal cell. J
Membr Biol 1997;59:99–111.
9. Waldum HL, Brenna E, Kleveland PM, et al. Gastrin—physiological and pathophysiological role:
clinical consequences. Dig Dis 1995;13:25–38.
10. Quigley EM. Gastric and small intestinal motility in health and disease. Gastroenterol Clin North Am
1996;25:113–145.
1162
booksmedicos.org
Chapter 45
Gastroduodenal Ulceration
Key Points
1 Mucosal infection with Helicobacter pylori is the factor that contributes to ulcer pathogenesis in most
patients.
2 H. pylori virulence factors include vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A
(CagA).
3 As a group, patients with duodenal ulcers have an increased capacity for gastric acid secretion
relative to normal people.
4 Current treatment of peptic ulceration involves a combination of an antisecretory drug, usually a
proton pump inhibitor, with antibiotics.
5 Hemorrhage is the leading cause of death associated with peptic ulcer. Patients with recurrent
hemorrhage and elderly patients are at greatest risk of death.
6 For perforation, current therapy includes omental patch closure with postoperative anti–H. pylori
therapy. Minimally invasive approaches are becoming standard practice.
7 Major trauma accompanied by shock, sepsis, respiratory failure, hemorrhage, or multiorgan injury is
often accompanied by acute stress gastritis.
EPIDEMIOLOGY
Peptic ulceration remains a major public health problem worldwide. Worldwide prevalence of peptic
ulcer disease ranges from 0.1% to 4.7% with an overall incidence of 0.2% to 0.3%.1 With improving
public hygiene and effective treatment of Helicobacter pylori, most epidemiologic studies are now
reporting falling incidence rates. The surgical treatment of peptic ulcer has changed fundamentally. New
insights into disease pathogenesis, especially the realization that gastric infection has a role in most
cases of peptic ulceration, have been especially exciting. Antibiotics are now front-line antiulcer
therapy. A number of powerful antisecretory drugs have been introduced into clinical practice. Medical,
endoscopic, and surgical therapies are frequently integrated in the care of individual patients.
PATHOPHYSIOLOGY
1 The pathogenesis of peptic ulceration is complex and multifactorial but increasingly understood.
Approximately 75% of peptic ulcer cases are caused by H. pylori, with almost all other cases due to use
of nonsteroidal anti-inflammatory drugs (NSAIDs).2 Both NSAID use and H. pylori infection are
independent risk factors for development of peptic ulcer disease. The development of peptic ulceration
is often depicted as a balance between chronic inflammatory injury, acid–peptic secretion, and mucosal
defense, with the equilibrium shifted toward disease. Although acid–peptic secretion is crucial in the
development of ulcers, usually a defect in mucosal defense induced by bacterial infection also exists to
tip the balance away from health. Mucosal infection with H. pylori is the factor that contributes to ulcer
pathogenesis in most patients.
Helicobacter pylori
The relation between H. pylori infection and ulceration is inferential but overwhelmingly strong; a
causal relation between H. pylori infection and peptic ulceration has not been tested directly. Because H.
pylori infection is difficult to eradicate with certainty, and because of the potentially serious
consequences of infection, the intentional exposure of humans to the organism to establish such a
1163
booksmedicos.org
relation is not justified.
Many lines of evidence establish H. pylori as a factor in the pathogenesis of duodenal ulceration:
H. pylori is the primary cause of chronic active gastritis, characterized by nonerosive inflammation of
the gastric mucosa. Antral gastritis is nearly always present histologically in patients with duodenal
ulcer, and H. pylori can be isolated from gastric mucosa in almost all cases.
Gastric metaplasia is extremely common in duodenal epithelium surrounding areas of ulceration. H.
pylori binds only to gastric-type epithelium, regardless of location; metaplastic gastric epithelium can
become colonized by H. pylori from gastric sources. Gastric metaplasia of the duodenal bulb is a
nonspecific response to damage and is the means by which antral gastritis with H. pylori is converted
to active chronic duodenitis.
Eradication of H. pylori with antimicrobials that have no effect on acid secretion leads to ulcer healing
rates superior to those seen with acid-suppressing agents.
Relapse of duodenal ulcer after antimicrobial therapy is preceded by reinfection of the gastric mucosa
by H. pylori.
In addition, half of patients evaluated for dyspepsia, but without ulceration, have histologic evidence
of mucosal bacterial infection. Furthermore, 20% of healthy volunteers harbor the bacteria; the
incidence of bacterial carriage in the healthy, asymptomatic population increases with age. The
occurrence of peptic ulcers in only a small proportion of people who carry the organism suggests that
other factors must also act to induce ulceration. The ability of H. pylori infection to induce alterations in
gastric acid secretion is a prerequisite for ulcer development in most patients.
H. pylori is the most common bacterial infection worldwide. H. pylori infection is usually acquired in
childhood and lasts lifelong in the absence of specific therapy. Epidemiologic studies suggest that H. pylori
infection occurs via person-to-person contact, usually among family members. Transmission is believed
to occur during a bout of gastroenteritis; the highest risk is associated with vomiting.
H. pylori is the only human bacterium to persistently infect the stomach. The organism is actually
somewhat fragile, being killed by exposure to high levels of oxygen and to the low pH found in the
acidic lumen of the stomach. To avoid the bactericidal activity of the stomach, the organism has evolved
mechanisms to move within the gastric environment, to adhere to gastric mucosa, and to protect itself
from the harmful effects of acid. Over 300 genes of H. pylori are regulated by acid.
H. pylori bacteria are spiral shaped with polar flagella. Most bacilli are free-swimming within the
mucous layer covering the gastric epithelium. The organisms orient according to a pH gradient, moving
away from the lower pH of the lumen toward the epithelium. The majority of organisms remain motile
within the mucous layer, but contact promotes adherence to epithelial cells, particularly in the region of
intercellular junctions. The products of more than 30 genes are expressed on the outer membrane of the
bacterium and function as adhesins to promote attachment to the gastric cells’ surface. The best-
characterized adhesin binds to the Lewis blood group antigen b. Adhesion triggers the expression of
other bacterial genes, including bacterial virulence factors.
2 All strains of H. pylori cause persistent infection and all strains induce gastric inflammation. Yet,
only 15% of infected individuals develop peptic ulceration and only 1% develop gastric
adenocarcinoma. Differential expression of bacterial virulence factors is presumed to account for these
observations. Two virulence factors are best characterized: vacuolating cytotoxin A (VacA) and
cytotoxin-associated gene A (CagA) (Table 45-1).3
VacA is a pore-forming cytotoxin. VacA is expressed in all strains of H. pylori but is polymorphic with
marked variation in two regions. The VacA protein is 88 kD. Upon secretion from the bacterium, the
protein moves to the host cell membrane, where it forms a ring structure in the shape of a flower.4 This
ring complex inserts into the membrane of the host cell, creating a pore. VacA pores are permeable to
anions and small neutral molecules, including urea. Pore formation may be a mechanism by which the
organism obtains nutrients from gastric epithelial cells.
VacA also inserts into endosomal membranes, leading to osmotic swelling. VacA induces gastric cell
death through apoptosis. This action is thought to occur via pore formation in mitochondrial
membranes. VacA has been reported to interfere with immune T-cell activation and proliferation. This
activity may inhibit clearance of the organism by immune mechanisms.
The second major virulence factor in H. pylori is termed CagA.5,6 The CagA gene is part of a region of
DNA that is inserted into the genome of more virulent strains of H. pylori, termed a pathogenicity island.5
The genes in this island that are adjacent to the CagA gene encode proteins, which function as
microscopic needles for the transfer of bacterial products into host gastric cells. CagA is transferred to
host cells through this injection mechanism.
1164
booksmedicos.org
Table 45-1 Helicobacter Pylori Virulence Factors
After CagA protein is transferred to host cells, it becomes phosphorylated on tyrosine residues by host
cell kinases. Phosphorylated CagA activates a number of cellular signaling pathways involved in cellular
polarity, cytoskeletal protein function, and cellular proliferation and differentiation. As a consequence,
infected gastric cells change shape and become more elongated. Apical junctions between cells become
disrupted, gaps develop between epithelial cells, and epithelial barrier function is lost. CagA protein
also stimulates transcription factors involved in regulation of cellular proliferation. Disturbance of
cellular function in favor of apoptosis affects epithelia restitution and may inhibit ulcer healing.
Acid-Secretory Status
3 The formation of duodenal ulcers depends on gastric secretion of acid and pepsin. As a group, patients
with duodenal ulcers have an increased capacity for gastric acid secretion relative to normal people
(Table 45-2). The maximal acid output of normal men is approximately 20 mEq/h in response to
intravenous histamine stimulation, whereas patients with duodenal ulcer secrete an average of
approximately 40 mEq/h. Considerable overlap exists between these two groups, and the values for
most people with duodenal ulcer fall within the normal range. The increase in acid secretion in some
patients with duodenal ulcer has been postulated to be due to an increase in the mass of parietal cells in
the acid-secreting gastric mucosa or to an increased sensitivity to circulating gastrin.
Groups of patients with duodenal ulcer demonstrate a prolonged and larger acid-secretory response to
a mixed meal than do groups of normal subjects. As with histamine-stimulated acid output, overlap
exists between patients with duodenal ulcer and normal subjects. Disturbances in gastric motility can
exacerbate meal-stimulated acid-secretory abnormalities.
Patients with duodenal ulcer have accelerated emptying of gastric contents, particularly liquids, after
a meal, and duodenal acidification fails to slow emptying appropriately. In such patients, the duodenal
mucosa can be exposed to low pH for prolonged periods relative to normal subjects.
ETIOLOGY
Table 45-2 Pathogenesis of Peptic Ulcer
Groups of patients with duodenal ulcer also demonstrate increased basal secretion of acid. Increased
1165
booksmedicos.org
basal secretion can be demonstrated by nocturnal collection of gastric secretions.
Studies indicate that most of these secretory abnormalities are a direct consequence of H. pylori
infection. Paradoxically, the earliest stages of H. pylori infection are accompanied by a marked decrease
in gastric acid secretion. Acute antral gastritis is followed by fundal inflammation. Fundal inflammation
is associated with mucosal production of a number of cytokines, including interleukin (IL)-1β, IL-6, IL-8,
and tumor necrosis factor-α (TNF-α). IL-1β is a potent inhibitor of gastric acid secretion. Investigators
have postulated that acute reduction in gastric acid secretion facilitates further gastric colonization with
H. pylori. Acute hypochlorhydria resolves despite persistence of H. pylori and is followed by a state of
chronically increased acid secretion.
Basal and peak acid outputs are increased in patients with duodenal ulcer infected with H. pylori
relative to uninfected healthy volunteers. With eradication of H. pylori infection, basal acid output
returns to normal within 4 weeks, and peak acid output declines to the normal range by 6 months. Peak
acid output reflects parietal cell mass; the slow return to normal levels suggests that H. pylori infection
may stimulate increases in the parietal cell mass.
Abnormalities in acid secretion and parietal cell mass appear to be due to H. pylori–induced
hypergastrinemia.7 H. pylori–infected patients have increased basal serum gastrin levels, increased
gastrin responses to meal stimulation, and an augmented gastrin response to intravenous gastrin-
releasing peptide. Eradication of H. pylori infection causes serum gastrin levels to return to baseline.
Gastric mucosal inflammatory cells and epithelial cells are activated by H. pylori infection to release
cytokines such as IL-8, interferon-γ, and TNF-α. These cytokines are stimulants of gastrin release from
cultured canine gastrin cells.
H. pylori expresses Nα-histamine methyltransferase activity. This enzyme produces Nα-
methylhistamine, an abnormal analogue of histamine that can act as a gastric acid-secretory stimulant.
The concentration of somatostatin in the antral mucosa and the number of somatostatin-producing
cells in the antrum are diminished in H. pylori–infected patients. Treatment of H. pylori infection is
followed by increases in numbers of somatostatin cells and in mucosal somatostatin messenger RNA
levels. These observations suggest that alterations in mucosal somatostatin metabolism may also
contribute to the hypergastrinemia seen in H. pylori–infected patients by removing the inhibitory effects
that somatostatin exerts on gastrin release. Somatostatin release is also suppressed by Nα-
methylhistamine.
Mucosal Defense against Peptic Injury

Gastric surface epithelial cells secrete mucus and bicarbonate, creating a pH gradient within the mucous
layer that is nearly neutral at the mucous cell surface, even when the lumen is highly acidic. Failure of
normal bicarbonate secretion locally would, in theory, result in exposure of surface epithelial cells to
the peptic activity of gastric secretions at low pH. Patients with duodenal ulcers have been
demonstrated to have significantly lower basal bicarbonate secretion in the proximal duodenum than
normal subjects. In addition, in response to a physiologically relevant amount of hydrochloric acid
instilled into the duodenal bulb, stimulated bicarbonate output was approximately 40% of the normal
response. Abnormalities in duodenal bicarbonate secretion normalize after elimination of H. pylori in
infected patients. These results suggest one mechanism by which ulceration could occur, even in
patients secreting normal amounts of acid.
Diminished mucosal prostaglandin production has also been proposed to exist in subsets of patients
with duodenal ulcer. Prostaglandins and prostaglandin analogues have been shown to exert
cytoprotective effects, to accelerate healing of established duodenal ulcers, and to decrease acid
secretion. In the duodenum, locally produced prostaglandins stimulate mucosal bicarbonate secretion. In
patients with active duodenal ulceration, gastric mucosal production of prostaglandin E2 and other
prostanoids has been shown to be diminished. An increase in prostanoid synthesis within the gastric
mucosa characterizes ulcer healing. Duodenal bicarbonate responses to prostaglandin E2 are impaired in
patients with duodenal ulcer.
Inflammatory responses to H. pylori infection are central to the pathogenesis of peptic ulceration.
While H. pylori infection always induces inflammation, the patterns of response are not uniform. Three
major patterns have been recognized.8,9 The most common pattern is a mild to moderate inflammation
of all regions of the stomach. This form is not associated with major alterations in gastric acidity and
most individuals are asymptomatic and do not develop peptic ulceration. Approximately 15% of infected
individuals develop an antral-predominant form of gastritis. These individuals exhibit an intense
inflammation limited to the antrum without involvement of the mucosa of the gastric corpus. Gastrin
1166
booksmedicos.org
levels are elevated and acid secretion is high. Inhibitory control of gastric acid production is impaired in
this form of gastritis. As a result, duodenal and prepyloric ulcers are common. The third form of
inflammatory response, occurring in 1% of infected individuals, is least common but most serious. This
form is characterized by corpus-predominant gastritis, hypochlorhydria, and gastric atrophy. This form
of inflammatory response is considered a precursor state for gastric cancer. Individuals with the third
pattern of inflammation demonstrate hypergastrinemia, low acid secretion, and diminished secretion of
pepsinogen.
Environmental Factors
NSAIDs have emerged as a significant risk factor for the development of acute ulceration. Although
acute mucosal injury caused by NSAIDs is more common in the stomach than in the duodenum, NSAID-
induced ulcer complications occur with equal frequency in these two sites. NSAIDs produce a variety of
lesions, ranging from hemorrhage, to superficial mucosal erosions, to deeper ulcerations. In the
duodenum, it appears likely that invasive NSAID-associated ulcers result from underlying peptic ulcer
diathesis compounded by the direct injurious effects of these drugs.
The ulcerogenic actions of NSAIDs have been attributed to their systemic suppression of prostaglandin
production. Numerous experimental models have demonstrated the ability of NSAIDs to injure the
gastroduodenal mucosa. Ulcers resembling those caused by NSAIDs can be produced experimentally by
antibodies to prostaglandins. Conversely, NSAID-associated gastric ulcers can be prevented by the
coadministration of prostaglandin analogues. Ulcers associated with NSAIDs usually heal rapidly when
the drug is withdrawn, corresponding to the reversal of antiprostaglandin effects. All available NSAIDs
appear to pose the hazard of gastroduodenal ulceration. Clinically important ulceration (of both the
stomach and duodenum) is estimated by the U.S. Food and Drug Administration to occur at a rate of 2%
to 4% per patient-year. The risks inherent with NSAID use appear to be increased by a history of H.
pylori infection, by cigarette smoking, and by alcohol use. The incidence of NSAID-caused ulcer
complications is highest in older patients, as is the attendant mortality rate. Peptic ulcer disease is rare
in individuals who are H. pylori negative and who are not receiving NSAID medications.
A role of NSAIDs in upper gastrointestinal (GI) hemorrhage is widely recognized. The risk of bleeding
is particularly acute for peptic ulceration. In three reports, spanning two decades, NSAIDs were linked
to 50% to 75% of bleeding peptic ulcers, one-third of deaths due to hemorrhage, and 30% of
hospitalizations.10,11 Use of NSAIDs increases the risk of bleeding from peptic ulcer threefold for those
under 65 years of age, but by eightfold for individuals over 75 years of age. The odds ratio for bleeding
is 13 for patients with a prior history of bleeding ulcer.
Because of the risk of gastrointestinal side effects, a selective class of cyclooxygenase-2 (COX-2)
inhibitors was developed for long-term pain relief and anti-inflammatory therapy. Selective COX-2
inhibitors have reduced potential to injure the gastrointestinal mucosa relative to standard NSAIDs.11
Concurrent use of aspirin with COX-2 inhibitors significantly undermines the safety advantages of the
COX-2 agents, as does smoking.12
DIAGNOSIS
The cardinal feature of duodenal ulceration is epigastric pain. The pain is usually confined to the upper
abdomen and is described as burning, stabbing, or gnawing. Unless perforation or penetration into the
head of the pancreas has occurred, referral of pain is not common. Many patients report pain on arising
in the morning. Ingestion of food or antacids usually provides prompt relief. In uncomplicated cases,
abnormal physical findings are minimal. The differential diagnosis is broad and includes a variety of
diseases originating in the upper gastrointestinal tract. The most common disorders to be distinguished
include nonulcerative dyspepsia, gastric neoplasia, cholelithiasis and related diseases of the biliary
system, and both inflammatory and neoplastic disorders of the pancreas. In dyspeptic patients, the
principal diagnoses that must be differentiated definitively are peptic ulceration and gastric cancer.
The evaluation of patients with suspected peptic ulceration usually involves endoscopy, the standard
against which other diagnostic modalities are measured. Endoscopy is employed because it permits
biopsy of the esophagus, stomach, and duodenum. Endoscopy must be recommended with discretion
because of associated morbidity (approximately 1 per 5,000 cases) and higher costs.
Duodenal ulcer is characterized by lesions that are erosive to the bowel wall. When viewed
endoscopically, the ulcers have a typical appearance. The edges are usually sharply demarcated and the
1167
booksmedicos.org
underlying submucosa is exposed. The ulcer base is often clean and smooth, although acute ulcers and
those with recent hemorrhage can demonstrate eschar or adherent exudate. Surrounding mucosal
inflammation is common. The most frequent site for peptic ulceration is the first portion of the
duodenum, with the second portion less commonly involved. Ulceration of the third or fourth portions
of the duodenum is unusual, and occurrence in these sites should arouse suspicion of an underlying
gastrinoma. Ulceration in the pyloric channel or the prepyloric area is similar in endoscopic appearance
to duodenal ulceration, and ulcers in these areas demonstrate other clinical features similar to duodenal
ulcers. Endoscopic demonstration of a duodenal ulcer should prompt mucosal biopsy of the gastric
antrum to demonstrate the presence of H. pylori and guide subsequent therapy.
The hallmarks of the histologic appearance of duodenal ulcers are chronicity and invasiveness.
Chronic injury is suggested by surrounding fibrosis; collagen is deposited in the submucosa during each
round of ulcer relapse and healing. The adjacent mucosa often demonstrates evidence of chronic injury
with infiltration of acute and chronic inflammatory cells. Gastric metaplasia, in which the duodenum
exhibits histologic features of gastric mucosa, is common in the surrounding nonulcerated mucosa. The
ulcer can extend for a variable distance through the wall of the duodenum, including the full thickness
of the bowel in cases of perforation.
DRUG TREATMENT OF ULCER DISEASE

4 In the absence of active treatment, H. pylori infection is lifelong. Spontaneous healing of infected
mucosa is very rare, occurring in less than 0.5% per patient-year. Current treatment of peptic ulceration
involves a combination of an antisecretory drug, usually a proton pump inhibitor, with antibiotics.13
This therapy is rational for most patients who are H. pylori positive and results in a high rate of
sustained ulcer healing.
A large number of drug regimens have been described, but the most widely used treatment protocols
combine a proton pump inhibitor, usually omeprazole, with two antibiotics, usually clarithromycin and
metronidazole or amoxicillin. A combination of antibiotics is more effective than one antibiotic alone in
almost all series. This triple therapy is administered for 7 or 14 days. Triple-drug therapy is cost
effective and associated with a low rate of side effects, low rates of antibiotic resistance, and acceptable
levels of patient compliance. H. pylori eradication rates of greater than 90% have been reported.
After elimination of H. pylori, ulcer recurrence rates reflect the rate of reinfection. In developed
countries, reinfection rates of less than 10% at 5 years have been reported. Eradication of H. pylori
improves quality of life, as measured by symptoms, drug prescriptions, physician visits, and days of
missed employment. To date, antibiotic resistance has been low, approximately 18% for clarithromycin,
14% for levofloxacin, and 35% for metronidazole. Resistance to amoxicillin has been close to zero.14
HISTAMINE-RECEPTOR ANTAGONISTS
Histamine, released into the interstitial fluid by cells in the fundic mucosa, diffuses to the mucosal
parietal cell. Histamine stimulates acid production by occupying a membrane-bound receptor and
activating parietal cell adenylate cyclase. Histamine is released in response to a number of physiologic
stimuli; blockade of histamine receptors inhibits most forms of stimulated acid secretion in humans.
Parietal cell histamine receptors are classified as H2 receptors because they are activated by agonists
such as 4-methylhistamine and are selectively blocked by agents such as cimetidine. Some H2-receptor
antagonists also possess nongastric actions by binding to androgen receptors, by interacting with the
hepatic microsomal oxidase system, and by crossing the blood–brain barrier. All clinically useful gastric
histamine receptor antagonists are of the H2 type.
H2-receptor antagonists bind competitively to parietal cell H2 receptors to produce a reversible
inhibition of acid secretion. An enormous worldwide experience has accumulated with the use of H2-
receptor antagonists. The agents are effective and safe when used in the treatment of peptic ulcer. The
various compounds have similar efficacy in terms of ulcer healing when used in doses that produce
similar reductions in acid output. It is clear that H2-receptor blockers do not affect the underlying ulcer
diathesis; if H2-receptor antagonists are stopped, recurrent ulceration occurs in more than half of
patients within 1 year. The current understanding of the role of H. pylori in ulcer pathogenesis has
changed the role of H2-receptor antagonists from primary therapy to that of a substitute for proton
1168
booksmedicos.org
pump inhibitors in conjunction with antibiotic treatment.
PROTON PUMP BLOCKERS

Acid secretion by the gastric parietal cells is due to the active transport of hydrogen ions from the
parietal cell cytoplasm into the secretory canaliculus in exchange for potassium. Because this so-called
proton pump is tissue specific, being present only in gastric mucosa, its blockade would be expected to
have minimal effects on nongastric functions. Omeprazole is representative of a family of compounds
that selectively block the parietal cell proton pump.
Omeprazole is a weak base, with a pKa of approximately 4. The drug is nonionized and lipid soluble
at neutral pH, but it becomes ionized and activated at a pH of less than 3. In its activated state,
omeprazole binds to the membrane-bound H+-K+-adenosine triphosphatase (ATPase) of the parietal
cell. Because the compound is a weak base, omeprazole accumulates selectively within the acidic
environment of the parietal cell secretory canaliculus; 4 hours after administration, the drug is
detectable in appreciable quantities only in the gastric mucosa. If enough drug is administered to occupy
all parietal cell–binding sites, anacidity can be produced. Omeprazole, in doses from 20 to 30 mg,
causes nearly complete inhibition of stimulated gastric acid secretion within 6 hours. At 24 hours after
drug administration, a 60% to 70% reduction in acid secretion persists.
Repeated daily dosing with omeprazole results in increasing inhibitory action on gastric secretion and
thus in decreased intragastric degradation of the drug. Acid suppression stabilizes after approximately 3
days. Because of tissue accumulation, the secretory actions of omeprazole do not correlate with plasma
levels. Several studies have demonstrated a significant inhibition of peak acid output, marked relief of
epigastric pain, and decreased use of supplemental antacids during omeprazole therapy. Direct
comparisons with H2-receptor antagonists have generally favored omeprazole in terms of pain relief and
rate of ulcer healing.
OPERATIVE TREATMENT OF ULCER DISEASE

Surgical Goals
Operative intervention is reserved for the treatment of complicated ulcer disease. Three complications
are most common and constitute the indications for peptic ulcer surgery – hemorrhage, perforation, and
obstruction. The first goal in the surgical treatment of the complications of ulcer disease is treatment of
coexisting anatomic complications, such as pyloric stenosis or perforation. The second major goal should
be patient safety and freedom from undesirable chronic side effects. To achieve these goals, the gastric
surgeon can direct therapy through endoscopic or operative means, the appropriate choice depending on
the clinical circumstances.
Operative Procedures
A number of operative procedures have been used to treat peptic ulcer, but with decreasing frequency
in the past decade. There is currently no indication for surgical treatment of uncomplicated ulcer
disease. Operative treatment of gastric outlet obstruction has decreased by approximately 50%. Most
surgical patients are now treated emergently for the complications of bleeding or perforation.
Three procedures – truncal vagotomy and drainage, truncal vagotomy and antrectomy, and proximal
gastric vagotomy – were widely used in the past in the operative treatment of peptic ulcer disease. With
increasing frequency, surgical therapy of peptic ulcer is directed exclusively at correction of the
immediate problem (e.g., closure of duodenal perforation) without gastric denervation. The underlying
ulcer diathesis is then addressed after surgery by antibiotic therapy directed at H. pylori. This approach
is applicable to most patients with peptic ulcer undergoing emergent operation and implies a very
limited role for vagotomy in the future.
Division of both vagal trunks at the esophageal hiatus – truncal vagotomy – denervates the acid-
producing fundic mucosa as well as the remainder of the vagally supplied viscera (Fig. 45-1). Because
denervation impedes normal pyloric coordination and can result in impairment of gastric emptying,
truncal vagotomy must be combined with a procedure to eliminate pyloric sphincteric function. Usually,
gastric drainage is ensured by performance of a pyloroplasty (Fig. 45-2).
When truncal vagotomy is combined with resection of the gastric antrum there is a further reduction
1169
booksmedicos.org
in acid secretion, presumably by removing antral sources of gastrin. The limits of antral resection are
usually defined by external landmarks, rather than the histologic transition from fundic to antral
mucosae. The stomach is divided proximally along a line from a point above the incisura angularis to a
point along the greater curvature midway from the pylorus to the gastroesophageal junction.
Restoration of gastrointestinal continuity by a gastroduodenostomy is termed a Billroth I reconstruction.
A Billroth II procedure uses a gastrojejunostomy (Fig. 45-3).
Figure 45-1. Truncal vagotomy and proximal gastric vagotomy. A: With truncal vagotomy, both nerve trunks are divided at the
level of the diaphragmatic hiatus. B: Proximal gastric vagotomy involves division of the vagal fibers that supply the gastric fundus.
Branches to the antropyloric region of the stomach are not transected, and the hepatic and celiac divisions of the vagus nerves
remain intact.
1170
booksmedicos.org
Figure 45-2. Pyloroplasty formation. A: A Heineke–Mikulicz pyloroplasty involves a longitudinal incision of the pyloric sphincter
followed by a transverse closure. B: The Finney pyloroplasty is performed as a gastroduodenostomy with division of the pylorus.
C: The Jaboulay pyloroplasty differs from the Finney procedure in that the pylorus is not transected.
1171
booksmedicos.org
Figure 45-3. Antrectomy involves resection of the distal stomach (pink area in inset). Restoration of gastrointestinal continuity may
be accomplished as a Billroth I gastroduodenostomy (A) or Billroth II gastrojejunostomy (B) reconstruction.
Physiologic Consequences of Operation

Division of efferent vagal fibers directly affects acid secretion by reducing cholinergic stimulation of
parietal cells. In addition, vagotomy also diminishes parietal cell responsiveness to gastrin and
histamine. Basal acid secretion is reduced by approximately 80% in the immediate postoperative period.
Acid secretion increases slightly within months of surgery but remains unchanged thereafter. The
maximal acid output in response to exogenously administered stimulants such as pentagastrin is reduced
by approximately 70% in the early period after surgery. After 1 year, pentagastrin-stimulated maximal
acid output rebounds to 50% of prevagotomy values but remains at this level on subsequent testing.
Acid secretion due to endogenous stimulation by a liquid meal is reduced by 60% to 70% relative to
normal subjects.
The inclusion of antrectomy with truncal vagotomy causes further reductions in acid secretion.
Pentagastrin-stimulated maximal acid output is reduced by 85% relative to values recorded before
surgery. Little rebound in acid secretion occurs with the passage of time.
Operations that involve vagotomy alter gastric emptying. Proximal gastric denervation abolishes
vagally mediated receptive relaxation. Thus, for any given volume ingested, the intragastric pressure
rise is greater and the gastroduodenal pressure gradient is higher than that in normal subjects. As a
result, emptying of liquids, which depends critically on the gastroduodenal pressure gradient, is
accelerated after proximal gastric vagotomy. Because nerve fibers to the antrum and pylorus are
preserved, the function of the distal stomach to mix and triturate solid food is preserved, and emptying
of solids is nearly normal in patients who have undergone proximal gastric vagotomy. Truncal
vagotomy affects the motor activities of both the proximal and distal stomach. Solid and liquid
emptying rates are usually increased when truncal vagotomy is accompanied by pyloroplasty.
Dumping, a postprandial symptom complex of abdominal discomfort, weakness, and vasomotor
symptoms of sweating and dizziness, occurs in 10% to 15% of patients with truncal vagotomy and
antrectomy in the early postoperative period and is chronically disabling in 1% to 2%. After truncal
vagotomy and pyloroplasty, dumping is present initially in 10% and remains severe in approximately
1172
booksmedicos.org
1%. Permanent symptoms of dumping are rare after proximal gastric vagotomy. The incidence of
diarrhea, which is presumably caused by denervation of the pylorus and small bowel and by elimination
of pyloric function, parallels the incidence of dumping after truncal vagotomy and antrectomy or
pyloroplasty. Persistent or disabling diarrhea is present in less than 1% of patients after proximal gastric
vagotomy.
Most prospective surgical series were reported in the era before the pathogenic role of H. pylori was
appreciated. With appropriate use of postoperative antimicrobials directed against H. pylori, ulcer
recurrence rates are currently much lower than historical standards. Although recurrence rates (without
H. pylori treatment) as low as 5% have been reported, a more generally accepted figure is 10%. This
rate is similar to that of reinfection with H. pylori after its successful eradication. The reported ulcer
recurrence rates after proximal gastric vagotomy can be adversely affected by the inclusion of
prepyloric and pyloric channel ulcers.
Hemorrhage
5 Hemorrhage is the leading cause of death associated with peptic ulcer, and the incidence of this
complication has not changed since the introduction of H2-receptor antagonists. The lifetime risk of
hemorrhage for patients with duodenal ulcer who have not had surgery and who do not receive
continuing maintenance drug therapy approximates 15% at 5 years.15 Most hemorrhages occur during
the initial episode of ulceration or during a relapse, and patients who have hemorrhaged previously
have a higher risk of bleeding again. Continued or recurrent bleeding occurs in 20% to 30% of patients,
and when this happens, mortality varies between 10% and 40%. Patients with recurrent hemorrhage
and elderly patients are at greatest risk of death, and these two groups should be resuscitated
vigorously, investigated promptly, and treated aggressively.16,17
The contemporary risk of mortality from bleeding ulcer approximates 10% to 20%. Operative risk is
increased in patients who have shock at admission, recurrent bleeding, delay in operative intervention,
or coexisting medical illnesses. Surgical delay may lead to recurrent hypovolemia and, subsequently,
multisystem organ failure.
Upper gastrointestinal endoscopy is the appropriate initial diagnostic test when hemorrhage from
duodenal ulceration is suspected. Endoscopy can correctly determine the site and cause of bleeding in
more than 90% of patients. An ulcer should be accepted as the bleeding source only if it has one of the
stigmata of active or recent hemorrhage. Active hemorrhage is defined by an arterial jet, active oozing,
or oozing beneath an adherent clot. The signs of recent hemorrhage include an adherent clot without
oozing, an adherent slough in the ulcer base, or a visible vessel in the ulcer. The ability of these
endoscopic findings to accurately predict recurrent hemorrhage has been extensively validated.
Approximately 30% of patients who have stigmata of recent hemorrhage experience rebleeding, and
most of the patients who experience recurrent hemorrhage require emergency treatment. These
stigmata are not sufficiently accurate to be used alone as indications for surgery. Rather, they serve as a
warning that aggressive therapy is needed and close follow-up mandatory. The occurrence of
hypovolemic shock, rebleeding during hospitalization, and a posteroinferior location of the ulcer are
additional clinical features that have been associated with increased risks of recurrent bleeding. A recent
study suggests that rebleeding risk in excess of 30% justifies second-look endoscopy as a means to
anticipate, and thus preemptively treat, ulcers at highest risk of recurrent hemorrhage.18 The role of
gastric acidity as a cause for in-hospital rebleeding appears to be inconsequential, and reduction of acid
secretion by H2-receptor antagonists or omeprazole is not sufficient to prevent recurrent hemorrhage.
The ability to visualize bleeding duodenal ulcers endoscopically has led to development of methods to
treat hemorrhage endoscopically. There are many different methods of endoscopic therapy, but the
most established consist of thermal coagulation, injection of alcohol, or sclerosants. Thermal
coagulation can be achieved by bipolar electrocoagulation or direct application of heat through a heater
probe. Injection of epinephrine into the base of the bleeding ulcer is also effective in control of ulcer
hemorrhage.
Proof of efficacy, in the form of lowered rebleeding rates and avoidance of operation, has been
convincingly demonstrated for all of these methods of endoscopic hemostasis. The analysis of reports of
endoscopic treatment of hemorrhage is complicated by the 70% rate of spontaneous, although
sometimes temporary, cessation of bleeding without intervention. In addition to endoscopic stigmata,
hemodynamic instability, need for continuing transfusion, red stool or hematemesis, age older than 60
years, and serious medical comorbidity are clinical features that mandate endoscopic therapy.
Rebleeding during hospitalization and the endoscopic findings of visible vessel, oozing, or bleeding
1173
booksmedicos.org
associated with an adherent clot are other indications for endoscopic hemostasis. Ulcers with clean bases
require no treatment. Failure of endoscopic hemostasis is usually due to inaccessibility because of
scarring, to rapid active bleeding obscuring the endoscopic view, or to an adherent clot. Patients treated
endoscopically should be observed closely for further hemorrhage. Patients who rebleed within 72
hours of initial endoscopic control may be successfully retreated without increasing the risk of
mortality.19
The efficacy of endoscopy is dependent on timing. Early endoscopy correctly identifies patients at low
risk for recurrent hemorrhage and permits safe avoidance of hospitalization. Early endoscopy also
benefits high-risk patients by directing active hemostatic therapy. Patients treated in this way have been
demonstrated to have fewer episodes of rebleeding, lower rates of operation, and shorter
hospitalizations.
Table 45-3 lists situations in which operative intervention is appropriate. The need for emergency
surgery significantly increases surgical risks; mortality rates are increased approximately 10-fold.
Operative therapy should consist of duodenostomy with direct ligation of the bleeding vessel in the
ulcer base.
INDICATIONS/CONTRAINDICATIONS
Table 45-3 Situations in Which Operative Intervention is Appropriate
Postoperatively, patients should receive antibiotics directed against H. pylori. This treatment
paradigm is based on the observation that peptic ulcer hemorrhage recurs in 20% of patients in whom
H. pylori is not eradicated, whereas rebleeding is reduced to 3% in patients who receive H. pylori
eradication therapy (Algorithm 45-1).20 The studies that support this practice were not specifically
designed to evaluate postoperative hemorrhage, but the results are so definitive that they support this
application (Fig. 45-4).
Perforation
The lifetime risk for perforation in patients with duodenal ulceration who do not receive therapy
approximates 10%. In contrast, ulcer perforation is unusual if initial ulcer healing has been achieved.
Perforation of a duodenal ulcer is usually accompanied by sudden and severe epigastric pain. The
pain, caused by the spillage of highly caustic gastric secretions into the peritoneum, rapidly reaches
peak intensity and remains constant. Radiation to the right scapular region is common because of right
subphrenic collection of gastric contents. Occasionally, pain is sensed in the lower abdomen if gastric
contents travel caudally through the paracolic gutter. Peritoneal irritation is usually intense and most
patients avoid movement to minimize discomfort.
Physical examination reveals low-grade fever, diminished bowel sounds, and rigidity of the
abdominal musculature. Usually, upright abdominal radiographs reveal pneumoperitoneum, but up to
20% of perforated ulcers do not show free intraperitoneal air. Computed tomography of the abdomen is
very sensitive for demonstrating perforation if pneumoperitoneum is not demonstrated but perforation
is still suspected.
1174
booksmedicos.org
Figure 45-4. Probability of freedom from recurrent hemorrhage according to posttreatment H. pylori status.
Algorithm 45-1. Treatment of bleeding duodenal ulceration.
Although occasional reports have described the nonoperative treatment of this complication,
perforation remains a strong indication for surgery in most circumstances. Laparotomy or laparoscopy
affords the opportunity to relieve intraperitoneal contamination and to close the perforation (Fig. 45-5).
Signs of antecedent duodenal ulceration, in terms of history of prior symptoms and anatomic evidence
of duodenal scarring, should be sought. A lack of antecedent symptoms is not protective. Reports
suggest that patients without antecedent symptoms are also at risk for recurrent ulceration. By 5 to 6
years, symptomatic ulcer recurrence in patients with acute ulcer perforation is similar to that for
patients with chronic disease. Before the role of H. pylori was appreciated, simple omental closure of
duodenal perforation resulting from chronic ulceration did not provide satisfactory long-term results; up
to 80% of patients so treated had recurrent ulceration, and 10% experienced reperforation if untreated.
Approximately four-fifths of all patients with perforation have H. pylori infestation and therefore are at
risk of recurrent disease.
The mortality of emergent ulcer operations is most clearly correlated with the following
circumstances: preoperative shock, coexisting medical illness, and presence of perforation for more than
48 hours.21 Mortality increases progressively with the number of prognostic variables present – the so-
called Boey Score – being 0%, 10%, 45%, and 100% with zero to three positive. Mortality with
perforated peptic ulcer disease has also been correlated with the American Society of Anesthesiology
(ASA) score and the Peptic Ulcer Perforation (PULP) score.22
6 Current reports advocate omental patch closure only, often laparoscopically, with postoperative
1175
booksmedicos.org
anti–H. pylori therapy. This approach presumes that most duodenal ulcers are caused by H. pylori, that
secure closure of the perforation can be obtained, and that further surgical therapy will be obviated by
the effects of medical therapy. Minimally invasive approaches are becoming standard practice.
Figure 45-5. Omental patching of perforated duodenal ulcer.
Three meta-analyses of surgical treatment of perforated peptic ulcer have compared open surgical
therapy with laparoscopic approaches.23–25 In terms of operative time, there is no clear superiority of
one approach over the other, but trials reported after 2001 have favored laparoscopic repair. While in-
hospital analgesic use is less in laparoscopically treated patients, the more important variable of hospital
length of stay was not significantly shorter for these patients. Overall rates of postoperative
complications were not statistically different between the two approaches. A lower rate of wound
infection in the laparoscopic group approached significance. Return to normal daily activities and work
favored the laparoscopic group. The pooled estimate of mortality favored laparoscopic repair. Thirty-
day mortality risk approximates 15%.26 Septic complications, organ space infection, and prolonged
ventilation are leading causes of postoperative morbidity.27
Obstruction
Gastric outlet obstruction can occur acutely or chronically in patients with duodenal ulcer disease. Acute
obstruction is caused by edema and inflammation associated with ulcers in the pyloric channel and the
first portion of the duodenum. Pyloric obstruction is suggested by recurrent vomiting, dehydration, and
hypochloremic alkalosis due to loss of gastric secretions. Acute gastric outlet obstruction is treated with
nasogastric suction, rehydration, and intravenous administration of antisecretory agents. In most
instances, acute obstruction resolves with such supportive measures within 72 hours.
Repeated episodes of ulceration and healing can lead to pyloric scarring and a fixed stenosis with
chronic gastric outlet obstruction.
Upper endoscopy is indicated to confirm the nature of the obstruction and to exclude neoplasm.
Endoscopic hydrostatic balloon dilatation of pyloric stenoses can also be attempted at this time (Fig. 45-
6). Approximately 85% of pyloric stenoses are amenable to balloon dilatation. Only 40% of patients
with gastric stenoses have sustained improvement by 3 months after balloon dilatation. Recurrent
stenoses are presumably due to residual scarring in the pyloric channel. Thus, although pyloric
dilatation is occasionally palliative, in most cases operative correction is required.
Operative management of gastric outlet obstruction should be focused on relief of the anatomic
abnormality. Antrectomy has been used with success in this circumstance, with low ulcer recurrence
rates and with satisfactory restoration of gastric emptying.
1176
booksmedicos.org
GASTRIC ULCER
Benign gastric ulcers are a form of peptic ulcer disease, occurring with one-third the frequency of
benign duodenal ulceration. In the United States, gastric ulcer is somewhat more common in men than
in women and occurs in a patient cohort approximately 10 years older than for duodenal ulceration.
Endoscopic Diagnosis
Upper gastrointestinal endoscopy is the preferred method for diagnosing gastric ulceration. The ulcer
base in benign disease is commonly smooth and flat and often covered by a gray, fibrous exudate. The
margin is usually slightly raised, erythematous, and friable. Differentiation of benign and malignant
gastric ulcers is reliably made only by histologic examination. Visual endoscopic differentiation of
benign from malignant ulcers is not reliable. All gastric ulcers should have multiple biopsies taken from
the perimeter of the lesion. The addition of lesional brushings to biopsy increases diagnostic accuracy to
approximately 95%.
Benign gastric ulcers may occur in any location in the stomach, but approximately 60% are located
along the lesser curvature proximal to the incisura angularis. Less than 10% of benign gastric ulcers are
located on the greater curvature. Virtually all gastric ulcers lie within 2 cm of the histologic transition
between fundic and antral mucosa. With increasing age, this mucosal transition zone moves proximally
along the lesser curvature. Movement of this transition zone is reflected by the greater prevalence of
proximal ulcers in elderly patients.
As with benign duodenal ulceration, H. pylori plays a central role in the pathogenesis of benign gastric
ulcers.28 Benign gastric ulcers associated with H. pylori respond to antibiotic therapy at a rate equivalent
to that of duodenal ulceration. The recurrence rate of ulcerations in these patients after H. pylori
eradication is equal to the rate of reinfection.
A strong association of benign gastric ulceration with the use of NSAIDs has been recognized.
Cigarette smoking is associated with development of gastric ulceration, and continued smoking impedes
medical therapy. Gastric and duodenal ulcers have been noted in patients receiving hepatic artery
chemotherapy in whom improper placement of the catheter permits perfusion of gastric and duodenal
mucosae. A variety of agents, including 5-fluorouracil, cisplatin, doxorubicin, and mitomycin C, have
been implicated.
Figure 45-6. Schematic representation of balloon dilatation of pyloric stenosis.
Therapy
The primary therapy for benign gastric ulceration in most patients is antimicrobial treatment of H. pylori
infection. The treatment protocols are similar to those used for benign duodenal ulceration. For many
patients, cessation of NSAID therapy is also required.
Indications for surgical treatment of gastric ulcer include hemorrhage, perforation, failure of a
recurrent ulcer to respond to medical therapy, and inability to exclude malignant disease.
For benign gastric ulcers, the elective operation of choice is usually a distal gastrectomy with
gastroduodenal (Billroth I) anastomosis. The ulcer should be included in the gastrectomy specimen.
With this approach, operative mortality rates of 2% to 3%, with ulcer recurrence rates of less than 5%,
have been reported. Because benign gastric ulcers are not associated with gastric acid hypersecretion,
1177
booksmedicos.org
inclusion of vagotomy is not necessary.
The occurrence of a gastric ulcer near the gastroesophageal junction represents a difficult surgical
problem. When possible, the ulcer should be excised. This usually requires a distal gastrectomy with an
extension along the lesser curvature near the esophageal wall and reconstruction with
gastrojejunostomy.
Emergency operations performed for hemorrhage or perforation require ulcer excision. Distal
gastrectomy, performed with gastroduodenal reconstruction, is usually the procedure of choice.
Operative mortality rates average 10% to 20% in the presence of hemorrhage or perforation.
POSTGASTRECTOMY SYNDROMES
A number of syndromes have been described that are associated with distressing symptoms after gastric
operations performed for peptic ulcer or gastric neoplasm. The occurrence of severe postoperative
symptoms is fortunately low, perhaps 1% to 3% of cases, but the disturbances can be disabling. The two
most common postgastrectomy syndromes, categorized according to predominant manifestation, are
dumping and alkaline reflux gastritis.
Dumping
The term dumping denotes a clinical syndrome with both gastrointestinal and vasomotor symptoms. The
precise cause of dumping is not known but is believed to relate to the unmetered entry of ingested food
into the proximal small bowel after vagotomy and either resection or division of the pyloric sphincter.
Early dumping symptoms occur immediately after a meal and include nausea, epigastric discomfort,
borborygmi, palpitations, and, in extreme cases, dizziness or syncope. Late dumping symptoms follow a
meal by 1 to 3 hours and can include reactive hypoglycemia in addition to the aforementioned
symptoms.
Although a relatively large number of patients experience mild dumping symptoms in the early
postoperative period, minor dietary alterations and the passage of time bring improvement in all but
approximately 1%. The somatostatin analogue octreotide has been reported to improve dumping
symptoms when 50 to 100 mg is administered subcutaneously before a meal. The beneficial effects of
somatostatin on the vasomotor symptoms of dumping are postulated to be due to pressor effects of the
compound on splanchnic vessels. In addition, somatostatin analogues inhibit the release of vasoactive
peptides from the gut, decrease peak plasma insulin levels, and slow intestinal transit, all effects that
might be expected to ameliorate dumping symptoms. Octreotide administration before meal ingestion
has been shown to prevent changes in pulse, systolic blood pressure, and packed red cell volume during
early dumping and blood glucose levels during late dumping.
Alkaline Reflux Gastritis

The term alkaline reflux gastritis should be reserved for patients who demonstrate the clinical triad of
postprandial epigastric pain often associated with nausea and vomiting, evidence of reflux of bile into
the stomach, and histologic evidence of gastritis. One or more of these findings occur transiently in 10%
to 20% of patients after gastric resection, but they persist in only 1% to 2%.
The differential diagnosis for a patient with postoperative epigastric pain includes recurrent
ulceration, biliary and pancreatic disease, afferent loop obstruction, and esophagitis in addition to
alkaline reflux gastritis. Serum gastrin measurements should be determined to exclude Zollinger–Ellison
syndrome and retained gastric antrum. Endoscopic examination is essential to exclude recurrent ulcer.
Endoscopically, the gastric mucosa appears red, friable, and edematous. Gastric inflammation is
patchy and nonulcerative. Histologic examination shows mucosal and submucosal edema and infiltration
of acute and chronic inflammatory cells into the lamina propria. Glandular atrophy and intestinal
metaplasia are frequent accompaniments.
No perfect solution to alkaline reflux gastritis exists. H2-receptor antagonists, proton pump inhibitors,
bile acid chelators, and dietary manipulations have not been demonstrated definitely to be beneficial.
The only proved treatment for alkaline reflux gastritis is operative diversion of intestinal contents from
contact with the gastric mucosa. The most common surgical procedure used for this purpose is a Roux-
en-Y gastrojejunostomy with an intestinal limb of 50 to 60 cm constructed to prevent reflux of intestinal
contents (Fig. 45-7). This procedure is effective in eliminating bilious vomiting (nearly 100%), but
recurrent or persistent pain is reported in up to 30% of patients, and up to 20% of patients are troubled
1178
booksmedicos.org
with postoperative delayed gastric emptying.
STRESS GASTRITIS
7 Major trauma accompanied by shock, sepsis, respiratory failure, hemorrhage, or multiorgan injury is
often accompanied by acute stress gastritis. Acute stress gastritis is particularly prevalent after thermal
injury with greater than 35% total surface area burned.29 Multiple superficial ulcerations and erosions
are noted in the proximal, acid-secreting portion of the stomach, with fewer lesions in the antrum and
only rare ulcerations in the duodenum.
The most sensitive diagnostic test for stress ulceration is endoscopic examination. If patients are
examined within 12 hours of the onset of injury, acute mucosal ulcerations may be observed that appear
as multiple, shallow areas of erythema and friability, often accompanied by focal hemorrhage. The
lesions are progressive during the first 72 hours after injury. When lesions are examined histologically,
they are seen to consist of coagulation necrosis of the superficial endothelium with infiltration of
leukocytes into the lamina propria. Chronic disease, characterized by fibrosis and scarring, is not
observed. With resolution of the underlying injury or sepsis, healing is accompanied by mucosal
restitution and regeneration.
Clinical observations and a large number of experimental studies suggest that mucosal ischemia is the
central event underlying the development of stress gastritis. In clinical practice, most patients who
contract stress gastritis do so after an episode of sepsis, hemorrhage, or cardiac dysfunction
accompanied by shock. Experimental studies that cause depletion of high-energy phosphate compounds
such as ATP predispose to the development of stress gastritis. Luminal gastric acid secretion, although
not the sole cause of stress gastritis, appears to be a necessary concomitant process. A number of
experimental observations suggest that a critical concentration of luminal acid is required to initiate
injury in the setting of mucosal ischemia. The fall in mucosal energy supply permits proton back-
diffusion into the mucosa; the resultant decrease in mucosal pH exacerbates ischemic damage.
1179
booksmedicos.org
Figure 45-7. Conversion of Billroth II gastrojejunostomy to Roux-en-Y gastrojejunostomy. The afferent limb is divided (A) and
intestinal continuity is reestablished by anastomosis 50 to 60 cm downstream from the original gastrojejunostomy (B).
Clinical risk factors that predict development of stress gastritis include adult respiratory distress
syndrome, multiple long-bone fractures, a major burn over 35% of the body surface, transfusion
requirement above 6 units, hepatic dysfunction, sepsis, hypotension, and oliguric renal failure. Scoring
systems of critical illness, exemplified by the Acute Physiology and Chronic Health Evaluation
(APACHE) system, accurately predict risk for acute stress gastritis.
The major complication of stress gastritis is hemorrhage. Admission to an intensive care unit is not an
independent risk factor for bleeding. However, the development of respiratory failure or coagulopathy
(platelet count less than 50,000/mm3, international normalized ratio (INR) >1.5, or partial
thromboplastin time (PTT) greater than two times normal) imparts the greatest risk for hemorrhage.
Diagnosis
Clinical studies that use bloody nasogastric discharge as a sign of stress gastritis probably underestimate
its incidence in critically ill patients. Conversely, studies based on endoscopy overestimate the incidence
of clinically important stress gastritis. In one endoscopically controlled study, 100% of patients with
life-threatening injuries had evidence of gastric erosions by 24 hours. Severely burned patients have
endoscopic evidence of gastric erosions in greater than 90% of cases, whereas significant upper
gastrointestinal hemorrhage occurs in between 25% and 50% of patients with burn wound infection.
Treatment and Prophylaxis

Critically ill patients are at risk for development of acute stress gastritis. Because hemorrhage associated
with stress gastritis significantly increases mortality, these patients should be treated
prophylactically.29–31 Seven randomized, controlled trials have compared H2-receptor antagonists with
proton pump inhibitors in prophylaxis of bleeding from stress ulceration.29 The consensus of these
studies is that proton pump inhibitors are more effective at maintaining gastric pH above 4.0, but no
convincing data exist that one agent is superior to the other in prevention of clinically important
bleeding. Stress ulcer prophylaxis with these agents is associated with colonization of the upper GI tract
with potentially pathogenic gram-negative organisms. No statistically significant differences in
incidence of pneumonia have been noted between H2-receptor antagonists and proton pump inhibitors
when used for stress ulcer prophylaxis. H2-receptor antagonists are involved in more drug-drug
interactions due to inhibitory effects on the cytochrome oxidase system. Prolongation of protime may
be noted in patients receiving coumadin. Increased plasma concentrations of diazepam, propranolol,
nifedipine, and several antibiotics may also be noted in patients receiving H2-receptor antagonists.
Early enteral feeding was first introduced as a component of burn care. Enteral feeding was designed
to address the hypermetabolic state that develops after burn injury and to prevent visceral protein loss
due to catabolic metabolism. Enteral nutrition has also been demonstrated to prevent bacterial
translocation across the intestinal wall. In addition, enteral nutrition has been noted to maintain
intragastric pH >3.5, suggesting that this modality may be used to prevent gastric hemorrhage from
stress ulceration. In burn patients, early enteral feeding decreases upper GI hemorrhage, effects that are
not potentiated by the addition of H2-receptor antagonists. It seems likely that early enteral feeding will
become widely employed in critically ill surgical patients, beyond those with thermal injury, as a
primary modality for stress ulcer prophylaxis.
References
1. Sung JJ, Kuipers EJ, El-Serag HB. Systematic review: the global incidence and prevalence of peptic
ulcer disease. Aliment Pharmacol Ther 2009;29:938–946.
2. Sanchez-Delgado J, Gene E, Suarez D, et al. Has H. pylori prevalence in bleeding peptic ulcer been
underestimated? A meta-regression. Am J Gastroenterol 2011;106;398–405.
3. Shiota S, Suzuki R, Yamaoka Y. The significance of virulence factors in Helicobacter pylori. J Dig Dis
2013;14:341–349.
4. Reyrat JM, Rappouli R, Telford JL. A structural overview of the Helicobacter cytotoxin. Int J Med
Microbiol 2000;290:375–379.
5. Wu J, Xu S, Zhu Y. Helicobacter pylori CagA: a critical destroyer of the gastric epithelial barrier.
1180
booksmedicos.org
Dig Dis Sci 2013;58:1830–1837.
6. Censini S, Lange C, Xiang Z, et al. Cag, a pathogenicity island of Helicobacter pylori encodes type I-
specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 1996;93:1259–1264.
7. Gillen D, El-Omar EM, Wirz AA, et al. The acid response to gastrin distinguishes duodenal ulcer
patients from Helicobacter pylori-infected healthy subjects. Gastroenterology 1998;114:50–57.
8. Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter pylori infection.
Gastroenterology 2008;134;306–323.
9. Cid TP, Fernandez MC, Martinez SB, et al. Pathogenesis of Helicobacter pylori infection.
Helicobacter 2013;18:12–17.
10. Lanas A, Perex-Aisa MA, Feu F, et al. A nationwide study of mortality associated with hospital
admission due to severe gastrointestinal events and those associated with nonsteroidal
antiinflammatory drug use. Am J Gastroenterol 2005;100:1685–1693.
11. Pilotto A, Franceshi M, Leandro G, et al. NSAID and aspirin use by the elderly in general practice:
effect on gastrointestinal symptoms and therapies. Drugs Aging 2003;20:701–710.
12. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Risk of upper gastrointestinal ulcer bleeding
associated with selective cyclooxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-
inflammatory drugs, aspirin and combinations. Gut 2006;55;1731–1738.
13. O’Connor A, Molina-Infante J, Gisbert JP, et al. Treatment of Helicobacter pylori infection 2013.
Helicobacter 2013;18(suppl 1):58–65.
14. Megraud F, Coenen S, Versporten A, et al. Helicobacter pylori resistance to antibiotics in Europe
and its relationship to antibiotic consumption. Gut 2013:62:34–42.
15. Zullo A, Hassan C, Campo SM, et al. Bleeding peptic ulcer in the elderly: risk factors and
prevention strategies. Drugs Aging 2007;24:815–828.
16. Zeiton JD, Rosa-Hezode I, Chryssostalis A, et al. Epidemiology and adherence to guidelines on the
management of bleeding peptic ulcer: a prospective multicenter observational study in 1140
patients. Clin Res Hepatol Gastroenterol 2012:36:227–234.
17. Rosenstock SJ, Moller MH, Larsson H, et al. Improving quality of care in peptic ulcer bleeding:
nationwide cohort study of 13,498 consecutive patients in the Danish clinical register of emergency
surgery. Am J Gastroenterol2013;108:1449–1457.
18. Imperiale TF, Kong N. Second-look endoscopy for bleeding peptic ulcer disease: a decision-
effectiveness and cost-effectiveness analysis. J Clin Gastroenterol2012;46;e71–e75.
19. Hepworth CC, Swain CP. Mechanical endoscopic methods of haemostasis for bleeding peptic ulcers:
a review. Baillieres Clin Gastroenterol 2000;14:467–476.
20. Sharma VK, Sahai AV, Corderi FA, et al. Helicobacter pylori eradication is superior to ulcer healing
with or without maintenance therapy to prevent further ulcer haemorrhage. Ailment Pharmacol Ther
2001;15:1939–1947.
21. Boey J, Choi SK, Alagaratnam TT, et al. Risk stratification for perforated duodenal ulcers: a
prospective validation of predictive factors. Ann Surg 1987;205:22–28.
22. Moller MH, Engebjerg MC, Adamsen S, et al. The peptic ulcer (PULP) score: a predictor of
mortality following peptic ulcer perforation. A cohort study. Acta Anaesthesiol Scand 2012;56:655–
662.
23. Lunevicius R, Morkevicius M. Systematic review comparing laparoscopic and open repair for
perforated peptic ulcer. Br J Surg 2005;92:1195–1207.
24. Sanabria AE, Morales CH, Villegas MI. Laparoscopic repair for perforated peptic ulcer disease.
25. Antoniou SA, Antoniou GA, Koch OO, et al. Meta-analysis of laparoscopic versus open repair of
perforated peptic ulcer. J Soc Laparoendo Surg 2013;17:15–22.
26. Hemmer PH, de Schipper JS, van Etten B, et al. Results of surgery for perforated gastroduodenal
ulcers in a Dutch population. Dig Surg 2011;28:360–366.
27. Burge N, Barton RG, Enniss TM, et al. Laparoscopic versus open repair of perforated
gastroduodenal ulcer: a national surgical quality improvement program analysis. Am J Surg
2013;206:957–963.
28. Atherton JC. The pathogenesis of Helicobacter pylori-induced gastro-duodenal disease. Annu Rev
Pathol 2006;1:63–96.
1181
booksmedicos.org
29. Greenwood JE, Pilkington KB, Wagstaff MJ. Prevention of gastrointestinal bleeding due to stress
ulceration: a review of current literature. Anaesth Crit Care 2012;40:253–259.
30. Alhazzani W, Alenezi F, Jaeschke RZ. Proton pump inhibitors versus histamine 2 receptor
antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-
analysis. Crit Care Med 2013;41:693–705.
31. Reveiz L, Guerrero-Lozano R, Camacho A, et al. Stress ulcer, gastritis, and gastrointestinal bleeding
prophylaxis in critically ill pediatric patients: a systematic review. Pediatr Crit Care Med
2010;11:124–132.
1182
booksmedicos.org
Chapter 46
Management of Obesity
Robert W. O’Rourke
Key Points
1 Obesity is defined and categorized using body mass index (BMI, weight [kg]/height [m]2) based on
World Health Organization definitions.
2 BMI directly correlates with the risk of multiple metabolic diseases and long-term mortality.
3 Lifestyle interventions as treatment for obesity, including diet, exercise, and psychological therapy,
are of limited efficacy; evolving strategies directed toward environmental manipulation demonstrate
potential.
4 Current pharmacotherapy for obesity includes a wide range of agents that act via multiple
mechanisms, are prone to side effects, and are of limited efficacy; active research in
pharmacotherapy for obesity holds significant promise.
5 Bariatric surgery is highly efficacious in treating obesity and metabolic disease, and includes a wide
range of procedures that have evolved over decades.
6 Current dominant bariatric surgery operations include gastric bypass, sleeve gastrectomy, and
gastric banding.
7 Classic mechanisms of action of bariatric surgery include restriction of caloric intake and
malabsorption of ingested calories, but evolving data suggest that other mechanisms predominate,
including but not limited to alterations in gut and satiety hormone homeostasis, bile acid
metabolism, and enteroenteric and enterocentral nervous systemic communications.
DIAGNOSIS AND EPIDEMIOLOGY

Obesity and Metabolic Disease
Excess adipose tissue is the defining feature of obesity, and metabolic disease arises in adipose tissue.
Metabolic disease is diverse, involving every organ system. The correlation between obesity and
metabolic disease, while strong, is not perfect – some patients develop metabolic disease at low body
weight, while others who are very obese are protected. Visceral adiposity imparts greater risk than
subcutaneous adiposity, and heterogeneity of visceral and subcutaneous adiposities partly explains the
imperfect correlation between obesity and metabolic disease. Lean patients also develop metabolic
disease, albeit less frequently than the obese, demonstrating that nonadipose tissue-based mechanisms
contribute to metabolic disease as well. It is beyond the scope of this chapter to discuss the wide
spectrum of specific treatment strategies for individual metabolic diseases. Rather, we will discuss the
treatment of obesity itself, the goal of which is reduction in adipose tissue mass, because despite the
variable relationship between body weight and metabolic dysfunction, in the vast majority of patients,
regardless of initial weight, weight loss has beneficial effects on virtually all metabolic diseases.
Treatment options for obesity may be broadly divided into medical and surgical approaches.
Diagnosis
1 Body mass index (BMI, weight [kg]/height [m]2) is the primary metric used to define obesity.
Originally devised in the 19th century as a general measure of human body habitus, BMI was coopted in
the 1940s by the insurance industry and used to stratify humans into high- and low-risk subpopulations
based on actuarial data for the purpose of setting life insurance rates. The medical community
subsequently used BMI to estimate risk of morbidity and mortality. Much debate exists regarding the
appropriate BMI cutoff points for optimal health, with various health and professional organizations
setting different values. World Health Organization (WHO) definitions, set in 1995 and agreed upon by
the U.S. Centers for Disease Control (CDC), are most commonly utilized and define overweight as BMI
1183
booksmedicos.org
>25 and <30 and obesity as BMI ≥30, and categorize obesity into classes 1 (BMI 30 to 34.9), 2 (BMI
35 to 39.9), and 3 (BMI ≥40).1
2 BMI correlates with long-term mortality and metabolic disease in a J-shaped curve, the nadir of
which is debated, but may be as low as 20 or as high as 25.2 BMI in the obese range (≥30) is clearly
associated with an increased risk in long-term mortality and multiple metabolic diseases relative to BMI
<30. For individuals with BMI 40 to 50, this risk translates into a 10-year decrease in life expectancy.
In contrast to obesity, data demonstrating a correlation between overweight BMI and health risk are
conflicting. Analyses are complicated by numerous confounding variables including but not limited to
gender, age, ethnicity, smoking, cancer, and diabetes. In addition, the choice of control/referent group
alters outcomes; for example, the correlations between overweight BMI and clinical outcomes weaken
significantly and may be masked when referent groups span a larger BMI range (e.g., 18 to 25) relative
to comparison with referent groups spanning a narrow BMI range (e.g., 21 to 23). Despite these
conflicting data, the preponderance of evidence suggests that BMI in the overweight range is associated
with an increased risk of long-term mortality, albeit lower than the risk associated with BMI in the
obese range.3 Furthermore, mortality aside, compelling data demonstrate that overweight BMI is
associated with an increased risk of cardiovascular disease, diabetes, and other metabolic diseases, and
is associated with an increased risk of future progression to frank obesity with its attendant risks. Taken
together, these observations suggest that overweight should be considered a serious health risk and a
predecessor to obesity.
These complex data demonstrate that BMI is not a perfect measure of adiposity. Indeed, muscular
athletes may have BMI within the obese range despite low body fat levels and an absence of metabolic
disease, while elderly people with a paucity of muscle mass may have low BMI despite increased
adiposity and metabolic disease. Ethnic differences further confound the predictive power of BMI, as
certain ethnicities, for example Asians, develop metabolic disease at lower BMI, prompting the WHO in
2004 to propose BMI cutoffs of 23 and 27.5 for overweight and obesity respectively in Asians. In certain
subpopulations, including patients with heart failure, renal failure, and other chronic diseases,
overweight and obesity are associated with decreased mortality, a phenomenon termed the “obesity
paradox.”4
These observations have led to a search for other measures of adiposity. Waist circumference and
waist–hip ratio are easily measured and in many studies correlate more accurately with metabolic
disease than BMI, reflecting the disproportionate effect of visceral adiposity on metabolic disease.5
Water displacement, dual-energy x-ray absorptiometry scanning, double-labeled isotope water
measurement, bioelectrical impedance analysis, and quantitative magnetic resonance imaging may
provide more accurate measures of adiposity and better predict metabolic disease, but have not gained
widespread acceptance due to cost and complexity. Despite its limitations, BMI remains the most
commonly used metric for obesity.
Epidemiology, Disease Burden

Human obesity has existed for millennia as evidenced by prehistoric figurines of obese humans (e.g.,
Venus of Willendorf) and periodic concerns regarding past obesity “epidemics” over the past two
centuries. Nonetheless, the worldwide prevalence of overweight and obesity has increased dramatically
over the past 50 years. BMI, like many clinical characteristics, spans a bell curve. Three large US
epidemiologic datasets, the National Health and Nutrition Examination Survey (NHANES), the National
Health Interview Survey (NHIS), and the Behavioral Risk Factor Surveillance System (BRFSS),
demonstrate similar trends, with a rightward shift of the BMI bell curve over the past three decades,
mean BMI increasing from 25.5 in the 1970s to 28.5 in 2005, and the prevalence of obesity more than
doubling in the same interval.6 The CDC reports that as of 2010, 69% of US adults were overweight or
obese, and 36% of US adults and 17% of US children were obese.7 Evidence suggests that the prevalence
of obesity has plateaued in the past 2 to 3 years in industrialized countries including the US, but
continues to rise in developing countries. Gender, ethnic, and regional differences complicate obesity
epidemiology. The rate of increase is higher in women compared to men, and while rates of increase are
similar across ethnicities, mean BMI is highest in Blacks, followed by Hispanics, then Caucasians. Data
regarding the association between obesity and socioeconomic status are conflicting; evidence suggests
an inverse correlation between low socioeconomic status and obesity in low- and middle-income
countries but a positive correlation in industrialized countries. Obesity prevalence is increased in rural
compared to urban environments in the United States, although this relationship is inverted in
developing countries.
1184
booksmedicos.org
The disease burden associated with obesity is substantial. Multiple confounders complicate
quantification of risk, not the least of which is variability in the degree of obesity itself, with increasing
BMI being associated with increasing risk of mortality and disease in a dose-dependent but nonlinear
fashion. Obesity is associated with decreased lifespan. Data from the Framingham Heart Study
demonstrate a loss of 3 and 6 years of life for overweight and obese men respectively,8 while NHANES
data demonstrate a loss of 13 years of life for severely obese men (BMI >45).9 Overweight and obesity
are associated with an increased risk of multiple diseases, among which type II diabetes is particularly
important. The association between obesity and diabetes is robust; relative risks for diabetes range from
2 to 15 for BMI in the overweight range and 20 to 90 for BMI in the obese range. The CDC estimates
that in the United States in 2011, the prevalence of type II diabetes was 8.3% among all adults and 27%
among those over 65 years of age. Furthermore, 35% of all US adults, and 50% of US adults over 65
years of age have elevated fasting blood glucose or HbA1c consistent with prediabetes. If current trends
persist, the prevalence of diabetes in the United States in 2050 will exceed 30%, and worldwide trends
parallel these US data.
Obesity is associated with an increased risk of multiple diseases, including atherosclerosis,
hypertension, hyperlipidemia, hepatic steatosis and steatohepatitis, sleep apnea, osteoarthritis,
gallbladder disease, endocrine disorders, autoimmune disease, allergy and atopy, multiple types of
cancer, and depression. Metabolic disease encompasses all of physiology. Risk ratios for overweight and
obesity-related diseases vary substantially depending on BMI, ranging from 2 to 5 for stage I obesity
with dramatic dose-dependent increases in risk with increasing BMI. For example, the prevalence of
hepatic steatosis in the general population is generally estimated to be approximately 30%, increases
progressively with increasing BMI, and exceeds 90% in obese patients with BMI >40. In the NHANES
population, the prevalence of sleep apnea was 3% in nonobese men and 12% in obese men (BMI
>30),10 but in a separate study of patients with severe obesity (BMI >40), prevalence exceeded 70%.11
This disease burden is associated with significant economic costs. While accurate quantification of
obesity-related healthcare costs is challenging and complicated by regional variability in payer systems
and patient demographics, a recent systematic review estimated that costs directly attributable to
overweight and obesity in the United States exceed 100 billion dollars annually and constitute 5% to
10% of total US healthcare spending.
MEDICAL MANAGEMENT
Treatment Strategies
The medical management of obesity falls into two primary categories: lifestyle intervention and
pharmacotherapy. Both strategies, with rare exceptions, achieve similar results, with modest weight loss
and high recidivism. Nonetheless, both strategies hold significant untapped promise, with advances
expected in coming decades, particularly in the areas of environmental engineering and
pharmacotherapy.
Lifestyle Interventions
3 Lifestyle interventions for obesity include any or all of three basic components: diet modification,
exercise, and psychological therapy. Interventions may be unsupervised or administered under the
supervision of clinicians, dieticians, or commercial weight loss plans, and may be individualized or
administered in group programs.
Diet modification is the mainstay of lifestyle intervention. Diet strategies vary with respect to
macronutrient composition, daily caloric intake, and food and caloric measurement methods, and
include low-carbohydrate diets, low-fat diets, meal replacement strategies, Mediterranean diets, very
low-calorie diets, and multiple commercial diet plans. No clear evidence demonstrates advantages of
any specific diet plan over others. Specifically, macronutrient composition does not impact on weight
loss when caloric intake is controlled – total calories, rather than the macronutrient composition of
those calories, is the variable that determines weight loss. In contrast to weight loss, conflicting
evidence exists regarding the role of macronutrient composition in improvement of metabolic disease,
with some evidence suggesting that low-carbohydrate diets (which include low-glycemic index–high-
fiber diets and very low-carbohydrate diets), when compared to low-fat diets, may be associated with
greater improvements in insulin resistance and triglyceride levels, and higher resting energy
expenditure. These studies must be interpreted with caution as follow-up is relatively short, and low-
1185
booksmedicos.org
carbohydrate diets may be associated with adverse changes in low-density lipoprotein levels.12 Low-
carbohydrate diets also appear to provide better compliance than other diet strategies over short-term
follow-up of less than 6 months, but compliance differences vanish at follow-up exceeding 1 year.
Physical activity is a central component of lifestyle intervention for obesity. Exercise alone achieves
only modest weight loss, but exercise and diet potentiate each other. Importantly, exercise reduces
obesity-related mortality and cardiovascular disease risk independent of weight loss. Data regarding the
optimal type, duration, frequency, and intensity of exercise are conflicting and specific evidence-based
guidelines remain elusive. High intensity exercise may be more effective for weight loss, but many
obese patients are unable to engage in even moderate intensity exercise due to comorbid diseases such
as osteoarthritis. Increased daily nonexercise activities such as walking and stair use nonetheless may
provide modest weight loss and cardiovascular health benefits.
Of the wide range of psychological techniques used to treat obesity, cognitive-behavioral therapy is
most common. Cognitive-behavioral therapy achieves modest weight loss in the obese of approximately
2 to 3 kg at 1-year follow-up, with increased weight loss when combined with diet and/or exercise.
Increased frequency of psychological intervention and group therapy compared with individual therapy
are associated with greater weight loss.
Intensive lifestyle interventions are supervised multicomponent plans that involve a combination of
diet, exercise, and behavioral modification, with periodic monitoring by coaches and dieticians, and
individual or group psychological counseling. Two NIH-sponsored randomized controlled trials suggest
that intensive lifestyle interventions provide more durable results than standard lifestyle interventions,
although long-term outcomes of metabolic disease are conflicting. The Diabetes Prevention Program
randomized 3,234 overweight or obese insulin-resistant patients (mean BMI 34) to 1 of 3 experimental
arms: intensive lifestyle interventions, metformin treatment, or placebo treatment.13 After a mean
follow-up of 2.8 years, average weight loss in the intensive lifestyle interventions group was 5.6 kg
compared with 2.1 kg and 0.1 kg for the metformin and placebo groups respectively; at 10 years an
average weight loss of 2 kg was maintained in both intensive lifestyle interventions and metformin
arms relative to the placebo arm. The cumulative risk of incident diabetes was 34% lower in the
intensive lifestyle interventions arm and 18% lower in the metformin arm relative to the placebo arm.
The NIH-sponsored Look AHEAD (Action for Health in Diabetes) study randomized 5,145 overweight or
obese diabetic patients to a 4-year intensive lifestyle intervention involving diet and exercise
modification with regular on-site visits and counseling, or standard primary care provider-supervised
diabetes and weight loss education. After 8 years, mean weight loss was 4.7% and 2.1% in the intensive
lifestyle intervention and standard care arms respectively.14 Nonetheless, the study was halted after 11
years after no difference in cardiovascular events was observed. These studies demonstrate that while
modest, weight loss may be maintained over long periods with intensive lifestyle interventions,
although the effects on metabolic disease are equivocal. Of importance, in Look AHEAD, a subset of
patients in each arm (27% and 17% in intensive lifestyle intervention and standard care arms,
respectively), maintained a loss of >10% of total starting weight, suggesting that subpopulations of
patients are more responsive than others to lifestyle interventions, and that identification of predictors
of responsiveness would permit better allocation of care.
Assessing the overall efficacy of lifestyle interventions for obesity is challenging, as results vary
depending on the subgroup studied, follow-up is variable and often short, and program and outcome
reporting methods are widely disparate. The resultant complex body of literature limits our current
understanding of the efficacy of such interventions. Nonetheless, a preponderance of data suggests that
results of lifestyle interventions for obesity are modest, with mean weight loss between 2% and 10% of
total body weight over follow-up periods from 6 to 48 months. Unsupervised individual efforts
underperform more intensive, multicomponent, supervised, group interventions. Compliance is a critical
issue; individual diet programs are associated with attrition that may exceed 90% over a year or more
while attrition for intensive supervised efforts is less. Weight regain after program discontinuation is
common and long-term adherence to lifestyle changes is low. Despite these limitations, modest weight
loss, or exercise in the absence of weight loss, appears to have measurable if modest beneficial effects
on metabolic disease, with a subset of patients being responsive to such interventions. As such, lifestyle
interventions should be a component of the treatment of all obese patients, but only rarely achieve
dramatic and durable results.
Environmental Interventions – The Future

An understanding of importance of the interaction between environment and human genetics in the
1186
booksmedicos.org
pathogenesis of obesity has shifted focus away from individual patient behavior modification and
toward manipulation of the obesogenic built environment. While rigorous data and proof of causality are
emerging, specific characteristics of the built environment have been linked to obesity, including
proximity and prevalence of fast food restaurants and full-service grocery stores, access to and quality
of exercise facilities, parks, and sidewalks, school and work environment food and exercise resources,
and public transit infrastructure. An emerging field of environmental and social engineering will shift
the focus of lifestyle intervention from individual to environment, and holds promise as next-generation
treatment for obesity.
Pharmacotherapy
4 The history of pharmacotherapy for obesity is replete with drugs that have been introduced with
much enthusiasm and variable efficacy but subsequently withdrawn due to unacceptable and in many
cases life-threatening side effects that became apparent only after widespread use. Sheep thyroid extract
was used in the late 19th century, while in the early 20th century, workers in the dye industry exposed
to 2, 4-dinitrophenol were observed to lose weight, leading to its use as a weight loss drug in the 1930s.
Amphetamines were popular weight loss drugs in the 1950–60s. All these agents were abandoned due to
prohibitive side effects. The modest efficacy of weight loss drugs is testament to the multiple redundant
physiologic systems that act to defend adipose tissue stores in the face of interventions designed to
reduce those stores. The frequent adverse effects of weight loss drugs speak to the interface between
body weight regulation and multiple fundamental physiologic processes, manipulation of which entails
substantial risk.
The largest and most important class of weight loss drugs targets monoamine signaling mediators
(norepinephrine, serotonin, dopamine, histamine) involved in CNS/hypothalamic control of satiety and
hunger. Many of these agents regulate multiple pathways and demonstrate overlapping activities.
Sympathomimetic agents that primarily potentiate norepinephrine release include phentermine,
introduced in 1959 and still in use today, and phenylpropanolamine, used as a decongestant and also as
a weight loss drug since the 1970s, but withdrawn from the market in 2000 after being associated with
an increased risk of stroke. Drugs that primarily potentiate serotonin activity include fenfluramine,
introduced in 1973 and withdrawn from the market in 1997, sibutramine (Meridia), a serotonin,
norepinephrine, and dopamine reuptake inhibitor with primary effects on serotonin and norepinephrine,
introduced in 1997 but withdrawn in 2010 after being linked to increased risks of myocardial infarction
and stroke, and lorcaserin (Belviq), a selective serotonin 2C agonist approved by the FDA in 2012.
Drugs that target dopamine signaling are currently being studied in clinical trials (e.g., bupropion,
tesofensine). Targeting multiple monoamine signaling pathways provides synergy. The combination
drug fenfluramine/phentermine (“Fen-phen”), introduced in 1992, demonstrated increased efficacy over
either agent alone, but was withdrawn from the market in 1997 after widespread use revealed serious
morbidity attributable to fenfluramine, including pulmonary hypertension and cardiac valvular disease.
In 2013, the FDA approved a combination drug of phentermine and topiramate, an antiepileptic with
multiple CNS activities (Qsymia). A combination formulation of bupropion and naltrexone, an opioid
antagonist which stimulates pro-opiomelanocortin neurons, is currently being studied in research trials.
Gut peptides have diverse metabolic functions including regulating satiety and hunger within the
hypothalamic feeding center, and include glucagon-like peptide 1 (GLP-1), cholecystokinin, ghrelin,
oxyntomodulin, pancreatic polypeptide, and amylin. Drugs based on these mediators show promise.
Many gut peptides have short biologic half-lives and research has focused on long-acting analogs or
mediators that target degradation pathways. GLP-1, secreted by ileal L cells in response to a meal,
induces satiety and potentiates insulin secretion and peripheral insulin sensitivity. Long-acting GLP-1
analogs, including liraglutide (Victoza) and exenatide (Byetta) are FDA approved for treatment of type
2 diabetes and are under investigation as primary weight loss agents.15 Ghrelin is so far the only known
orexigenic hormone, and ghrelin antagonists, agonists of ghrelin degradation pathways, and antighrelin
vaccines are in development. Amylin, released by pancreatic beta cells, induces satiety via CNS-based
mechanisms and also potentiates peripheral insulin resistance; pramlintide (Symlin), a human amylin
agonist, is approved for treatment of diabetes and induces modest weight loss. Orlistat (Xenical),
approved by FDA in 1999, is a pancreatic lipase inhibitor that blocks intestinal absorption of fat, and the
only drug to date that functions by reducing absorption of ingested calories. Side effects of orlistat
include diarrhea, steatorrhea, and increased risks of kidney stones and pancreatitis. Second-generation
lipase inhibitors are in development.
Agents designed to manipulate neuropeptide signaling within the hypothalamus, while not yet
1187
booksmedicos.org
approved for use in humans, are important targets, and include drugs directed toward leptin,
melanocortin-4 receptor (MC4R), neuropeptide Y, and melanin-concentrating hormone. While leptin
resistance has confounded development of leptin as a therapeutic agent, recent data from animal models
suggest that concomitant treatment of endoplasmic reticulum stress may abrogate leptin resistance,16
while separate research demonstrates that amylin agonists also restore leptin sensitivity.17 These lines
of research have reinvigorated interest in leptin therapy. Mutations in the MC4R gene, a central
hypothalamic satiety mediator, are implicated in up to 5% of cases of common human obesity, and
MC4R agonists are currently in development. Other central-acting agents are directed toward
endocannabinoid signaling: rimonabant (Acomplia), a selective endocannabinoid antagonist, was denied
FDA approval in 2008 despite promising weight loss results in clinical trials due to an association with
depression and suicide, but interest in manipulation of endocannabinoid signaling persists.
Manipulation of thermogenesis and metabolic rate remains an active field of research. Thyroid
hormone achieves weight loss by increasing metabolic rate, but is associated with cardiac toxicity and
has detrimental effects on glucose homeostasis. Despite these failures, research persists. Many agents
discussed above that regulate food intake, most notably the sympathomimetics, also increase metabolic
rate, and it is unclear to what extent these effects contribute to weight loss. Agents that regulate steroid
metabolism, fatty acid oxidation and other aspects of adipose tissue, and skeletal muscle metabolism are
under study. Dietary constituents also regulate thermogenesis, including methylxanthines (e.g.,
caffeine), polyphenols (e.g., resveratrol, quercetin), capsaicinoids (found in chili peppers and mustards),
and medium-chain fatty acids, all of which represent potential therapeutic agents.
Overall efficacy of current obesity pharmacotherapy is modest, achieving weight loss of 3% to 10% of
total body weight. Most agents demonstrate synergy with lifestyle interventions. Current drugs
approved by the FDA specifically for weight loss include orlistat, the only drug approved for long-term
use; phentermine, approved for short-term use (<12 weeks) due to addiction potential and
cardiovascular toxicity; lorcaserin, FDA approved for use as an adjunct to lifestyle interventions; and
phentermine/topiramate. The XENDOS study (XENical in the Prevention of Diabetes in Obese Subjects)
randomized 3,305 patients to lifestyle intervention combined with either orlistat or placebo and at 4
years, and demonstrated a 5.8-kg weight loss in the orlistat arm compared with a 3.0-kg weight loss in
the placebo arm, as well as a reduced incidence of diabetes with orlistat therapy.18 Lorcaserin induced
5% weight loss compared with 3% in placebo-treated patients at 1 year.19 The phentermine/topiramate
combination drug achieved 10.5% weight loss compared with 1.8% in placebo-treated patients at 2-year
follow-up.20
A complete summary of obesity pharmacotherapy is beyond the scope of this chapter, which has by
necessity omitted important areas of research, including drugs that target steroid metabolism, lipid
metabolism, adipocyte differentiation and proliferation, and efforts to shift white adipose tissue toward
a brown adipose tissue phenotype (the “browning” of adipose tissue). This discussion has focused on
agents designed to treat obesity directly with the goal of weight loss, but an important parallel class of
drugs target metabolic disease independent of or in conjunction with weight loss. The activities of
weight loss drugs are complex and overlapping, with many agents regulating body weight and
metabolism via multiple mechanisms. Multiple redundancies in the regulation of energy homeostasis
suggest that drug combinations will enhance efficacy. As an understanding of these mechanisms
increases, safe and effective pharmacotherapy for obesity and metabolic disease will emerge.
SURGICAL MANAGEMENT
Bariatric Surgery – Beginnings
5 In contrast to lifestyle interventions and pharmacotherapy, surgical management of obesity is highly
efficacious. Modern bariatric surgery (Gr. baros, heavy, burden) is the result of over a half-century of
evolution in surgical technique that has its genesis in the 1940–50s with experiments in animals and
isolated operations in humans that employed small intestinal resection and jejunocolic and ileocolic
bypasses of various anatomic configurations. These operations involved substantial morbidity and did
not achieve widespread acceptance, but set the stage for development of the jejunoileal bypass, the first
bariatric operation to be widely applied in humans. Jejunoileal bypass involved division of the jejunum
14 inches distal to the ligament of Treitz and creation of a jejunoileostomy 4 inches proximal to the
ileocecal valve, and was thus referred to as a “14–4 bypass” (Fig. 46-1). In 1969, Payne and Dewind21
published the first report describing long-term clinical outcomes in a large group of patients who
1188
booksmedicos.org
underwent jejunoileal bypass in the 1950–60s, describing dramatic weight loss (“A total of 10,373
pounds have been lost by the (80) patients”) along with improvements in insulin resistance,
hypercholesterolemia, and hepatic steatosis. Jejunoileal bypass was widely used throughout the 1960s
and early 1970s.
Despite its efficacy, as experience accumulated, it became clear that jejunoileal bypass was associated
with significant morbidity. Diarrhea, steatorrhea, dehydration, electrolyte imbalances, and micro- and
macronutrient deficiencies resulted from the highly malabsorptive nature of the operation. Patients also
suffered a host of complications not obviously linked to malabsorption, including liver disease,
nephropathy, arthropathy, neuropathy, and myopathy. While the cause of these latter complications was
not completely clear, an immune response directed toward bacterial overgrowth in the blind intestinal
limb was implicated. Overall morbidity afflicted as many as 70% of patients and led to abandonment of
jejunoileal bypass by the late 1970s. Nonetheless, up to 30% of patients achieved good results, and the
clinician may still encounter rare remaining patients. Indications for reversal or conversion to modern
bariatric operations are not well established and must be considered on an individual basis, but include
progressive liver or kidney disease not attributable to other causes. Some clinicians advocate reversal
and conversion to a modern bariatric operation in all patients who are good operative candidates
regardless of the presence or absence of complications.
Figure 46-1. Jejunoileal bypass. The jejunum is divided 14 in distal to the ligament of Treitz, and a jejunoileostomy is created 4
in proximal to the ileocecal valve. Note that the defunctionalized jejunoileal limb is out of continuity with biliopancreatic effluent,
predisposing to limb stasis.
Gastric Bypass – The Gold Standard

With the decline of jejunoileal bypass, surgeons began searching for alternatives. In the 1960s, Edward
Mason at the University of Iowa experimented with operations based on observations that patients who
underwent gastric resections for ulcer disease had difficulty maintaining their weight. Mason’s efforts
led to the development of the gastric bypass, for which he earned the title “father of bariatric surgery.”
Mason’s original gastric bypass consisted of a pouch gastroplasty with a loop gastrojejunostomy
reconstruction. Gastric bypass subsequently evolved through a number of iterations, all with important
clinical implications. Large horizontal fundal-based pouches were replaced with smaller vertical lesser
curve-based pouches, which improve gastric emptying. Undivided gastric pouches were associated with
high rates of staple-line dehiscence and gastrogastric fistula, and were replaced with divided gastric
bypass, expedited by the development of cutting staplers. Roux-en-Y reconstruction, compared to loop
reconstruction, reduces tension on the gastrojejunal anastomosis and prevents bile reflux gastritis, but
may be associated with higher rates of anastomotic ulcer disease. Retrocolic Roux limbs may improve
pouch emptying and generate less tension on the gastrojejunostomy, but at the price of higher rates of
mesocolic internal hernias. Banding of the gastrojejunal anastomosis may increase weight loss, but also
increases risks of stenosis, obstruction, and erosion. Variations persist, including retrocolic Roux limbs,
loop reconstructions (“minigastric bypass”), and prosthetic-banded gastric pouches. The modern gastric
bypass practiced by the majority of surgeons today consists of a divided, unbanded, lesser curve-based
pouch gastroplasty of 15 to 30 cc with an antecolic Roux-en-Y gastrojejunal reconstruction with a 100-
cm Roux/alimentary limb and a 50- to 100-cm afferent/biliopancreatic limb (Fig. 46-2). The modern
gastric bypass is a robust operation because within limits, subtle variations in technique, including
pouch size and morphology and intestinal limb length and position, do not greatly affect efficacy or
morbidity. Gastric bypass remains, as of this writing, the dominant bariatric operation worldwide and
the gold standard against which all other operations are measured.
1189
booksmedicos.org
Figure 46-2. Anatomy of modern Roux-en-Y gastric bypass. Modern gastric bypass consists of a divided pouch gastroplasty with
Roux-en-Y jejunojejunal reconstruction. The Roux limb is most commonly placed in the antecolic position. Intestinal limbs are
termed with either standard Roux (Roux, afferent, efferent) or bariatric (alimentary, biliopancreatic, common channel)
nomenclature as shown.
Malabsorption Revisited
Despite the failure of jejunoileal bypass, interest in operations that relied on small intestine bypass
persisted. Biliopancreatic diversion consists of an antrectomy with a gastrojejunostomy and distal Roux-
en-Y jejunoileostomy. The duodenal switch modification of the biliopancreatic diversion involves a sleeve
gastrectomy, division of the duodenum distal to the pylorus, and a duodenojejunostomy and distal
Roux-en-Y jejunoileostomy, thus maintaining the pylorus in the alimentary stream (Fig. 46-3).
Biliopancreatic diversion/duodenal switch differs from jejunoileal bypass in two important regards.
First, maintenance of forward flow of biliopancreatic effluent in the bypassed afferent limb prevents
stasis and bacterial overgrowth. Second, common channel length was increased to 100 cm, reducing
malabsorptive complications. Biliopancreatic diversion/duodenal switch provides weight loss and
metabolic disease remission equivalent to, and in many series, greater than gastric bypass. Morbidity
and mortality for biliopancreatic diversion/duodenal switch span a wide range, with centers with
significant expertise reporting low rates similar to gastric bypass. Nonetheless, when the literature as a
whole is considered, biliopancreatic diversion/duodenal switch is associated with higher morbidity and
mortality than gastric bypass. Perioperative mortality reported by meta-analyses is at least twofold
higher than gastric bypass, possibly due to a higher risk of anastomotic dehiscence, as laparoscopic
creation of the duodenojejunal anastomosis associated with the duodenal switch modification is
technically challenging.22 Late malabsorptive complications which may require surgical revision, while
much improved over jejunoileal bypass, range from 2% to 20%. Unlike gastric bypass, in which small
changes in pouch size or limb length do not substantially alter clinical outcome, outcomes of
biliopancreatic diversion/duodenal switch are relatively sensitive to differences in efferent limb length,
small changes in which may make the difference between poor weight loss and malabsorptive
complications. Predicting the correct efferent limb length for an individual patient is challenging. Most
surgeons advocate a fixed length of 100 cm, while others advocate an ad hoc limb length proportional to
total small intestine length. While advocated by select surgeons and associated with good outcomes in
centers with significant experience, biliopancreatic diversion/duodenal switch is nonetheless waning in
use, currently comprising less than 2% of bariatric operations.
1190
booksmedicos.org
Figure 46-3. Biliopancreatic diversion (BPD). BPD involves a distal antrectomy with a Roux-en-Y jejunoileal reconstruction;
BPD+DS involves a sleeve gastrectomy with a Roux-en-Y duodenolieal reconstruction, with the duodenoileostomy created 2 cm
distal to the pylorus, thus preserving the pyloric emptying mechanism. Note that, unlike JIBP, the afferent/biliopancreatic
jejunoileal limb is in continuity with biliopancreatic effluent, reducing limb stasis.
Pure Restriction
In Mason’s era, morbidity from gastric bypass was not trivial. In an effort to design a simpler and safer
operation, Mason experimented with gastroplasties that precluded the need for small intestinal
reconstruction. Like gastric bypass, these operations evolved through a number of iterations, eventually
leading to the modern vertical banded gastroplasty, which involves creation of a partitioned upper
stomach pouch with a prosthetic band restricting pouch outlet diameter (Fig. 46-4). Vertical banded
gastroplasty achieved widespread acceptance and peaked in the 1970–80s. Vertical banded gastroplasty
weight loss is substantially less and late weight regain substantially greater compared to gastric bypass,
however, and vertical banded gastroplasty has therefore been relegated to a minority operation that is
rapidly being eliminated from use.
Study of prosthetic bands applied to the upper stomach to limit food intake began in the late 1970s
using devices made from prolene, marlex, and other materials. These devices were nonadjustable and
plagued with complications related to erosion, migration, stenosis, and obstruction. Efforts persisted,
eventually culminating in the modern adjustable gastric band, a silicone device that was FDA approved in
the United States in 2001 (Fig. 46-5). A primary advantage of gastric band is its technical simplicity and
low rates of major morbidity and mortality. Unlike gastric bypass, which continues to be associated
with low but finite rates of anastomotic dehiscence and mortality, gastric band is associated with 5 to
10 lower rates of life-threatening complications and mortality. Much enthusiasm accompanied the
introduction of gastric band in the late 1990s, but over the past decade, enthusiasm has waned for two
reasons. First, therapeutic efficacy of gastric band in the majority of patients is substantially less than
gastric bypass. Second, as years passed, late complication rates have increased. These complications,
including band slippage, erosion, and esophageal dilation and development of gastroesophageal reflux
disease (GERD), are usually not life-threatening, but range between 10% and 50% and often lead to
band removal.23 Despite these problems, gastric band efficacy, while not as high as gastric bypass, is
acceptable. Gastric band remains the bariatric operation with the lowest major morbidity and mortality
rates, an appealing quality for risk-averse patients. Gastric band does not require Roux-en-Y
reconstruction, an advantage in patients with complex abdominal surgical histories. For these reasons,
gastric band remains an important component of the bariatric surgery repertoire.
1191
booksmedicos.org
Figure 46-4. Vertical banded gastroplasty. A partitioned proximal gastric pouch is created with a linear stapler, and outflow
limited with a prosthetic band. Variations included a divided staple line and different materials used for banding.
Figure 46-5. Gastric band. A silicone adjustable band is positioned around the upper stomach, creating a gastric pouch. A port
attached to the band via silicone tubing is placed in the subcutaneous tissue in the abdominal wall, permitting percutaneous access
and adjustment of band diameter.
Sleeve gastrectomy was introduced initially as a component of the duodenal switch modification of
biliopancreatic diversion, but did not gain significant attention as a stand-alone bariatric operation until
the early 2000s. Sleeve gastrectomy involves a lateral gastrectomy, leaving a narrow “sleeve” of
stomach 32 to 40 Fr in diameter (Fig. 46-6). Originally proposed as the first step in a staged approach
for high BMI patients prior to definitive gastric bypass, early follow-up data demonstrated excellent
results, and long-term efficacy appears similar to gastric bypass. Sleeve gastrectomy is associated with
perioperative complication rates similar to gastric bypass, but late complications are rare, in part due to
elimination of morbidity associated with alterations in small intestinal anatomy. For these reasons,
sleeve gastrectomy has engendered significant enthusiasm and is rapidly increasing in utilization.
Figure 46-6. Sleeve gastrectomy. A lateral gastrectomy is performed with a linear cutting stapler, creating narrow gastric reservoir
32 to 40 Fr in diameter.
Modern Bariatric Surgery

6 Bariatric operations in addition to those described above exist, including variants of gastric bypass,
biliopancreatic diversion/duodenal switch, and vertical banded gastroplasty as well as distinct
alternative operations. Currently gastric bypass, sleeve gastrectomy, and gastric band are the mainstays,
1192
booksmedicos.org
while biliopancreatic diversion/duodenal switch comprises a waning minority. Worldwide utilization
rates in 2011 were gastric bypass 47%, sleeve gastrectomy 28%, gastric band 18%, and biliopancreatic
diversion/duodenal switch 2% of all bariatric operations, with a marked increase in sleeve gastrectomy
and decrease in gastric band in recent years.24 The introduction of laparoscopy in the early 1990s
provided significant advantages for many surgical patients but perhaps none more so than the obese.
Wound infections and ventral hernias afflicted 30% to 90% of patients undergoing bariatric surgery via
laparotomy, complications that were virtually eliminated with laparoscopy. Surgeons began exploring
laparoscopic gastric bypass in the mid-1990s, but laparoscopy came with a price, introducing technical
challenges dissimilar from open bariatric surgery, with a long, arduous learning curve that may exceed
100 cases for laparoscopic gastric bypass. These challenges engendered a response that included
fellowship training programs and programmatic efforts to codify technique and care, including
certification of bariatric surgery centers by surgical societies. These efforts, along with increasing
surgeon experience, have reduced current morbidity and mortality to levels substantially lower than in
the prelaparoscopic era. Currently, a laparoscopic approach is considered standard of care for bariatric
surgery patients in the absence of a prohibitive prior surgical history.
Efficacy
Bariatric surgery achieves dramatic results. Weight loss is commonly reported as a percent age of excess
weight lost (EWL), defined as the difference between presurgical weight and ideal weight, with ideal
weight calculated for BMI = 25 for height. Weight loss typically peaks 1 to 2 years after surgery and
may approach 80% to 90% EWL, followed by partial weight regain 3 to 10 years after surgery, leading
to a plateau at 50% to 70% EWL at long-term follow-up.25 The mechanisms underlying this weight loss
pattern are unknown but may involve development of adaptive eating patterns that increase caloric
intake over time. For gastric band, weight loss is typically slower and more gradual, with a plateau
after 2 to 3 years. These varying patterns of weight loss complicate comparison of results of different
operations and analysis of published data due to variable length of follow-up among studies. Analysis is
further complicated by significant attrition of patients over long-term follow-up in most studies. Despite
these challenges, meta-analyses, controlled trials, and uncontrolled case series provide estimates of the
efficacy of bariatric operations (Table 46-1). Weight loss is highest for biliopancreatic
diversion/duodenal switch, ranging from 55% to 75% EWL, followed by gastric bypass and sleeve
gastrectomy (50% to 70% EWL) and gastric band (40% to 60% EWL).
Table 46-1 Bariatric Surgery Long-Term Weight Loss Responses
Rates of improvement and remission of metabolic diseases parallel weight loss, with gastric bypass,
sleeve gastrectomy, and biliopancreatic diversion/duodenal switch associated with higher remission
rates than gastric band. Diabetes, steatosis, sleep apnea, hypertension, and hyperlipidemia
improvement/remission rates range from 60% to over 90% (Table 46-2). Weight loss is durable, lasting
decades in most patients, and accompanied by marked reductions in long-term incident diabetes,
cardiovascular disease, and cancer, increased quality of life, reduced long-term healthcare costs, and a
25% to 40% reduction in long-term mortality. Randomized controlled trials demonstrate that bariatric
surgery is substantially more efficacious than medical therapy for weight loss and diabetes, and multiple
medical societies, including the American Diabetes Association, the International Diabetes Federation,
and the American Heart Association, endorse bariatric surgery as treatment for metabolic disease.
1193
booksmedicos.org
Despite its efficacy, results of bariatric surgery are variable, with a substantial minority of patients
achieving significantly better than average weight loss and disease response rates, while a similar
minority experience suboptimal results. Anywhere from 10% to 30% of patients achieve <50% EWL,
which may be due to failure to lose weight initially, or weight regain after a period of adequate weight
loss. Mechanisms underlying such failures are poorly defined, and identification of accurate predictors
of response to surgery is an important area of research. While suboptimal results are often attributed to
lack of patient compliance with postoperative diet and exercise, these arguments ring false, echoing
similar arguments that attribute obesity itself to a lack of “willpower.” Instead, compelling evidence
implicates genetic and epigenetic mechanisms. Like obesity itself, responses to bariatric surgery are
highly hereditable. Ethnicity is a predictor of outcome, with Caucasians and Hispanics experiencing
greater weight loss than Blacks and Asians. Multiple single-nucleotide polymorphisms have been linked
to surgical outcome. Future research will identify clinical and genetic predictors of response and permit
optimization of allocation of surgical resources.
Perioperative Mortality and Morbidity
Morbidity and mortality associated with bariatric surgery have decreased over the past two decades as
surgeon experience increased and techniques evolved. Currently, gastric bypass and gastric band are
associated with mortality risks similar to hip replacement and laparoscopic cholecystectomy,
respectively. Perioperative mortality is highest for biliopancreatic diversion/duodenal switch, followed
by gastric bypass and sleeve gastrectomy, then gastric band (Table 46-3). Life-threatening perioperative
morbidity associated with gastric bypass and sleeve gastrectomy consists primarily of anastomotic
dehiscence, staple-line leaks, hemorrhage, thromboembolic events, and cardiac events. Life-threatening
perioperative morbidity associated with gastric band is rare and consists primarily of gastric
perforation, thromboembolic events, and cardiac events.
The most dire perioperative complication of gastric bypass is anastomotic dehiscence of the
gastrojejunostomy which usually occurs within 2 weeks of surgery. Incidences in most series range from
0.1% to 4%, although recent data suggest that anastomotic dehiscence rates are decreasing and high-
volume centers report rates in the range of 0.1% to 0.2%. Signs and symptoms are similar to those of
anastomotic dehiscence after any intestinal operation, but may be less apparent in the obese. Persistent
tachycardia and abdominal pain are important but nonspecific sentinel signs. Upper GI radiographs may
be of diagnostic utility but lack sensitivity. Abdominal CT scan, even within a few days of surgery, may
be useful, as the lack of a fluid collection near the gastrojejunostomy has a high negative predictive
value for leak, while contrast extravasation has a high positive predictive value. Nonetheless, data are
conflicting regarding the sensitivity and specificity of radiologic studies for diagnosing anastomotic
dehiscence, and laparoscopic reexploration should be employed aggressively in suspected cases.
Operative management consists of washout, wide drainage, judicious attempt at repair, and distal
enteral access, usually with a gastrostomy tube in the remnant stomach, although a jejunostomy tube in
the distal Roux limb or biliary limb is an option if access to the remnant stomach is difficult.
Anastomotic dehiscence can be managed laparoscopically in some cases, reducing the high risk of
ventral hernia associated with laparotomy. Most will heal if sepsis is controlled.
Staple-line leaks are an equally dire event after sleeve gastrectomy, occurring anywhere from 1–2
weeks to many months after surgery. Leaks may occur at any point along the staple line, but when
involving the thicker tissue of the antrum may be less prone to heal, and interval conversion to gastric
bypass with resection of the involved portion of gastric sleeve may be necessary. Proper stapler
selection and use during primary operation with avoidance of overly narrow sleeves (current consensus
recommends 32- to 40-Fr diameter) reduce the risk of sleeve gastrectomy staple-line leaks, which
currently occur with an incidence of approximately 1% to 3%. Gastric band is only rarely associated
with perioperative septic complications, most often in the form of gastric perforation, which occurs in
0% to 0.5% of cases. Perforation, if not recognized, may be life-threatening and is a primary cause of
rare perioperative mortality and major morbidity after gastric band.
Table 46-2 Bariatric Surgery Long-Term Comorbidity Responses
1194
booksmedicos.org
Table 46-3 Bariatric Surgery Perioperative Mortality and Morbidity
Perioperative hemorrhage after gastric bypass occurs with an incidence of 1% to 4%, often originates
from staple lines, and may be intraperitoneal or intraluminal. Intraluminal bleeding presents with
melena and is often self-limited, requiring only transfusion and observation. Infrequently, endoscopic or
operative intervention may be necessary. Hemorrhage after sleeve gastrectomy ranges from 1% to 4%,
is usually intraperitoneal from the gastric staple line, and may require operative intervention, although
observation in the hemodynamically stable patient is a reasonable initial course. Early small bowel
obstruction, and thromboembolic, pulmonary, and cardiac events comprise the majority of the
remainder of acute postoperative complications after bariatric surgery. Pathophysiology is not
substantially different than after nonbariatric GI operations, although the obese may be at higher risk,
reinforcing the importance of preoperative evaluation and preparation.
Late Morbidity
Late morbidity after bariatric surgery is similar to that associated with complex nonbariatric GI
operations, may occur months or years later, and often presents with abdominal pain. Gallbladder
disease and small bowel obstruction from adhesions and ventral/trocar hernias may occur after all
bariatric operations. Other complications are operation specific. While definitions vary, overall late
morbidity rates for gastric bypass range from 5% to 10%. Many late complications of gastric bypass
result from Roux-en-Y anatomy. Internal hernias occur in 0.5% to 9% of patients, and are categorized as
mesenteric (common to all Roux-en-Y reconstructions, in which bowel passes through the mesenteric
split in the Roux limb), mesocolic (specific to retrocolic reconstructions, in which bowel passes through
the mesocolic defect created for the Roux limb), and Petersen’s (more often associated with antecolic
than retrocolic reconstructions, in which bowel passes under the Roux limb and its mesentery) (Fig. 46-
7).26 Although closure of internal hernia defects at primary operation is straightforward and
recommended, long-term clinical follow-up data do not demonstrate that this practice reduces hernia
rates compared with series in which routine closure was not performed, possibly because of lack of scar
tissue formation at the sites of closure, and/or loss of mesenteric adipose tissue with weight loss leading
to late patency of previously closed defects. Patients often present years after surgery with a history of
severe episodic abdominal pain. Diagnosis may be challenging, as obstipation may be absent and
imaging normal even in the face of incarceration, especially if the biliopancreatic limb, which is out of
continuity with the alimentary stream, is involved. A low threshold for operative exploration must be
maintained in any patient with unrelenting abdominal pain after gastric bypass. Operative reduction and
closure of internal hernia defects can usually be performed via a laparoscopic approach.
1195
booksmedicos.org
Figure 46-7. Internal hernias. Internal hernias may occur after any Roux-en-Y reconstruction, and include mesenteric, Petersen’s,
and mesocolic hernias. Weight loss after gastric bypass and loss of adipose tissue in the intestinal mesentery may predispose to
internal herniation.
Gastrojejunal anastomotic ulcer occurs in 0.5% to 25% of patients after gastric bypass, with the
majority of series reporting incidences between 2% and 8%. Tobacco or NSAID use increases risk, but
ulcers may occur in the absence of these risk factors. Diagnosis by upper endoscopy is usually
straightforward. Upper GI radiography is advisable to rule out an associated gastrogastric fistula,
especially if an ulcer is recalcitrant to medical treatment or is associated with weight regain. Most
ulcers heal with high-dose antacid therapy, and once healed, most surgeons recommend maintenance
antacid therapy for life, although data supporting this practice are sparse. Rarely, ulcers recalcitrant to
medical therapy require resection with anastomotic revision. Large pouches are a risk factor for ulcers
due to retention of parietal cells in the distal gastric pouch that do not participate in negative inhibition
of gastrin secretion, thus rationalizing pouch resection and anastomosis revision as a treatment strategy.
Gastrogastric fistula occurs with an incidence of 0% to 2% and may be associated with ulcers.
Gastrogastric fistula incidence has decreased substantially since the advent of divided gastric bypass.
Gastrogastric fistula often results from incomplete division of the gastric pouch from the gastric
remnant at primary operation. Stenosis of the gastrojejunostomy typically presents with intolerance of
solid foods and vomiting within 1 to 3 months of surgery with a wide range of reported incidences from
<1% to >20%, but most commonly 3% to 7%. Stenosis is usually easily treated with endoscopic
dilation, although rare cases may require anastomotic revision. Retrograde intussusception at the
jejunojejunostomy is a rare cause of abdominal pain after gastric bypass with a reported incidence of
0.1%. Pathogenesis is likely related to motility disorders resulting from disruption of enteroenteric
nerves and divorce of the small intestine from duodenal pacemaker plexi with subsequent development
of aberrant ectopic pacemakers in the involved intestinal limbs. Diagnosis may be challenging and
imaging unreliable. Treatment consists of either plication/pexy of involved limbs or resection and
revision of the jejunojejunostomy, with the latter approach associated with lower rates of recurrence.
The clinical presentation and differential diagnosis of abdominal pain after gastric bypass is diverse
and diagnostic imaging may be unreliable. The clinician is not infrequently faced with a gastric bypass
patient who presents with persistent pain in the absence of a clear cause after thorough diagnostic
1196
booksmedicos.org
evaluation. Exploratory laparoscopy in such patients provides a diagnosis in up to 90% of cases. Even in
the absence of intraoperative findings other than patent internal hernia defects without incarceration,
closure of defects provides relief in the majority of patients. Less commonly, in the absence of a clear
cause, pain is presumed to result from atypical motility disorders associated with Roux-en-Y anatomy
and may be difficult to treat (Algorithm 46-1).
Late complications after gastric band are common, afflicting 10% to 50% of patients, may occur years
after primary operation, and include band slippage, band erosion, and development of GERD and
esophageal motility disorders. Treatment often requires band explant, with late explant rates of 30% to
50% in some series. While long-term data are evolving, late complications after sleeve gastrectomy
appear to be uncommon, with infrequent reports of sleeve stenosis (0.5% to 3%) and development of
GERD.
Bariatric operations alter absorption of macro- and micronutrients. Protein and lipid malabsorption,
steatorrhea, and protein wasting are rare after modern gastric bypass and virtually absent with gastric
band and sleeve gastrectomy, but afflict anywhere from 2% to 20% of patients after biliopancreatic
diversion/duodenal switch. The elimination of the pyloric emptying mechanism in gastric bypass is
associated with dumping and hypoglycemic syndromes, the underlying mechanisms of which are not
well understood. Early dumping occurs within 10 to 30 minutes of a meal, and is thought to result from
intraluminal fluid shifts and acute intravascular volume depletion secondary to rapid emptying of
hyperosmolar gastric contents into the small intestine. Early dumping is associated with tachycardia and
diaphoresis. Aberrations in gut hormone secretion, including elevated secretion of vasoactive intestinal
polypeptide, enteroglucagon, pancreatic polypeptide, and GLP-1, have been associated with a
predisposition to early dumping. Late dumping occurs hours after a meal and is thought to be due to
hypersecretion of insulin with subsequent reactive hypoglycemia; excess secretion of GLP-1 has also
been implicated. Dumping and hypoglycemia typically respond to a low-carbohydrate diet and
preprandial acarbose therapy. In cases recalcitrant to these measures, pharmacotherapy with agents that
reduce insulin secretion, including octreotide, diazoxide, and calcium channel blockers, may be of
benefit. Surgical banding of the gastric pouch to delay emptying has been employed with variable
efficacy.
Micronutrient deficiencies are underreported after bariatric surgery. The reported prevalences of
deficiencies of virtually all micronutrients after surgery span a broad range from 10% to >80% for
biliopancreatic diversion/duodenal switch and gastric bypass. Deficiencies are less common after sleeve
gastrectomy and gastric band. An understanding of the anatomic sites and mechanisms of micronutrient
absorption affected by gastric bypass foregut diversion guides diagnosis and management. Anemia,
neurologic, dermatologic, and GI symptoms are common clinical manifestations of many micronutrient
deficiencies (Table 46-4). Acute deficiencies may involve dramatic presentations (e.g., thiamine
deficiency and Wernicke encephalopathy). Chronic occult micronutrient deficiencies are associated with
increased risk of chronic disease. Chronic magnesium deficiency, for example, is associated with an
increased risk of type II diabetes. Chronic selenium deficiency has been associated with an increased
risk of cancer and cardiovascular disease. The most common deficiencies associated with gastric bypass
involve calcium, vitamin D, folate, iron, and B12. Vomiting due to stenosis or gastroenteritis increases
the risks of severe micronutrient deficiencies, and nutritional status should be monitored carefully in
any bariatric surgery patient with significant vomiting. It is important to note that obesity is associated
with multiple micronutrient deficiencies independent of bariatric surgery, which should be identified
and corrected in the preoperative period, and which may resurface in the postoperative period.
Patient Selection, Choice of Operation, Preoperative Preparation
Current criteria for candidacy for bariatric surgery are based on a 1991 NIH consensus conference, and
include BMI ≥40, or BMI ≥35 with at least one serious comorbidity of obesity. While widely used,
these criteria are based on expert opinion rather than definitive epidemiologic data, and were
established over two decades ago. Recent data suggest that bariatric surgery provides benefits to
diabetic patients with BMI 30 to 34.9.27 While consensus is evolving, the American Society for
Metabolic and Bariatric Surgery (ASMBS) had issued a statement in support of bariatric surgery in this
low BMI patient population, and the FDA, as the regulatory body that authorizes device use, approved
gastric band for this subgroup in 2011. As data accrue, candidacy criteria will expand. Good outcomes
have been reported in carefully selected patients with organ transplants, end-stage renal disease,
compensated cirrhosis, HIV, and adolescents. Active uncontrolled cardiac, pulmonary, or psychiatric
disease and uncompensated liver disease are generally considered absolute contraindications.
1197
booksmedicos.org
Algorithm 41-6. Algorithm for management of abdominal pain months or years after Roux-en-Y reconstruction.
The choice of bariatric operation is a complex decision. Gastric bypass is considered the gold-standard
operation by many, although sleeve gastrectomy may soon supplant gastric bypass in this regard. The
high failure rate of gastric band has led some to argue that it should be eliminated from the repertoire,
although this is debated. While highly individualized, clinical considerations guide choice of operation.
Gastric bypass is highly effective in ameliorating GERD; sleeve gastrectomy and gastric band, in
contrast, may exacerbate GERD. Gastric bypass may provide theoretical advantages in the treatment of
diabetes (discussed below), but sleeve gastrectomy and to a lesser extent gastric band are also highly
efficacious in this regard. Gastric bypass is associated with increased intestinal oxalate absorption and
hyperoxaluria, and sleeve gastrectomy or gastric band should therefore be considered in patients with a
history of oxalate nephrolithiasis. Patients with severe gastroparesis may benefit from gastric bypass
rather than sleeve gastrectomy or gastric band, although data in this subgroup are sparse, and gastric
bypass itself may rarely lead to gastroparesis. Gastric band should be avoided in patients with dysphagia
or esophageal motility disorders. Sleeve gastrectomy and gastric band avoid the need for manipulation
of the small intestine and thus may be good choices in patients with complex abdominal surgical
histories. Despite its high late morbidity and long-term failure rates, gastric band remains an option for
risk-averse patients who are unaccepting of the relatively higher risk of perioperative morbidity and
mortality associated with gastric bypass and sleeve gastrectomy.
Preoperative preparation includes thorough medical, psychological, and dietary evaluations. Patients
should undergo age-appropriate cancer screening, and treatment for active medical issues should be
optimized. Sleep apnea testing should be performed in most if not all patients, as the prevalence of
sleep apnea in the obese population may exceed 70%, and appropriate treatment with continuous
positive airway pressure (CPAP) should be instituted prior to surgery and continued through the
perioperative period. Diabetes should be well controlled; while data do not support a specific value, a
preoperative HbA1c <8 is a common target. Some degree of preoperative surgeon–supervised diet-
induced weight loss should be achieved in most patients, as data suggest that this practice reduces
hepatic steatosis, may reduce perioperative complications, and may be associated with improved long-
term outcomes. Preoperative testing and treatment for Helicobacter pylori is recommended, although
data suggesting that this practice decreases postoperative anastomotic ulcer risk is equivocal.
1198
booksmedicos.org
Operative Considerations
A thorough discussion of the technical aspects of bariatric surgery is beyond the scope of this chapter,
but a few important issues warrant mention. Obesity is a risk factor for DVT, and aggressive DVT
prophylaxis should be employed. Optimal prophylaxis agents and regimens have not been determined,
but unfractionated or low–molecular-weight heparin during operation and continued through the
hospitalization period is typical. Subtherapeutic dosing of these agents is common in the obese, and the
American College of Chest Physicians recommends weight-based dosing.
Table 46-4 Select Micronutrient Deficiencies Associated with Bariatric Surgery
Hand-sewn, linear stapler, and circular stapler techniques are used to create the gastrojejunostomy in
gastric bypass. No single technique demonstrates a clear advantage, although stenosis rates may be
higher with the circular stapler technique. Absorbable suture should be used for all anastomoses, as
1199
booksmedicos.org
nonabsorbable suture is a nidus for ulcer formation. Routine intraoperative testing of the gastrojejunal
anastomosis with EGD-air insufflation or methylene blue instillation may be associated with reduced
anastomotic dehiscence rates and is advisable. The use of drains at the gastrojejunal anastomosis is
practiced selectively, and no clear data demonstrate that routine drain placement aids in early detection
or reduced morbidity of anastomotic dehiscence. Some data suggest that drains may allow for
nonoperative management of such events. Routine closure of internal hernia defects during gastric
bypass is controversial, as data do not clearly demonstrate that this practice reduces late hernia
incidence. Nonetheless, closure is straightforward, entails low morbidity, and is therefore
recommended. Risk–benefit analyses do not support prophylactic cholecystectomy during laparoscopic
bariatric surgery in the absence of cholelithiasis, or in the presence of asymptomatic cholelithiasis. It is
therefore reasonable to manage cholelithiasis in bariatric surgery patients as in all patients, that is,
perform cholecystectomy only if symptoms are present.
As with any laparoscopic operation, conversion to laparotomy is a reasonable option if laparoscopy
presents insurmountable technical challenges. That said, bariatric surgeons are well aware that “open”
bariatric surgery is not “easier” than laparoscopic surgery, but simply presents qualitatively different
technical challenges. Often, hepatomegaly is a major obstacle. Left hepatic lobe size should be assessed
at the beginning of every operation, and if adequate liver retraction is not possible, consideration
should be given to aborting the planned procedure, especially if significant steatosis is present that
might be mitigated by further preoperative diet-induced weight loss.
Perioperative and Postoperative Management

Perioperative care of the bariatric surgery patient is similar to that of any patient undergoing complex
GI surgery but must be tailored to the obese. Inpatient, outpatient, and operating room facilities should
be equipped with beds, chairs, lifting and transfer apparatuses, and other equipment capable of bearing
the weight of obese patients. Anesthesia, nursing, dietician, physical therapy, and other subspecialty
staff with experience in the management of obese patients are necessary. Hospital stays after
laparoscopic gastric bypass and sleeve gastrectomy are typically 1 to 3 days, while gastric band is
generally performed on an outpatient basis.
The dietary regimen in the first few weeks after surgery is designed to prevent food impaction at an
edematous surgical site and maintain adequate hydration, and includes clear liquids progressing to soft
foods. Caloric intake in the early postoperative period may be less than 500 cal/day, which is
acceptable as long as hydration is maintained. Within 2 to 3 weeks of surgery, solid foods may be
introduced and caloric intake will slowly rise, with a long-term maintenance target of 1,200 to 1,500
calories and 50 to 70 g of protein per day. Within a few months of surgery, most patients are able to eat
any foods in small quantities with few exceptions. Deviation from this pattern should raise concerns for
anastomotic stenosis, ulcer, or other complications. Persistent vomiting, unless clearly associated with a
specific food that when eliminated ameliorates symptoms, is abnormal and should prompt a diagnostic
workup, usually with UGI and/or EGD.
The incidence of cholelithiasis after bariatric surgery ranges from 15% to over 70%, but only
approximately 7% of patients will require cholecystectomy. Prophylactic treatment with
ursodeoxycholic acid reduces the risk of postoperative cholelithiasis, from 28% to 9% in one recent
meta-analysis. Such therapy entails little morbidity and a 6-month postoperative treatment regimen is
common practice. Data are equivocal, however, regarding whether this practice reduces
cholecystectomy rates or is cost-effective.
The variability in surveillance practices makes accurate estimation of the incidence of postoperative
nutritional deficiencies challenging, and a wide range of supplementation practices exist. Interpretation
of the data is made more difficult because obese patients are at high risk for pre-existing micronutrient
deficiencies independent of surgery. Vitamin D and zinc deficiencies, for example, afflict over 50% and
30% of obese patients, respectively. Abnormal serum levels of micronutrients after surgery are
common, ranging from 10% to >80% depending on the micronutrient, operation, and patient
population studied; clinically symptomatic deficiencies are less common. Consensus guidelines from the
American Association of Clinical Endocrinologists, the Obesity Society, and the ASMBS recommend that
gastric bypass patients undergo annual surveillance of 25-hydroxyvitamin D, calcium, iron, and B12
levels, along with a complete blood count, electrolyte and lipid panels, and liver function tests and
periodic bone scans, and receive lifelong daily multivitamin (including folate), calcium citrate, vitamin
D, and vitamin B12 supplementation, with iron supplementation in menstruating women.28 Sleeve
gastrectomy patients likely have a lower risk of nutritional deficiencies, but similar regimens are
1200
booksmedicos.org
recommended. Gastric band patients receive a daily multivitamin, calcium, and vitamin D
supplementation.
Clinical follow-up after bariatric surgery should be lifelong. Primary care providers play a critical role
in preoperative and postoperative care. Endocrinology expertise may be required, especially in the early
postoperative period when diabetes may resolve rapidly. A medical bariatrician subspecialty is evolving
to care for this expanding patient population.
Physiologic Mechanisms Underlying Bariatric Surgery Efficacy
Restriction of caloric intake and nutrient malabsorption are the classic presumed mechanisms of
bariatric operations. These mechanisms are important, but their relationship to outcome is complex and
nonlinear. For example, data are conflicting regarding the correlation between gastric bypass pouch size
and weight loss. In general, pouch volumes <50 cc are associated with good results with little evidence
that smaller pouches achieve greater weight loss, while efficacy may decrease substantially as pouch
sizes increase beyond 50 cc. Similarly, common channel length teeters on a less well-defined threshold,
above which weight loss is poor and below which malnutrition results. Other features of restriction are
counterintuitive: more rapid gastric pouch emptying on oral contrast studies is associated with greater
weight loss after gastric bypass while sleeve gastrectomy is associated with increased gastric emptying
rates compared to native anatomy. These observations suggest a complex relationship between weight
regulation, metabolism, and gut anatomy and motility.
7 Complex mechanisms in addition to restriction and malabsorption contribute to weight loss and
improved metabolism after surgery, with qualitatively different responses than those associated with
diet-induced weight loss. Satiety is increased, hunger decreased, and metabolic rate increased after
bariatric surgery, the opposite of responses observed with diet-induced weight loss. Bariatric surgery
somehow “sidesteps” the normal compensatory responses that act to defend body weight with
nonsurgical weight loss. The mechanisms underlying these counterintuitive responses are not well
established. Among putative mechanisms are changes in gut hormone secretion secondary to altered
intestinal anatomy. Decades ago, it was observed that an oral glucose load elicits a greater insulin
response than an intravenous glucose load, leading to postulation of the existence of incretins, gut
hormones secreted in response to a meal that regulate systemic glucose metabolism. Subsequent
research led to the discovery of GIP and GLP-1, incretins secreted by duodenal K cells and ileal L cells,
respectively, in response to nutrient delivery to the small intestine. Incretins have diverse effects on
glucose homeostasis, potentiating central insulin secretion and peripheral insulin sensitivity. Alterations
in incretin hormone secretion secondary to gut anatomic derangements were invoked to explain the
observation that diabetes often improved within days of gastric bypass, well before substantial weight
loss.
The foregut and hindgut hypotheses have been proposed to explain this phenomenon: bypass of the
alimentary stream from the stomach, duodenum, and proximal jejunum (the foregut hypothesis), and
increased caloric delivery to the distal jejunum and ileum (the hindgut hypothesis) alter secretion of gut
hormones with improvement in glucose homeostasis. While data are less compelling for GIP and other
putative foregut hormones, evidence supports the hindgut hypothesis, including data demonstrating
increased serum GLP-1 levels after gastric bypass. While debate persists regarding the magnitude of
these effects on diabetes remission after gastric bypass, an understanding of incretin physiology has led
to the development of GLP-1 agonists as pharmacologic therapy for diabetes independent of bariatric
surgery.
Gut anatomic derangements mediate additional metabolic changes. Gastric bypass and sleeve
gastrectomy reduce secretion of the orexigenic hormone ghrelin from the gastric fundus, which may
reduce hunger after surgery. Gastric bypass and sleeve gastrectomy are associated with increased
secretion of peptide YY and oxyntomodulin, gut hormones secreted by L cells in parallel with GLP-1 in
response to a meal that induce satiety and inhibit gut motility and are central mediators of the “ileal
brake” mechanism. Roux-en-Y anatomy alters bile acid metabolism, increasing serum levels of
conjugated bile acids with beneficial effects on glucose and lipid metabolism. Bariatric surgery disrupts
vagal and enteroenteric innervations of the gut and alters CNS satiety responses. Finally, gastric bypass
is associated with alterations in gut microbiota that contribute to weight loss and resolution of
metabolic disease. The precise mechanisms by which these diverse effects contribute to weight loss and
metabolic disease remission remain unclear.
Mechanisms other than restriction and malabsorption underlie the systemic effects of bariatric
surgery. An emerging field of metabolic surgery is exploring operations designed to mimic the metabolic
effects of gastric bypass (e.g., ileal transposition, foregut exclusion) in animals and lean diabetic humans
1201
booksmedicos.org
with promising results. Also in development are endoscopic and laparoscopic gastric plications,
intragastric balloon placement, vagal nerve blockade, gastric simulators, and impermeable intraluminal
duodenal and jejunal stents designed to prevent caloric absorption. Bariatric surgery in the 21st century
will evolve to include a broad array of procedures applied to a diverse patient population as these
efforts mature.
References
1. Henderson RM. The bigger the healthier: are the limits of BMI risk changing over time? Econ Hum
Biol 2005;3(3):339–366.
2. Chen SE, Florax RJ. Zoning for health: the obesity epidemic and opportunities for local policy
intervention. J Nutr 2010;140(6):1181–1184.
3. Berrington de Gonzalez A, Hartge P, Cerhan JR, et al. Body-mass index and mortality among 1.46
million white adults. N Engl J Med 2010;363:2211–2219.
4. Oreopoulos A, Padwal R, Kalantar-Zadeh K, et al. Body mass index and mortality in heart failure: a
meta-analysis. Am Heart J 2008;156(1):13–22.
5. Ashwell M, Gunn P, Gibson S. Waist-to-height ratio is a better screening tool than waist
circumference and BMI for adult cardiometabolic risk factors: systematic review and meta-analysis.
Obes Rev 2012;13(3):275–286.
6. Lewis CE, McTigue KM, Burke LE, et al. Mortality, health outcomes, and body mass index in the
overweight range: a science advisory from the American Heart Association. Circulation
2009;119(25):3263–3271.
7. Odgen CL, Carroll MD, Kit BK, et al. Prevalence of Obesity in the United States, 2009–2010 NCHS Data
Brief, No 82. Hyattsville, MD: National Center for Health Statistics; 2012.
8. Peeters A, Barendregt JJ, Willekens F, et al. Netherlands Epidemiology and Demography
Compression of Morbidity Research Group. Obesity in adulthood and its consequences for life
expectancy: a life-table analysis. Ann Intern Med 2003;138(1):24–32.
9. Fontaine KR, Redden DT, Wang C, et al. Years of life lost due to obesity. JAMA 2003;289(2):187–
193.
10. Li C, Ford ES, Zhao G, et al. Prevalence of self-reported clinically diagnosed sleep apnea according
to obesity status in men and women: National Health and Nutrition Examination Survey, 2005–
2006. Prev Med 2010;51(1):18–23.
11. Lopez PP, Stefan B, Schulman CI, et al. Prevalence of sleep apnea in morbidly obese patients who
presented for weight loss surgery evaluation: more evidence for routine screening for obstructive
sleep apnea before weight loss surgery. Am Surg 2008;74(9):834–838.
12. Samaha FF, Iqbal N, Seshadri P, et al. A low-carbohydrate as compared with a low-fat diet in severe
obesity. N Engl J Med 2003;348:2074–2081.
13. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with
lifestyle intervention or metformin. N Engl J Med 2002;346(6):393–403.
14. Wadden TA, Bantle JP, Blackburn G, et al. Eight-year weight losses with an intensive lifestyle
intervention: the look AHEAD study. Obesity (Silver Spring) 2014;22(1):5–13.
15. Cho YM, Wideman RD, Kieffer TJ. Clinical application of glucagon-like peptide 1 receptor agonists
for the treatment of type 2 diabetes mellitus. Endocrinol Metab (Seoul) 2013;28(4):262–274.
16. Ozcan L, Ergin AS, Lu A, et al. Endoplasmic reticulum stress plays a central role in development of
leptin resistance. Cell Metab 2009;9(1):35–51.
17. Trevaskis JL, Coffey T, Cole R, et al. Amylin-mediated restoration of leptin responsiveness in diet-
induced obesity: magnitude and mechanisms. Endocrinology 2008;149:5679–5687.
18. Torgerson JS, Hauptman J, Boldrin MN, et al. XENical in the prevention of diabetes in obese
subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the
prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27(1):155–161.
19. Smith SR, Weissman NJ, Anderson CM, et al. Behavioral Modification and Lorcaserin for
Overweight and Obesity Management (BLOOM) Study Group. Multicenter, placebo-controlled trial
of lorcaserin for weight management. N Engl J Med 2010;363(3):245–256.
20. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with
1202
booksmedicos.org
controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a
randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95(2):297–308.
21. Payne JH, DeWind LT. Surgical treatment of obesity. Am J Surg 1969; 118:141–147.
22. Sudan R, Jacobs DO. Biliopancreatic diversion with duodenal switch. Surg Clin North Am
2011;91(6):1281–1293.
23. Arapis K, Chosidow D, Lehmann M, et al. Long-term results of adjustable gastric banding in a
cohort of 186 super-obese patients with a BMI≥ 50 kg/m2. J Visc Surg 2012;149(2):e143–e152.
24. Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg 2013;23(4):427–
436.
25. Sjöström L, Narbro K, Sjöström CD, et al. Swedish Obese Subjects Study. Effects of bariatric surgery
on mortality in Swedish obese subjects. N Engl J Med 2007;357(8):741–752.
26. O’Rourke RW. Management strategies for internal hernia after gastric bypass. J Gastrointest Surg
2011;15(6):1049–1054.
27. Maggard-Gibbons M, Maglione M, Livhits M, et al. Bariatric surgery for weight loss and glycemic
control in nonmorbidly obese adults with diabetes: a systematic review. JAMA 2013;309(21):2250–
2261.
28. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists,
the Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for
clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the
bariatric surgery patient. Obesity 2009;17(supp 1):S1–S70.
29. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-
analysis. JAMA 2004;292(14):1724–1737.
30. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann
Intern Med 2005;142(7):547–559.
31. O’Brien PE, McPhail T, Chaston TB, et al. Systematic review of medium-term weight loss after
bariatric operations. Obes Surg 2006;16(8):1032–1040.
32. Garb J, Welch G, Zagarins S, et al. Bariatric surgery for the treatment of morbid obesity: a meta-
analysis of weight loss outcomes for laparoscopic adjustable gastric banding and laparoscopic
gastric bypass. Obes Surg 2009;19(10):1447–1455.
33. Padwal R, Klarenbach S, Wiebe N, et al. Bariatric surgery: a systematic review of the clinical and
economic evidence. J Gen Intern Med 2011; 26(10):1183–1194.
34. Chang SH, Stoll CR, Song J, et al. The effectiveness and risks of bariatric surgery: an updated
systematic review and meta-analysis, 2003–2012. JAMA Surg 2013;149(3):275–287.
35. Yip S, Plank LD, Murphy R. Gastric bypass and sleeve gastrectomy for type 2 diabetes: a systematic
review and meta-analysis of outcomes. Obes Surg 2013;23:1994–2003.
36. Lynch J, Belgaumkar A. Bariatric surgery is effective and safe in patients over 55: a systematic
review and meta-analysis. Obes Surg 2012;22(9):1507–1516.
37. Trastulli S, Desiderio J, Guarino S, et al. Laparoscopic sleeve gastrectomy compared with other
bariatric surgical procedures: a systematic review of randomized trials. Surg Obes Relat Dis
2013;9(5):816–829.
38. Banka G, Woodard G, Hernandez-Boussard T, et al. Laparoscopic vs. open gastric bypass surgery:
differences in patient demographics, safety, and outcomes. Arch Surg 2012;147(6):550–556.
39. Finks JF, Kole KL, Yenumula PR, et al. Michigan Bariatric Surgery Collaborative, from the Center
for Healthcare Outcomes and Policy. Predicting risk for serious complications with bariatric
surgery: results from the Michigan Bariatric Surgery Collaborative. Ann Surg 2011;254(4):633–640.
40. Carlin AM, Zeni TM, English WJ, et al. Michigan Bariatric Surgery Collaborative. The comparative
effectiveness of sleeve gastrectomy, gastric bypass, and adjustable gastric banding procedures for
the treatment of morbid obesity. Ann Surg 2013;257(5):791–797.
41. Courcoulas AP, Christian NJ, Belle SH, et al. Longitudinal Assessment of Bariatric Surgery (LABS)
Consortium. Weight change and health outcomes at 3 years after bariatric surgery among
individuals with severe obesity. JAMA 2013;310(22):2416–2425.
42. Flum DR, Belle SH, King WC, et al. Longitudinal Assessment of Bariatric Surgery (LABS)
Consortium. Perioperative safety in the longitudinal assessment of bariatric surgery. N Engl J Med
2009;361(5):445–454.
1203
booksmedicos.org
Chapter 47
Gastric Neoplasms
Hari Nathan and Rebecca M. Minter
Key Points
1 The presence of a gastric adenomatous polyp is a marker of increased risk for the development of
cancer in the remaining gastric mucosa, and therefore these patients should be enrolled in an
appropriate endoscopic surveillance program.
2 Helicobacter pylori infection is the predominant risk factor for gastric carcinogenesis. However,
additional cofactors also play an important role and likely drive the progression from a premalignant
condition to adenocarcinoma in most individuals.
3 The symptoms produced by gastric cancer are not specific and can mimic those associated with a
number of nonneoplastic gastroduodenal diseases, especially benign gastric ulcer.
4 The extent of gastric resection is determined by the need to obtain a resection margin free of
microscopic disease, and examination of a minimum of 15 nodes is suggested for adequate staging.
5 Multimodality treatment should be the standard of care for treating locally advanced resectable
gastric cancer.
6 Low-grade gastric MALT lymphomas are usually effectively treated with eradication of H. pylori
infection alone.
7 Almost all (95%) gastrointestinal stromal tumors (GISTs) express the KIT antigen, and this is an
important molecular target for medical therapy.
Gastric cancer is a relatively common, frequently lethal affliction and remains a serious and unsolved
problem in general surgery. The disease often is not recognized until it is at an advanced stage. Gastric
cancer usually cannot be controlled by surgery alone, and surgical cure rates have remained
disappointingly low. Increasingly, a multidisciplinary approach is being applied to these difficult
neoplasms, with some modest improvements in outcome finally being observed. Technical innovations
and basic scientific investigations continue to be applied to this disease, and cautious optimism for the
future is appropriate.
ADENOCARCINOMA
Epidemiology
Starting in 1930, the incidence of gastric cancer declined dramatically in the United States. By 1990, the
incidence of gastric cancer (10 cases per 100,000 population) was approximately one-fourth the
incidence recorded in 1930.1 By 2010, gastric cancer accounted for 2% of cancer deaths in the United
States, compared with 20% to 30% in the 1930s.1 Nevertheless, more than 22,000 new cases continue to
be diagnosed annually in the United States, with over 10,000 deaths per year attributable to the disease.
Worldwide, its impact is much larger, and gastric cancer remains the third leading cause of cancer death
among men and the fifth leading cause among women, accounting for 10% of cancer deaths overall.2 It
has long been thought that environmental exposures play a role in gastric carcinogenesis, a notion that
is supported by the finding that groups who migrate from regions with high prevalence of gastric cancer
to those with low prevalence experience a decreasing incidence of gastric cancer with time.3,4 It has
been theorized that dietary changes and reductions in smoking have contributed to decrease in gastric
cancer incidence in some parts of the world.2 Food preservation methods using large amounts of salt
and nitrites have been partially supplanted by improved refrigeration, and fresh fruits and vegetables
have become more widely available. The strongest known risk factor for gastric cancer, however, is
infection with Helicobacter pylori, which is associated with a six-fold increased risk of (noncardia) gastric
cancer.5,6 Approximately 75% of gastric cancer cases are attributable to H. pylori infection, making this
1204
booksmedicos.org
organism the dominant infectious cause of cancer in the world.7
Due at least in part to these environmental factors, there is marked worldwide geographic variability
in the incidence of gastric cancer (Fig. 47-1).8 The highest incidence occurs in Eastern Asia, but Central
and Eastern Europe and South America also have high incidence of gastric cancer. The lowest incidence
of gastric cancer is seen in Africa and North America.2 In the United States, higher gastric cancer
incidence and mortality are seen in black, Asian American/Pacific Islander, American Indian/Alaska
Native, and Hispanic patients as compared with non-Hispanic white patients.1 The anatomic distribution
of gastric cancers also varies, with proximal cancers occurring more commonly in relatively younger,
white, and male patients.9
Premalignant Lesions
The risk for development of gastric cancer is greater in stomachs that harbor polyps. This risk is related
most closely to polyp histologic type, size, and number. Variations in these three factors account for the
wide range in reported risk associated with gastric polyps. In terms of malignant potential, gastric
polyps can be divided into two broad categories—hyperplastic polyps and adenomatous polyps.
Although not premalignant, hyperplastic polyps are discussed here because they are common,
occurring in up to 1% of the general population and accounting for 75% of all gastric polyps. The
hyperplastic polyp contains an overgrowth of histologically normal-appearing gastric epithelium. Atypia
is rare, and hyperplastic gastric polyps have no neoplastic potential. Hyperplastic polyps are generally
asymptomatic. Dyspepsia and vague epigastric discomfort are the most common complaints, although
coexistent gastroduodenal disease is also frequently identified. Complications are unusual, and
gastrointestinal hemorrhage occurs in less than 20% of patients. When hyperplastic polyps are
discovered, endoscopic removal for histologic examination is indicated and is sufficient treatment.
Subsequent surveillance is not necessary, given the lack of neoplastic potential in these polyps.
Figure 47-1. Worldwide geographic variability in gastric cancer incidence. (From Ferlay J, Soerjomataram I, Ervik M, et al.
GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International
Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on August 1, 2015.)
1 Adenomatous polyps also tend to be asymptomatic, but in contrast to hyperplastic polyps,

adenomatous polyps carry a distinct risk for the development of malignancy.10 Mucosal atypia is
frequent, and mitotic figures are more common than in hyperplastic polyps. Dysplasia and carcinoma in
situ have developed in adenomatous polyps observed over time. The risk for the development of
carcinoma has been estimated at 10% to 20% and is greatest for polyps more than 2 cm in diameter.
The presence of multiple adenomatous polyps increases the risk of cancer. The presence of an
adenomatous polyp is also a marker indicating a diffusely increased risk for the development of cancer
in the remainder of the gastric mucosa.
Endoscopic removal is indicated for pedunculated lesions and is sufficient if the polyp is completely
removed and shows no evidence of invasive cancer on histologic examination. Operative excision is
recommended for sessile lesions larger than 2 cm, for polyps with biopsy-proved invasive carcinoma,
and for polyps complicated by pain or bleeding. After removal, repeat endoscopic surveillance is
indicated to rule out recurrence at the site of previous excision, evaluate for new or missed polyps or an
early carcinoma, and confirm eradication of H. pylori, if applicable.
Gastritis
1205
booksmedicos.org
The incidence of both gastric cancer and atrophic gastritis increases with age. Chronic gastritis is
frequently associated with intestinal metaplasia and mucosal dysplasia, and these histologic features are
often observed in mucosa adjacent to gastric cancer. Gastritis is frequently progressive and severe in the
gastric mucosa of patients with cancer.
Gastric malignancy seems to be increased in patients with chronic gastritis associated with pernicious
anemia, although the risk appears to have been overstated in the past. This disease, characterized by
fundic mucosal atrophy, loss of parietal and chief cells, hypochlorhydria, and hypergastrinemia, is
present in 3% of people older than 60 years. For people in whom pernicious anemia has been active for
more than 5 years, the risk of gastric cancer is twice that of age-matched control subjects. Patients with
pernicious anemia also have an increased risk of gastric carcinoid development. This increased risk
warrants aggressive investigation of new symptoms in patients with long-standing pernicious anemia,
but it is not high enough to justify repeated endoscopic surveillance.
Intestinal metaplasia, the presence of intestinal glands within the gastric mucosa, is also commonly
associated with both gastritis and gastric cancer. The evolution from metaplasia to dysplasia to
carcinoma to invasive cancer has been demonstrated in other organs and in adenocarcinoma arising in
the gastroesophageal junction. However, no direct evidence has been provided for this progression in
gastric cancer.
Helicobacter Pylori
2 As outlined above, infection with H. pylori has been unequivocally associated with chronic
inflammatory conditions in the stomach, and this association has stimulated interest in the role of
chronic infection by this organism in gastric carcinogenesis. Childhood acquisition of H. pylori infection
is frequent in areas of high gastric cancer incidence, and high rates of infection have been identified in
patients with premalignant lesions and invasive cancer. Infection with H. pylori is associated with an
increased risk of adenocarcinoma of both major histologic types (intestinal and diffuse) and of both the
body and the antrum of the stomach.11 In contrast, H. pylori infection is not a risk factor for cancers of
the gastroesophageal junction, which are frequently associated with mucosal abnormalities of Barrett
esophagus and which seem to follow the metaplasia to dysplasia to carcinoma pattern of development.
The mechanism of carcinogenesis related to H. pylori infection is incompletely understood but is
thought to be related to the chronic inflammation caused by the organism.12 However, only ∼1% of
patients chronically infected with H. pylori will develop the gastric cancer phenotype, which consists of
corpus-predominant gastritis, multifocal atrophic gastritis, high gastrin levels, hypo/achlorhydria, and
low pepsinogen I/II ratio. The majority of subjects infected with H. pylori will develop the simple
gastritis phenotype which is not associated with any significant clinical outcome, or the duodenal ulcer
phenotype (10% to 15% of infected subjects) which consists of antral-predominant gastritis and high
gastrin and acid secretion and actually provides protection from developing gastric cancer.13 Of note,
there is variable distribution of these three phenotypes geographically, with particular prevalence of the
gastric cancer phenotype in certain parts of Asia where gastric cancer is common.14 Bacterial virulence
factors, environmental exposures, and host genetic factors also clearly play an important role in the
pathogenesis of gastric carcinogenesis following infection-related gastritis.12,13,15 Eradication of H. pylori
may not prevent the development of gastric cancer once premalignant lesions have already developed.16
Previous Gastric Surgery

A number of uncontrolled reports have suggested that gastric cancer is more likely to develop in people
who have undergone previous partial gastrectomy, with patients who have undergone a gastrojejunal
(Billroth II) anastomosis at apparently higher risk for carcinogenesis than those reconstructed with a
gastroduodenal anastomosis (Billroth I).17,18 The so-called gastric remnant cancer is a true clinical entity,
although the risk for development of this gastric neoplasm appears to have been overestimated. Several
large, prospective studies with long-term follow-up indicate that the relative risk is not increased for up
to 15 years after gastric resection, likely due to surgical removal of mucosa at risk for development of
gastric cancer, followed by modest increases in cancer risk (three times the control value) observed only
after 25 years.19–22
The cellular mechanisms that contribute to the development of neoplasia in the remnant stomach are
unknown. Decreased luminal pH, bacterial overgrowth with increased production of N-nitroso
carcinogens, and reflux of bile acids into the stomach have been postulated to promote cancer
development, but remains unproved. Vagotomy, often performed in conjunction with gastric surgery for
benign disease, does not appear to promote cancer development. A population-based study from Sweden
1206
booksmedicos.org
of 7,198 vagotomized patients followed for up to 18 years did not report increased risk.20
A recent study explored genetic alterations in gastric remnant cancer and found that the microsatellite
instability high (MSI-H) phenotype was much more common (43%) in gastric remnant cancers than in
sporadic gastric cancers (6%), and that this incidence was much higher in patients who had undergone a
Billroth II anastomosis (67%) as compared to those who had undergone a Billroth I anastomosis (11%).
The MSI-H phenotype in these tumors was associated with inactivation of the DNA mismatch repair
genes hMLH1 and hMSH2. The significance of this relationship is not yet clear.23 Reported 5-year
survival ranges from only 7% to 33% for gastric remnant cancers, but this poor prognosis is most likely
due to the fact that these cancers are usually diagnosed at an advanced stage when treatment options
are limited.
Hereditary Syndromes
Approximately 5% to 10% of gastric cancer may have a familial component, and 3% to 5% are
associated with known inherited cancer syndromes. Hereditary diffuse gastric cancer (HDGC) is an
autosomal dominant syndrome that confers a lifetime risk for the development of gastric cancer by age
80 years of 67% for men and 83% for women.24 The average age at diagnosis is 37 years, and cancers
tend to be of the diffuse type. Germline mutations in CDH1, a tumor suppressor gene that encodes the
cell-to-cell adhesion protein E-cadherin, are found in 25% of patients with HDGC.25 Patients with
documented CDH1 mutations and a family history of gastric cancer may be offered prophylactic
gastrectomy at a young age. Other familial cancer syndromes associated with an increased risk of
gastric cancer include Lynch syndrome, juvenile polyposis syndrome, and Peutz–Jeghers syndrome.
Surveillance upper endoscopy may be considered in patients with these syndromes.
Clinical Features
3 The symptoms produced by gastric cancer are nonspecific and can closely mimic those associated with
a number of nonneoplastic gastroduodenal diseases, especially benign gastric ulcer (Fig. 47-2). In early
gastric cancers, epigastric pain is present in over 70% of patients.26 The pain is often constant,
nonradiating, and unrelieved by food ingestion. In a surprising number of patients, pain can be relieved,
at least temporarily, by antacids or gastric antisecretory drugs. Anorexia, nausea, and weight loss are
present in less than 50% of patients with early gastric cancers but become increasingly common with
disease progression. Dysphagia is present in 20% of patients with proximal gastric lesions. Overt
gastrointestinal hemorrhage is present in only 5%. Perforation is uncommon (1%).
Figure 47-2. Clinical symptom frequency in benign gastric ulcer, early gastric cancer, and advanced gastric cancer. (After Meyer
WC, Damiano RJ, Postlethwait RW, et al. Adenocarcinoma of the stomach: changing patterns over the past four decades. Ann Surg
1987;205:18.)
In most patients with early gastric cancers, physical examination is unremarkable. Stool tests positive
for occult blood in one-third. Abnormal physical findings usually reflect advanced disease (Table 47-1).
Cachexia, abdominal mass, hepatomegaly, and supraclavicular adenopathy usually indicate metastasic
disease.27 There are no simple laboratory tests specific for gastric neoplasms.

Fiberoptic endoscopy is the most definitive diagnostic method when gastric neoplasm is suspected. In
the initial stages, gastric cancers can appear polypoid, as flat, plaquelike lesions, or as shallow ulcers.
Advanced lesions are typically ulcerated. The ulcer border can have an irregular, beaded appearance
because of infiltrating cancer cells, and the base is frequently necrotic and shaggy. The ulcer can appear
1207
booksmedicos.org
to arise from an underlying mass. Although each of these features suggests a malignant ulcer,
differentiation of benign from malignant gastric ulcers can be made definitively only with gastric
biopsy. Multiple biopsies of any gastric ulcer should be performed. The sensitivity of a single biopsy for
diagnosing a gastric cancer is 70%, but performing multiple biopsies can increase the sensitivity to
greater than 98%.28 False-negative results occur in approximately 10% of patients, usually as the result
of sampling error or due to the absence of a mucosal abnormality as can occur with linitis plastica; false-
positive results are rare. Diagnostic accuracy can be further enhanced by the addition of endoscopic
ultrasound (EUS) with fine-needle aspiration biopsy for infiltrative tumors involving the wall of the
stomach without obvious mucosal abnormalities.
DIAGNOSIS
Table 47-1 Common Symptoms and Physical Findings in Gastric Cancer
Figure 47-3. Early cancer survival rate in Japan.
Annual mass screening programs have been instituted in some countries (e.g., Japan, Venezuela,
Chile) with high incidence of gastric cancer. Whether such programs significantly reduce gastric cancer
mortality is unclear. In Japan, compliance with screening has been associated with a 50% decrease in
gastric cancer mortality, but most of this benefit is attributable to confounding factors such as baseline
general health.29 A large cohort study failed to show any effect of screening on mortality.30 Cancers
detected in screened patients tend to be earlier cancers with fewer nodal metastases,31 and patients with
resected gastric cancer diagnosed by screening have better survival than those diagnosed after
development of symptoms (Fig. 47-3). However, a survival difference between screened and unscreened
gastric cancer patients persists even after accounting for stage,31 suggesting that patient selection
confounds the effect of screening on mortality. The Japanese findings that early detection and
identification of early gastric cancer can improve survival has been confirmed by European
1208
booksmedicos.org
investigations, in which patients with early gastric cancers have been shown to have survival rates
equivalent to those of patients with benign gastric ulcer (Fig. 47-4).26 Mass screening programs have
been found to be cost-effective in high-incidence countries such as Japan and China,32 but they are
unlikely to be cost-effective in lower-incidence countries such as the United States. The cost-
effectiveness of the Japanese screening program is likely to change given the significant decrease in the
rate of chronic H. pylori infection in Japanese under the age of 30 (25% vs. 60% as compared to their
parents).33
Figure 47-4. Early cancer survival rate in Europe.
Barium-contrast radiographs have, in the past, been the standard method for diagnosing gastric
neoplasm. Single-contrast examinations have a diagnostic accuracy of 80%. This diagnostic yield
increases to approximately 90% when double-contrast (air and barium) techniques are used. Typical
findings include ulceration, the presence of a gastric mass, loss of mucosal detail, and distortion of the
gastric silhouette (Fig. 47-5). Contrast radiography has been largely supplanted by endoscopy because
of the ability to obtain biopsy material by the latter technique.
Figure 47-5. Barium-contrast radiograph demonstrating extensive involvement of the gastric body by infiltrating adenocarcinoma
(linitis plastica). The gastric silhouette is narrowed (arrows), and the stomach is nondistensible.
1209
booksmedicos.org
Figure 47-6. Computed tomography scan demonstrating mass along lesser curvature of the stomach (black arrow) and associated
lymph node enlargement (white arrow).
Computed tomography (CT) can provide information both about the primary tumor and visceral
metastatic disease. Because it is noninvasive and widely available, it is often the first staging modality
that is employed in a patient diagnosed with gastric cancer. Patients who are found to have metastatic
disease can be spared further, potentially invasive staging studies. When performed with intraluminal
and intravenous contrast, CT can demonstrate infiltration of the gastric wall by tumor, gastric
ulceration, and the presence of hepatic metastases (Figs. 47-6 and 47-7). CT may overestimate depth of
invasion, but serosal involvement can be reliably assessed (sensitivity 83% to 100%, specificity 80% to
97%).34 The technique is less reliable for detection of small peritoneal metastases, which may be missed
in 30% of cases.35 Similarly, evaluation of nodal disease by CT is limited, with accuracy of 70% to 80%
even with modern CT techniques.36
EUS is another useful method of preoperative evaluation for local staging and diagnosis. EUS can
assess subepithelial lesions that may be confused with gastric cancer and guide biopsy of submucosal
tumors within the wall of the stomach. Investigation of submucosal masses, infiltrative gastric
disorders, and enlarged gastric epithelial folds, as well as differentiation of gastric lymphoma from
gastric adenocarcinoma are all aided by EUS. This technique has the ability to assess the depth and
pattern of gastric wall penetration by the tumor as well as relationship to adjacent structures, and has
good correlation with intraoperative assessment and histologic findings. Perigastric lymph nodes
involved with tumor are also reliably identified by EUS, and therefore EUS provides the most accurate
assessment of local stage of disease (TN status), with an accuracy of 65% to 90% for staging depth of
tumor invasion34 and 50% to 78% for nodal involvement.37 EUS is generally not useful for detecting
metastatic disease, but it can help identify patients at risk for radiographically occult metastatic disease
(e.g., peritoneal metastases) for staging laparoscopy.35 Therefore, EUS serves as a useful adjunct to
cross-sectional imaging and can help guide selection of patients for further staging studies or
multimodality therapy.
Metabolic imaging with positive emission tomography (PET) using 18F-fluorodeoxyglucose has been
found to be less accurate than cross-sectional imaging and EUS for staging locoregional involvement,
but more sensitive for detecting distant metastases in patients with gastric cancer.37 A meta-analysis
comparing PET, ultrasound, CT, and magnetic resonance imaging (MRI) found that PET scan was the
most sensitive imaging modality for detecting hepatic metastases.38 A separate study found that tumors
which responded metabolically on PET to neoadjuvant chemotherapy correlated highly with
histopathologic response and improved patient survival.39 Therefore, current recommendations
regarding the use of PET for staging gastric cancer are for selective use for patients with locally
advanced tumors where the metastatic potential is high, and in cases where neoadjuvant therapy is
being considered.37 In these patients, the addition of PET can result in net cost savings by reducing the
number of futile surgical procedures.40
1210
booksmedicos.org
Figure 47-7. Computed tomography scans of the upper abdomen showing extensive thickening of the gastric wall (black arrows)
caused by infiltrating adenocarcinoma and associated hepatic metastasis (white arrow).
Staging Laparoscopy
The peritoneal lining, omentum, and liver capsule are common sites for gastric cancer metastasis that
are difficult to evaluate preoperatively by CT scanning. In prospective studies, diagnostic laparoscopy
has been superior to preoperative CT or percutaneous ultrasound in detection of peritoneal, hepatic, or
lymphatic metastasis.41 Accurate identification of patients with metastatic disease is important in order
to spare them futile, ultimately noncurative surgical procedures. In up to 25% of patients, laparoscopy
will detect metastatic disease that precludes curative resection.42–44 Relative to laparotomy, the shorter
hospitalization and reduced operative trauma following laparoscopy may both hasten recovery and
facilitate earlier initiation of systemic chemotherapy. Most patients with systemic metastasis can be
treated without the need for palliative surgical resection.45
In addition to grossly evident intra-abdominal metastatic disease, patients with microscopic metastatic
disease are at high risk for early recurrence and death after attempted curative resection.46,47 Based on
this finding, patients with positive cytology in peritoneal washings are considered to have M1 disease.
Approximately one-fourth of patients subjected to staging laparoscopy prior to planned curative
resection of gastric cancer will have positive peritoneal cytology; one-third of these patients will not
have grossly apparent metastatic disease. Patients who clear their initially positive peritoneal cytology
after systemic chemotherapy have an improved prognosis, but cure remains highly unlikely.46
Diagnostic laparoscopy may be considered in patients being considered for surgical resection without
neoadjuvant therapy. In these situations, the procedure can be conducted at the beginning of the
planned resection so as to avoid an additional general anesthesia. Patients with locally advanced (T3–T4
or node-positive) tumors who would typically be selected for neoadjuvant therapy should be considered
for diagnostic laparoscopy with peritoneal washings prior to initiation of chemotherapy. The finding of
positive peritoneal cytology should prompt adoption of a noncurative paradigm of treatment in most
cases.
Pathology
1211
booksmedicos.org
Gastric adenocarcinoma occurs in two distinct histologic subtypes—intestinal and diffuse. These
subtypes are characterized by differing pathologic and clinical features and by differing patterns of
metastatic spread.
In the intestinal form of gastric cancer, the malignant cells tend to form glands. The intestinal form of
malignancy is more frequently associated with gastric mucosal atrophy, chronic atrophic gastritis,
intestinal metaplasia, and dysplasia. Gastric cancer with the intestinal histologic subtype is more
common in populations at high risk (e.g., Japan), and it occurs with increased frequency in men and
older patients. Clinical studies suggest that this subtype more frequently demonstrates bloodborne
metastases.
The diffuse form of gastric adenocarcinoma does not demonstrate gland formation and tends to
infiltrate tissues as a sheet of loosely adherent cells. Lymphatic invasion is common. Intraperitoneal
metastases are frequent. The diffuse form of gastric adenocarcinoma tends to occur in younger patients,
in women, and in populations with a relatively low incidence of gastric cancer (e.g., the United States).
The prognosis is poorer for patients with the diffuse histologic subtype.
Sporadic gastric adenocarcinomas demonstrate a number of chromosomal and genetic abnormalities.
Cytometric analysis reveals that gastric tumors with a large fraction of aneuploid cells (with a greater-
than-normal amount of nuclear DNA) tend to be more highly infiltrative and have a poorer prognosis.
Amplifications of both the HER-2/neu and K-ras proto-oncogenes have been consistently detected in
gastric adenocarcinomas, and in a small percentage of tumors a lack of expression of the tumor
suppressor gene MKK4 is robustly associated with poor survival.48 The exact mechanisms by which
these genetic abnormalities contribute to gastric oncogenesis are currently unclear. Additionally, a
number of growth factors, including epidermal growth factor, platelet-derived growth factor, and
transforming growth factor-β, are overexpressed in gastric carcinoma cells.49
In the United States, the incidence of proximal gastric cancers has been increasing; such that in 2001
the rate of proximal cancers, defined as cancers arising in the cardia and fundus, exceeded that of distal
cancers, defined as cancers arising in the antrum and pylorus. Proximal cancers are more likely to occur
in young white men and distal cancers are more likely to occur in Asian, African American, and Hispanic
patients within the United States. The proportion of tumors involving the proximal stomach has
dramatically increased over the past decades; in the 1960s, only 16% involved this region, and a clear
explanation for this rise in proximal disease remains elusive. In 10% of cases, the stomach is diffusely
involved at the time of diagnosis.27 Prognosis is poorer for tumors arising from the proximal stomach or
for those with diffuse involvement of the organ relative to distal tumors, and these patients are much
more likely to need neoadjuvant and adjuvant therapy.9,50
Figure 47-8. Gastric cancer survival by stage. Used with the permission of the American Joint Committee on Cancer (AJCC),
Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by
Springer Science and Business Media LLC, www.springer.com
CLASSIFICATION AND STAGING

Table 47-2 Seventh Edition AJCC Staging System for Gastric Cancer
1212
booksmedicos.org
The seventh edition American Joint Committee on Cancer (AJCC) staging system for gastric cancer is
presented in Table 47-2.51 The staging system accurately discriminates prognosis based on pathologic
factors for tumors located 5 cm distal to the esophagogastric junction (EGJ) and below or arising within
5 cm of, but not crossing, the EGJ (Fig. 47-8). The AJCC recommends that cancers arising within 5 cm
of the EGJ that cross into the EGJ or esophagus be staged and treated as esophageal cancers. A
consideration of staging data illustrates the high frequency with which lymph node metastases are
present at the time of diagnosis in the United States, and the severe impact lymphatic involvement has
on survival. Even early gastric cancers (tumors restricted to the mucosa and submucosa) have a 15%
prevalence of nodal metastasis.
Curative-Intent Treatment
Surgical resection is the only potentially curative therapy for gastric cancer, but an advanced stage of
disease at the time of diagnosis precludes curative resection for most patients.
Since the mid-1990s, the surgical treatment of gastric cancer has continued to evolve, with minimally
invasive approaches increasingly pursued for early cancers and increasingly radical operations
advocated by some for advanced tumors. Japanese surgeons have reported the largest experience with
early gastric cancer. The Japanese Gastric Cancer Association defines early gastric cancer as tumor in
which invasion is restricted to the mucosa or submucosa.52 The presence or absence of lymph node
1213
booksmedicos.org
metastasis is not considered in this classification. While the presence of lymphatic metastasis cannot be
correctly judged by endoscopic findings, it is critically important in prognosis. For tumors confined to
the mucosa, lymphatic metastasis is present in 1-3% of cases; with submucosal involvement, the rate of
nodal positivity increases to 14-20%.53,54
Endoscopic Resection
For intestinal-type mucosal tumors less than 2 cm in size without ulceration or evidence of
lymphovascular invasion, endoscopic mucosal resection (EMR) may be performed. With this approach,
postoperative bleeding or perforation has been reported in 5%, and in 17% histologic examination
revealed submucosal invasion that required further operative treatment.55 Earlier reports suggested
underestimation of tumor invasion in 45% and missed lymphatic metastasis in 9% urged caution before
widespread acceptance of this technique.56 However, in experienced centers good results can be
obtained. A Japanese series of 131 patients reported disease-free survival of 99% at 10 years.57
Endoscopic submucosal dissection (ESD) is an emerging technique that may allow larger tumors to be
endoscopically resected than with EMR. In the absence of randomized trials comparing EMR and ESD
against surgical resection, surgical resection remains the gold standard for potentially curative therapy
in appropriate-risk patients.
Surgical Resection
4The fundamental principle of surgical resection of gastric cancer is complete extirpation of the primary
tumor. The extent of gastric resection is determined primarily by the need to obtain a resection margin
free of microscopic disease (R0 resection). Microscopic involvement of the resection margin by tumor
cells (R1 resection) is associated with poor prognosis.27 Patients with positive surgical margins are at
high risk for development of recurrent disease, and histologically positive margins are strongly
correlated with the development of anastomotic recurrence. In the setting of ≥5 positive nodes,
however, margin positivity does not impact survival,58 because these patients are at higher risk for
systemic recurrence. In contrast to other gastrointestinal malignancies such as colon cancer, gastric
cancer frequently demonstrates extensive intramural spread, especially the diffuse type. The propensity
for intramural spread is related, in part, to the extensive anastomosing capillary and lymphatic network
in the wall of the stomach. Retrospective studies suggest that when performing a subtotal gastrectomy,
a margin of 6 cm from the tumor mass proximally and 3 to 5.9 cm distally is necessary to minimize
anastomotic recurrence.59 Frozen section evaluation of resection margins may be obtained prior to
proceeding with reconstruction in order to improve the probability that R0 resection can be achieved.
1214
booksmedicos.org
Figure 47-9. Surgical options for resection of gastric neoplasms. A: Subtotal gastrectomy with gastrojejunal reconstruction. B: Total
gastrectomy with esophagojejunostomy. C: Esophagogastrectomy with anastomosis in cervical or thoracic position.
1215
booksmedicos.org
Figure 47-10. Postoperative radiograph after total gastrectomy with esophagojejunal anastomosis, showing esophagus (E) and
jejunum (J).
For lesions in the distal two-thirds of the stomach, distal subtotal gastrectomy is usually sufficient for
complete removal of the primary tumor. In contrast, lesions in the upper third of the stomach may
require total gastrectomy or esophagogastrectomy to encompass the tumor (Figs. 47-9 and 47-10). For
tumors involving the cardia without involvement of the gastroesophageal junction, some have
advocated proximal gastrectomy as an alternative to total gastrectomy with esophagojejunostomy with
the goal of preserving a gastric reservoir to lessen postoperative weight loss. This procedure does not
compromise oncologic outcomes,60,61 but there is a significantly higher incidence of severe reflux
esophagitis with proximal gastrectomy.37 Use of a jejunal interposition has been proposed to mitigate
reflux esophagitis, but quality-of-life data are conflicting.
Radical gastric operations can be performed with acceptable morbidity and low mortality rates in the
older age groups at greatest risk for gastric cancer. Mortality rates for total gastrectomy range from 3%
to 7%.62 There is some evidence that outcomes are superior at higher-volume centers. Defining what
constitutes a high-volume center is problematic, but one review suggests that hospitals with at least 21
gastric cancer resections per year may achieve optimal outcomes.63 Nutritional support in the
immediate postoperative period is an important adjunctive measure as patients resume oral intake,64
and many surgeons place a jejunal feeding tube at the time of total gastrectomy to ensure that optimal
enteral nutrition can be delivered in the postoperative period. Surgical reconstructions that interpose a
small intestinal reservoir between the esophagus and the jejunum have been advocated after total
gastrectomy, but a clear nutritional benefit has not been demonstrated.65–68
Because gastric cancer metastasizes so frequently to lymph nodes, radical extirpation of draining
lymph nodes has both therapeutic and staging implications.69 The value of routine-extended
lymphadenectomy beyond the perigastric lymph nodes in the treatment of gastric adenocarcinoma,
however, is controversial. The first favorable experience was reported from Japan.70,71 Resections in the
original Japanese system are shown in Table 47-3, and the current nomenclature used to define extent
of lymphadenectomy is shown in Table 47-4 and Figure 47-11. Only retrospective studies of extended
perigastric lymphadenectomy have been reported from Japan. Initial reports suggested an improvement
of approximately 10%, stage for stage, for patients with advanced disease treated with D2 or D3
operations.70–73 The benefits of extended lymphadenectomy have not been confirmed in non-Japanese
centers, and several randomized trials in Western centers have failed to show a survival benefit for
extended lymphadenectomy when the entire patient population was analyzed.74–78 Long-term (median
15-year) follow-up results from the Dutch trial of D1 versus D2 lymphadenectomy have shown a lower
gastric cancer–related death rate in the D2 group (37% vs. 48%) and lower rates of local and regional
recurrence.79 The significance of this finding is unclear given the absence of an overall survival benefit
and the long period of time it took for this difference to manifest. Improvements in adjuvant therapy
also complicate the interpretation of historical results of extended lymphadenectomy.
1216
booksmedicos.org
MANAGEMENT
Table 47-3 Lymphadenectomy Resections in the Original System of the Japanese
Research Society for Gastric Cancer
The safety of extended lymphadenectomy is disputed. Data from a national Japanese registry indicate
a contemporary mortality of less than 1%.80 Low mortality risks have been reported from multi-
institutional trials conducted in Italy and Germany.78,81 Investigations from the United States, Britain,
and the Netherlands have been less optimistic, indicating increased short-term morbidity and in-hospital
mortality.74,75
MANAGEMENT
Table 47-4 Current Nomenclature Used to Describe the Extent of
Lymphadenectomy Performed in Conjunction with Gastrectomy
1217
booksmedicos.org
Figure 47-11. Lymph node locations and groupings. D1 dissection: removal of N1 nodes. D2 dissection: removal of N1 and N2
nodes. D3 dissection: removal of N1, N2, and N3 nodes. D4 dissection: removal of N1–N4 nodes.79
Histologically positive lymph nodes are frequently present in the splenic hilum and along the splenic
artery, and routine splenectomy has been practiced in some centers. Splenectomy has not been
demonstrated to improve outcome for similarly staged patients.82,83 Likewise, resection of the tail or
body of the pancreas has not been demonstrated to improve survival. Thus, associated splenectomy or
pancreatosplenectomy is only beneficial when there is direct extension or bulky adenopathy at the
splenic hilum.84 Resection of adjacent organs may be required for local control if direct invasion has
occurred. In this circumstance, operative morbidity is increased and the long-term survival rate is
approximately 25%.85
In some centers in the United States, greater emphasis has been placed on the total number of nodes
removed and histologically examined rather than the location of the nodes (e.g., D1 vs. D2
lymphadenectomy). Current recommendations of the AJCC staging for gastric cancer suggest that a
minimum of 15 nodes be evaluated for accurate staging.51
Laparoscopic gastrectomy has also been reported for treatment of gastric malignancy, with
advantages of reduced pain, shorter hospitalization, and improved quality of life,86 and studies from
Japan, Korea, and Italy have demonstrated that distal, subtotal, and total gastrectomy with
lymphadenectomy is feasible with acceptable morbidity and mortality. However, the majority of the
patients in these studies had early gastric cancer.37 A meta-analysis of four small single-institution
randomized trials from Asia demonstrated lower nodal harvests with a laparoscopic approach for early
gastric cancer. Complication rates were lower in the laparoscopic group but did not translate into
differences in time to oral intake or length of stay.87 A single-institution Western randomized trial of
laparoscopic versus open subtotal gastrectomy for distal gastric cancer (both early and locally
advanced) did report equivalent lymph node retrieval (33.4 ± 7.4 in the open group vs. 30 ± 14.9 in
the laparoscopic group), as well as similar rates of perioperative morbidity and mortality. Five-year
overall and disease-free survival were also similar for both groups: 55.7% and 54.8% for the
laparoscopic group versus 58.9% and 57.3% for the open group.88 More recently, interim results of a
Korean multicenter randomized trial focused on early gastric cancer demonstrated equivalent
perioperative morbidity and mortality, but no data on oncologic outcomes have been published to
date.89 As such, there are still no published multi-institutional randomized data to confirm the oncologic
equivalency of laparoscopic gastrectomy as compared with the open approach.
Neoadjuvant and Adjuvant Therapies

5 Given the largely disappointing outcomes of locally advanced gastric cancer in Western countries,
significant interest has focused on the use of multimodality therapy. Several neoadjuvant and adjuvant
approaches have been explored. Although there is no consensus on the optimal approach, it is clear that
all patients with locally advanced disease should be considered for multimodality therapy. Two general
approaches are popular in the West.
Adjuvant chemoradiotherapy may be considered both for patients known to have locally advanced
disease from the outset as well as for those thought to have early gastric cancer who are subsequently
upstaged after surgical resection. The largest (n = 556) and most recent trial evaluating this approach
was the US Intergroup INT0116 trial, which compared surgical resection followed by 5-fluorouracil
(5FU), leucovorin, and external beam radiation versus resection alone in patients with gastric or EGJ
cancer.90 Most patients (69%) had T3/T4 tumors, and 85% had nodal metastases. Three-year overall
survival (50% vs. 41%) and 5-year overall survival (43% vs. 28%) were significantly improved with
multimodality therapy. Both local and distant failures were reduced by chemoradiation. The primary
criticism of this trial was that the extent of lymphadenectomy was not standardized, and less than D1
lymph node dissection was performed in 54% of the patients, which may have contributed to the poor
outcomes in the surgery-only group and led to overstatement of the true benefit of chemoradiation.
Additionally, one-third of patients were unable to complete their adjuvant chemoradiation due to
perioperative complications or treatment-associated toxicities. Finally, due to changes in the staging
system for gastric cancer, the benefit of this regimen for patients with T2N0 disease is questionable.
A more common approach in Europe is to administer preoperative chemotherapy, with or without
additional postoperative chemotherapy. The most influential trial evaluating this approach was the
Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, which randomly
assigned 503 patients with gastric, distal esophageal, or EGJ adenocarcinomas to surgery plus
1218
booksmedicos.org
perioperative chemotherapy or surgery alone.91 Planned chemotherapy consisted of three preoperative
and three postoperative cycles of epirubicin, cisplatin, and 5FU (ECF regimen). Patients with T2 and
higher tumors were eligible. This study demonstrated a significant survival benefit in patients receiving
perioperative chemotherapy (5-year survival 36% vs. 23%), with reduced local and distant failures.
Extent of lymphadenectomy was improved as compared to the Intergroup trial, but there were
significantly more patients with T1/2 tumors and N0/1 disease in the perioperative chemotherapy
group, suggesting a baseline imbalance in prognosis. Additionally, only 42% of patients completed all
courses of chemotherapy. Finally, as with the Intergroup trial it is unclear whether T2N0 patients are as
likely to benefit from this approach as those with more advanced disease. Despite the limitations of
these studies, the improved survival observed in both trials makes it clear that a multimodality
approach is superior to surgery alone. Numerous ongoing studies are investigating the relative benefits
of various chemotherapeutic regimens as well as the incremental benefit of chemoradiotherapy versus
chemotherapy alone. Targeted therapies are also being investigated. For example, the Trastuzumab for
Gastric Cancer (ToGA) trial demonstrated a modest but statistically significant survival benefit with the
addition of trastuzumab to cytotoxic chemotherapy in patients with HER2-positive gastric cancer.92
Patients with locally advanced resectable gastric cancer are optimally treated in a center where a
collaborative multidisciplinary treatment approach can be devised and executed (Algorithm 47-1).
Palliative Treatment
When preoperative evaluation demonstrates disseminated disease, palliation of symptoms becomes a
primary consideration. Palliation does not usually require surgery. Obstruction and bleeding can be
managed nonoperatively with endoscopic techniques or radiotherapy in selected patients. Dysphagia
and bleeding caused by proximal lesions can also be alleviated endoscopically (laser therapy or stenting)
in the majority of patients. Nonetheless, for a minority of patients, surgical palliation may be indicated.
In the setting of metastatic gastric cancer, palliative resection does not improve survival. Noncurative
resection may be indicated, for example, in the setting of intractable bleeding from the primary tumor.
Surgical palliation of obstructive symptoms (resection or gastrojejunostomy) should generally be
reserved for cases in which less invasive methods are contraindicated, technically infeasible, or
unsuccessful. In addition to radiotherapy and endoscopic ablation or stenting, placement of a feeding
jejunostomy tube with or without venting gastrostomy may be used to palliate gastric outlet
obstruction, especially in patients with limited life expectancy.
Algorithm 47-1. Treatment of gastric adenocarcinoma.
1219
booksmedicos.org
GASTRIC LYMPHOMA
Clinical Features
The stomach is the site of more than half of gastrointestinal lymphomas and is the most common organ
involved in extranodal lymphomas. Non-Hodgkin lymphomas account for approximately 5% of
malignant gastric tumors; lymphoma represents an increasing proportion of gastric neoplasms diagnosed
currently. Patients are considered to have primary gastric lymphoma if initial symptoms are gastric and
the stomach is exclusively or predominantly involved with the tumor. Patients who do not fulfill these
criteria are considered to have secondary gastric involvement from systemic lymphoma.
Gastric lymphoma is distinctly uncommon in children and young adults. The peak incidence is in the
sixth and seventh decades. Symptoms are usually indistinguishable from those of peptic ulcer disease
and gastric adenocarcinoma. Epigastric pain, weight loss, anorexia, nausea, and vomiting are common.93
Systemic B symptoms such as fever and night sweats occur in a minority of patients but may be
suggestive of the diagnosis. Although gross bleeding is uncommon, occult hemorrhage and anemia are
observed in more than half of patients. Patients rarely have spontaneous perforation.
Diagnosis
Radiologic findings are similar to those for adenocarcinoma (gastric thickening and lymphadenopathy).
Endoscopic examination is the diagnostic method of choice. The endoscopic appearance of lesions may
be ulcerated, polypoid, or infiltrative, and this morphology may be further characterized by EUS.
Gastric lymphoma is most commonly localized to the middle or distal stomach and unusually involves
the proximal stomach, in contrast to gastric adenocarcinoma. Endoscopic biopsy, combined with
endoscopic brush cytology and EUS, provides positive diagnosis in 90% of cases. Submucosal growth
without ulceration of the overlying mucosa can occasionally render endoscopic biopsy nondiagnostic.
EUS-guided biopsy is useful in this circumstance.
Appropriate staging should search for evidence of systemic disease. CT of the chest and abdomen (to
detect lymphadenopathy), bone marrow biopsy, and biopsy of enlarged peripheral lymph nodes are all
appropriate.
Mucosa-Associated Lymphoid Tissue

The concept that low-grade gastric lymphomas have features resembling mucosa-associated lymphoid
tissue (MALT) is a major advance in the understanding of gastric lymphomas. The gastric submucosa
does not ordinarily contain lymphoid tissue, and the development of lymphoid tissue resembling small
intestinal Peyer patches is believed to occur in response to infection with H. pylori.94 A number of
observations support a causal relationship between chronic H. pylori infection and gastric lymphoma
development. H. pylori is present in the stomachs of more than half of patients with gastric lymphoma 95
and 90% of those with gastric MALT lymphoma.96 As with gastric adenocarcinoma, geographic regions
with a high prevalence of H. pylori also have a high incidence of gastric lymphoma. Infection with H.
pylori has been noted to precede development of gastric lymphoma.97
Gastric MALT lymphoma is postulated to begin with chronic inflammation due to infection with H.
pylori. Chronic gastritis leads to the accumulation of CD4+ lymphocytes and B cells in the gastric
lamina propria. H. pylori-derived antigens drive T-cell activation, interleukin-2 (IL-2) release, and B-cell
proliferation.98 Progressive genetic rearrangements lead to IL-2–independent B-cell proliferation. With
cumulative genetic defects, low-grade MALT lymphoma progresses to high-grade disease.
Low-grade MALT lymphomas resemble Peyer patches. Lymphoma cells invade between follicles and
into gastric epithelium; invasion of gastric glands forms characteristic lymphoepithelial lesions. Low-
grade lesions are often multifocal. Low-grade MALT lesions are less likely than high-grade tumors to
invade transmurally, involve perigastric lymph nodes, or invade adjacent organs.97 Approximately 40%
of gastric lymphomas are low-grade MALT lymphomas.99
6 The concept that low-grade lymphoma depends on continued H. pylori antigenic stimulation
supports eradication of H. pylori with antibiotics as first-line antineoplastic therapy. Complete regression
of low-grade gastric MALT lymphomas with antibiotic treatment has been reported in 70% to 100% of
cases.100,101 The median time to complete response is 5 months.102 Most patients with partial responses
were subsequently determined also to have foci of high-grade lymphoma. Radiation and chemotherapy
have been proposed as salvage for antibiotic treatment failures or for the minority of patients with H.
pylori-negative gastric MALT lymphoma.
1220
booksmedicos.org
Non-MALT Lymphomas
Most non-MALT gastric lymphomas are diffuse large B-cell lymphomas (DLBCL), including those that
were previously called “high-grade MALT lymphomas.” DLBCL typically exhibit more aggressive
behavior and worse prognosis than MALT lymphomas. Other histologies, such as mantle cell, follicular,
and peripheral T-cell lymphomas can also be seen. Survival for gastric lymphoma is closely linked to
stage at diagnosis (Fig. 47-12). In the past, a multimodality treatment program was used in most centers
for primary gastric lymphomas, with gastrectomy as the first step in the therapeutic strategy.103 This
approach evolved empirically, without prospective data to support it. Several advantages of this
approach had been cited: (a) more accurate histologic evaluation was possible; (b) in cases with
localized tumor, the procedure could be curative; and (c) gastrectomy eliminated the risk of life-
threatening hemorrhage or perforation which may occur with the treatment of tumors involving the full
thickness of the gastric wall.104 However, the role of gastrectomy for both staging and treatment of
gastric lymphoma has diminished significantly, based in part on results of a randomized trial
demonstrating superior outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and
prednisone) chemotherapy than with surgery, surgery plus radiotherapy, or surgery with CHOP (Fig.
47-13).105. It has also been recognized that the incidence of perforation during chemotherapy is only
5%. Most patients are currently treated with chemotherapy (commonly CHOP with rituximab) with or
without radiotherapy. Surgical intervention is generally reserved for complications such as obstruction,
bleeding, or perforation.
Figure 47-12. Survival with gastric lymphoma, by stage.
Figure 47-13. Relapse-free survival by treatment assignment for primary gastric diffuse large B-cell lymphoma.
GASTRIC CARCINOIDS
Gastric carcinoid tumors were previously considered to be very rare tumors, but more recent studies
have reported that as many as 10% to 30% of all carcinoids occur in the stomach, and they account for
at least 1% of all gastric neoplasms.106 Most patients with small gastric carcinoids are asymptomatic,
and these tumors are most commonly diagnosed incidentally. Occasionally, however, larger tumors can
present with abdominal pain, bleeding, or symptoms related to the secretion of bioactive substances
which can be produced by the tumor. When viewed endoscopically at an early stage, carcinoids are
reddish-pink to yellow submucosal nodules in the proximal stomach. Endoscopic biopsy is usually
diagnostic if deep enough to sample submucosal tumor cells.
Four types of gastric carcinoids have been described. Type 1 is the most common (70% to 80%) and is
1221
booksmedicos.org
associated with chronic atrophic gastritis and pernicious anemia. These tumors tend to be small (<1
cm) and multiple, and their behavior indolent. When they are less than 2 cm in size, they metastasize
less than 10% of the time.107 They can typically be followed and removed endoscopically, but surgery
may be necessary for larger or very numerous tumors. Type 2 tumors comprise approximately 5% of
gastric carcinoids and occur in patients with Zollinger–Ellison syndrome (gastrinomas), often in the
setting of multiple endocrine neoplasia type 1 (MEN1). Like type 1 tumors, they are often small,
multiple, and indolent, and they can be treated endoscopically for the most part. Both type 1 and type 2
gastric carcinoid tumors are associated with hypergastrinemia. Type 1 and 2 gastric carcinoids arise
from enterochromaffin-like (ECL) cells, which mediate the secretion of histamine and in turn stimulate
parietal cells to secrete acid. Hypergastrinemia (due to chronic atrophic gastritis in type 1 and
gastrinoma in type 2) is thought to cause ECL cell hyperplasia and lead to the development of gastric
carcinoids over time.108
Type 3 lesions account for 20% of gastric carcinoids. Type 3 gastric carcinoids tend to be larger,
solitary lesions. They are associated with normal gastrin levels and behave much more aggressively
than other gsatric carcinoid tumors.108 Metastases are common, and these tumors can cause an atypical
carcinoid syndrome. Type 3 carcinoids are best dealt with by resection and lymphadenectomy, the
extent of which depends on the size of the tumor.
GASTROINTESTINAL STROMAL TUMORS OF THE STOMACH

Gastrointestinal stromal tumors (GISTs) were historically misclassified as leiomyomas,
leiomyosarcomas, and leiomyoblastomas due to a mistaken belief that they arose from the smooth
muscle in the bowel wall. However, it is now recognized that GISTs represent a distinct mesenchymal
tumor type, and actually arise from the interstitial cells of Cajal, intestinal pacemaker cells located in
and around the myenteric plexus in the bowel wall. While GISTs can arise anywhere within the
gastrointestinal tract, approximately 50% of these tumors are found in the stomach. With a slight male
predominance, GISTs are typically present in middle-aged and elderly individuals, with a median age at
presentation of approximately 60. They are typically asymptomatic and are most commonly identified
incidentally during endoscopy performed for other reasons. Their endoscopic appearance is that of a
submucosal mass with normal overlying mucosa. If these tumors become large, however, they may
present with symptoms of abdominal pain and bleeding. GISTs frequently have prominent extraluminal
growth patterns, and central necrosis is common as these tumors become very large and outgrow their
blood supply (Fig. 47-14). If the majority of the growth is extraluminal, endoscopic examination may be
unrevealing or only demonstrate umbilication of the mucosa suggestive of an underlying mass. EUS or
CT imaging may be helpful for diagnosis in these cases. With large tumors, symptoms related to mass
effect may occur. Additionally, ulceration of the overlying gastric mucosa may occur with tumor
necrosis, and these patients may present with significant and intermittent gastrointestinal hemorrhage.
Figure 47-14. CT scan of GIST of stomach arising from lesser curvature. The arrow indicates central tumor necrosis. The lesion
caused mucosal erosion with gastrointestinal hemorrhage.
7 The molecular hallmark of GISTs is overexpression of the CD117 antigen, which is part of the KIT
transmembrane receptor tyrosine kinase. Mutations in c-kit, the proto-oncogene that encodes KIT, can
lead to constitutive activation of the receptor and abnormal cell proliferation. Approximately 95% of
GISTs overexpress KIT. Of those that do not, many have activating mutations in platelet-derived growth
factor receptor alpha (PDGFRA), another receptor tyrosine kinase. However, some GISTs lack mutations
1222
booksmedicos.org
in either of these genes, and many of these are characterized by inactivating mutations in the succinate
dehydrogenase (SDH) complex. The molecular pathogenesis of GIST is important because of the
availability of tyrosine kinase inhibitors (TKIs), such as imatinib and sunitinib, which can inhibit GIST
cell growth. However, GISTs that lack KIT or PDGFRA mutations, as well as those with certain types of
KIT or PDGFRA mutations, may be variably resistant to TKI therapy.
All GISTs should be considered potentially malignant, especially those >1 cm in size.109 Tumor size
and mitotic index are the most important prognostic variables (Table 47-5).110 Site of origin is also
prognostic, with gastric GISTs behaving less aggressively than intestinal GISTs.111 For localized GISTs,
surgical resection is the treatment of choice. When GISTs do metastasize, they do so by a hematogenous
route (most commonly to peritoneal surfaces and the liver). Therefore, associated lymphadenectomy is
typically not performed at the time of gastric resection for GIST. Additionally, unlike adenocarcinoma,
GISTs do not present with an intramural growth pattern and thus gross margins of 1 to 2 cm are deemed
adequate for resection of a GIST. Ultimately the goal of resection is a negative microsopic margin. If the
tumor involves adjacent structures, then en bloc resection of nonvital structures should be performed
whenever possible. Due to the less radical nature of surgery required for appropriate oncologic
resection of these tumors as compared to adenocarcinoma of the stomach, minimally invasive surgical
techniques have become widely accepted as an appropriate and acceptable operative approach for these
tumors. A nomogram has been developed to allow prediction of outcomes following surgical resection
of GISTs.112
For patients with metastatic or locally advanced, unresectable GISTs, imatinib is first-line therapy.
Although most patients will respond to imatinib therapy, development of resistance is common, likely
due to selection of clones with secondary KIT mutations.113,114 These patients may be managed either
with imatinib dose escalation or by using another TKI (e.g., sunitinib). Imatinib is also indicated in the
adjuvant setting for tumors at high risk for recurrence. The ACOSOG Z9001 trial evaluated the efficacy
of 1 year of adjuvant imatinib versus placebo in patients with resected GIST ≥3 cm in size and KIT-
positive.115 Recurrence-free survival at 1 year was significantly lower in the imatinib arm (98% vs.
83%). No overall survival difference was shown, likely because patients were allowed to cross over to
the imatinib arm after the study was unblinded. The Scandinavian Sarcoma Group evaluated the effect
of 1 versus 3 years of adjuvant imatinib after resection of high-risk GIST and found differences in 5-year
recurrence-free survival (66% vs. 49%) and overall survival (92% vs. 82%).116 Based on these data, 3
years of imatinib therapy are recommended after resection of high-risk GIST. Rates of recurrence after
discontinuation of imatinib therapy are similar to those in untreated patients, suggesting that TKI
therapy may simply be delaying recurrences rather than actually preventing them. The use of imatinib
in the neoadjuvant setting has been reported in retrospective series and was found to be safe in a phase
II trial, but there are currently insufficient prospective data to guide this treatment approach.
CLASSIFICATION AND STAGING

Table 47-5 Risk of Aggressive Behavior in Gastrointestinal Stromal Tumors
References
1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29.
2. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69–90.
3. Haenszel W, Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases
1223
booksmedicos.org
among Japanese in the United States. J Natl Cancer Inst 1968;40:43–68.
4. McMichael AJ, McCall MG, Hartshorne JM, et al. Patterns of gastro-intestinal cancer in European
migrants to Australia: the role of dietary change. Int J Cancer 1980;25:431–437.
5. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined
analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49:347–353.
6. An international association between Helicobacter pylori infection and gastric cancer. The
EUROGAST Study Group. Lancet 1993;341:1359–1362.
7. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer
2006;118:3030–3044.
8. Ferlay J, Soerjomataram I, Ervik MD, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality
Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on
Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on January 13, 2015.
9. Wilkinson NW, Howe J, Gay G, et al. Differences in the pattern of presentation and treatment of
proximal and distal gastric cancer: results of the 2001 gastric patient care evaluation. Ann Surg
Oncol 2008;15:1644–1650.
10. Harju E. Gastric polyposis and malignancy. Br J Surg 1986;73:532–533.
11. Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of
gastric cancer. N Engl J Med 2001;345:784–789.
12. Crowe SE. Helicobacter infection, chronic inflammation, and the development of malignancy. Curr
Opin Gastroenterol 2005;21:32–38.
13. Amieva MR, El-Omar EM. Host-bacterial interactions in Helicobacter pylori infection.
14. Naylor GM, Gotoda T, Dixon M, et al. Why does Japan have a high incidence of gastric cancer?
Comparison of gastritis between UK and Japanese patients. Gut 2006;55:1545–1552.
15. Forman D, Pisani P. Gastric cancer in Japan–honing treatment, seeking causes. N Engl J Med
2008;359:448–451.
16. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a
high-risk region of China: a randomized controlled trial. JAMA 2004;291:187–194.
17. Caygill CP, Hill MJ, Kirkham JS, et al. Mortality from gastric cancer following gastric surgery for
peptic ulcer. Lancet 1986;1:929–931.
18. Lundegardh G, Adami HO, Helmick C, et al. Stomach cancer after partial gastrectomy for benign
ulcer disease. N Engl J Med 1988;319:195–200.
19. Hansson LE. Risk of stomach cancer in patients with peptic ulcer disease. World J Surg
2000;24:315–320.
20. Lundegardh G, Ekbom A, McLaughlin JK, et al. Gastric cancer risk after vagotomy. Gut
1994;35:946–949.
21. Tersmette AC, Offerhaus GJ, Giardiello FM, et al. Long-term prognosis after partial gastrectomy for
benign conditions. Survival and smoking-related death of 2633 Amsterdam postgastrectomy
patients followed up since surgery between 1931 and 1960. Gastroenterology 1991;101:148–153.
22. von Holstein CS. Long-term prognosis after partial gastrectomy for gastroduodenal ulcer. World J
Surg 2000;24:307–314.
23. Aya M, Yashiro M, Nishioka N, et al. Carcinogenesis in the remnant stomach following distal
gastrectomy with Billroth II reconstruction is associated with high-level microsatellite instability.
Anticancer Res 2006; 26:1403–1411.
24. Pharoah PD, Guilford P, Caldas C; International Gastric Cancer Linkage C. Incidence of gastric
cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric
cancer families. Gastroenterology 2001;121:1348–1353.
25. Fitzgerald RC, Caldas C. Clinical implications of E-cadherin associated hereditary diffuse gastric
cancer. Gut 2004;53:775–778.
26. Moreaux J, Bougaran J. Early gastric cancer. A 25-year surgical experience. Ann Surg
1993;217:347–355.
27. Wanebo HJ, Kennedy BJ, Chmiel J, et al. Cancer of the stomach. A patient care study by the
American College of Surgeons. Ann Surg 1993;218:583–592.
1224
booksmedicos.org
28. Graham DY, Schwartz JT, Cain GD, et al. Prospective evaluation of biopsy number in the diagnosis
of esophageal and gastric carcinoma. Gastroenterology 1982;82:228–231.
29. Mizoue T, Yoshimura T, Tokui N, et al. Prospective study of screening for stomach cancer in Japan.
Int J Cancer 2003;106:103–107.
30. Inaba S, Hirayama H, Nagata C, et al. Evaluation of a screening program on reduction of gastric
cancer mortality in Japan: preliminary results from a cohort study. Prev Med 1999;29:102–106.
31. Kunisaki C, Ishino J, Nakajima S, et al. Outcomes of mass screening for gastric carcinoma. Ann Surg
Oncol 2006;13:221–228.
32. Dan YY, So JB, Yeoh KG. Endoscopic screening for gastric cancer. Clin Gastroenterol Hepatol
2006;4:709–716.
33. Marshall BJ, Windsor HM. The relation of Helicobacter pylori to gastric adenocarcinoma and
lymphoma: pathophysiology, epidemiology, screening, clinical presentation, treatment, and
prevention. Med Clin North Am 2005;89:313–344, viii.
34. Kwee RM, Kwee TC. Imaging in local staging of gastric cancer: a systematic review. J Clin Oncol
2007;25:2107–2116.
35. Power DG, Schattner MA, Gerdes H, et al. Endoscopic ultrasound can improve the selection for
laparoscopy in patients with localized gastric cancer. J Am Coll Surg 2009;208:173–178.
36. Chen CY, Hsu JS, Wu DC, et al. Gastric cancer: preoperative local staging with 3D multi-detector
row CT–correlation with surgical and histopathologic results. Radiology 2007;242:472–482.
37. Ly QP, Sasson AR. Modern surgical considerations for gastric cancer. J Natl Compr Canc Netw
2008;6:885–894.
38. Kinkel K, Lu Y, Both M, et al. Detection of hepatic metastases from cancers of the gastrointestinal
tract by using noninvasive imaging methods (US, CT, MR imaging, PET): a meta-analysis. Radiology
2002;224:748–756.
39. Ott K, Herrmann K, Lordick F, et al. Early metabolic response evaluation by fluorine-18
fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in
gastric cancer: long-term results of a prospective study. Clin Cancer Res 2008;14:2012–2018.
40. Smyth E, Schoder H, Strong VE, et al. A prospective evaluation of the utility of 2-deoxy-2-[(18)
F]fluoro-D-glucose positron emission tomography and computed tomography in staging locally
advanced gastric cancer. Cancer 2012;118:5481–5488.
41. Mortensen MB, Scheel-Hincke JD, Madsen MR, et al. Combined endoscopic ultrasonography and
laparoscopic ultrasonography in the pretherapeutic assessment of resectability in patients with
upper gastrointestinal malignancies. Scand J Gastroenterol 1996;31:1115–1119.
42. Blackshaw GR, Barry JD, Edwards P, et al. Laparoscopy significantly improves the perceived
preoperative stage of gastric cancer. Gastric Cancer 2003;6:225–229.
43. Lowy AM, Mansfield PF, Leach SD, et al. Laparoscopic staging for gastric cancer. Surgery
1996;119:611–614.
44. Sarela AI, Miner TJ, Karpeh MS, et al. Clinical outcomes with laparoscopic stage M1, unresected
gastric adenocarcinoma. Ann Surg 2006;243:189–195.
45. D’Ugo DM, Coppola R, Persiani R, et al. Immediately preoperative laparoscopic staging for gastric
cancer. Surg Endosc 1996;10:996–999.
46. Mezhir JJ, Shah MA, Jacks LM, et al. Positive peritoneal cytology in patients with gastric cancer:
natural history and outcome of 291 patients. Ann Surg Oncol 2010;17:3173–3180.
47. Badgwell B, Cormier JN, Krishnan S, et al. Does neoadjuvant treatment for gastric cancer patients
with positive peritoneal cytology at staging laparoscopy improve survival? Ann Surg Oncol
2008;15:2684–2691.
48. Cunningham SC, Kamangar F, Kim MP, et al. MKK4 status predicts survival after resection of
gastric adenocarcinoma. Arch Surg 2006;141:1095–1099; discussion 100.
49. Katano M, Nakamura M, Fujimoto K, et al. Prognostic value of platelet-derived growth factor-A
(PDGF-A) in gastric carcinoma. Ann Surg 1998; 227:365–371.
50. Harrison LE, Karpeh MS, Brennan MF. Proximal gastric cancers resected via a transabdominal-only
approach. Results and comparisons to distal adenocarcinoma of the stomach. Ann Surg
1997;225:678–683; discussion 83–85.
51. Edge SB, American Joint Committee on Cancer. AJCC Cancer Staging Manual. 7th ed. New York,
1225
booksmedicos.org
NY: Springer; 2010.
52. Adachi Y, Shiraishi N, Kitano S. Modern treatment of early gastric cancer: review of the Japanese
experience. Dig Surg 2002;19:333–339.
53. Kunisaki C, Shimada H, Takahashi M, et al. Prognostic factors in early gastric cancer.
Hepatogastroenterology 2001;48:294–298.
54. Nakamura K, Morisaki T, Sugitani A, et al. An early gastric carcinoma treatment strategy based on
analysis of lymph node metastasis. Cancer 1999;85:1500–1505.
55. Ono H, Kondo H, Gotoda T, et al. Endoscopic mucosal resection for treatment of early gastric
cancer. Gut 2001;48:225–229.
56. Korenaga D, Orita H, Maekawa S, et al. Pathological appearance of the stomach after endoscopic
mucosal resection for early gastric cancer. Br J Surg 1997;84:1563–1566.
57. Uedo N, Iishi H, Tatsuta M, et al. Longterm outcomes after endoscopic mucosal resection for early
gastric cancer. Gastric Cancer 2006;9:88–92.
58. Kim SH, Karpeh MS, Klimstra DS, et al. Effect of microscopic resection line disease on gastric
cancer survival. J Gastrointest Surg 1999;3:24–33.
59. Bozzetti F, Bonfanti G, Bufalino R, et al. Adequacy of margins of resection in gastrectomy for
cancer. Ann Surg 1982;196:685–690.
60. Harrison LE, Karpeh MS, Brennan MF. Total gastrectomy is not necessary for proximal gastric
cancer. Surgery 1998;123:127–130.
61. Katai H, Sano T, Fukagawa T, et al. Prospective study of proximal gastrectomy for early gastric
cancer in the upper third of the stomach. Br J Surg 2003;90:850–853.
62. Schwarz RE, Karpeh MS, Brennan MF. Factors predicting hospitalization after operative treatment
for gastric carcinoma in patients older than 70 years. J Am Coll Surg 1997;184:9–15.
63. Dixon M, Mahar A, Paszat L, et al. What provider volumes and characteristics are appropriate for
gastric cancer resection? Results of an international RAND/UCLA expert panel. Surgery
2013;154:1100–1109.
64. Daly JM, Weintraub FN, Shou J, et al. Enteral nutrition during multimodality therapy in upper
gastrointestinal cancer patients. Ann Surg 1995;221:327–338.
65. Bozzetti F, Bonfanti G, Castellani R, et al. Comparing reconstruction with Roux-en-Y to a pouch
following total gastrectomy. J Am Coll Surg 1996;183:243–248.
66. Chareton B, Landen S, Manganas D, et al. Prospective randomized trial comparing Billroth I and
Billroth II procedures for carcinoma of the gastric antrum. J Am Coll Surg 1996;183:190–194.
67. de Almeida AC, dos Santos NM, Aldeia FJ. Long-term clinical and endoscopic assessment after total
gastrectomy for cancer. Surg Endosc 1993;7:518–523.
68. Nakane Y, Okumura S, Akehira K, et al. Jejunal pouch reconstruction after total gastrectomy for
cancer. A randomized controlled trial. Ann Surg 1995;222:27–35.
69. Shiu MH, Moore E, Sanders M, et al. Influence of the extent of resection on survival after curative
treatment of gastric carcinoma. A retrospective multivariate analysis. Arch Surg 1987;122:1347–
1351.
70. Maruyama K, Okabayashi K, Kinoshita T. Progress in gastric cancer surgery in Japan and its limits
of radicality. World J Surg 1987;11:418–425.
71. Noguchi Y, Imada T, Matsumoto A, et al. Radical surgery for gastric cancer. A review of the
Japanese experience. Cancer 1989;64:2053–2062.
72. Adachi Y, Kamakura T, Mori M, et al. Role of lymph node dissection and splenectomy in node-
positive gastric carcinoma. Surgery 1994;116:837–841.
73. Baba H, Maehara Y, Takeuchi H, et al. Effect of lymph node dissection on the prognosis in patients
with node-negative early gastric cancer. Surgery 1995;117:165–169.
74. Bonenkamp JJ, Hermans J, Sasako M, et al. Extended lymph-node dissection for gastric cancer. N
Engl J Med 1999;340:908–914.
75. Cuschieri A, Fayers P, Fielding J, et al. Postoperative morbidity and mortality after D1 and D2
resections for gastric cancer: preliminary results of the MRC randomised controlled surgical trial.
The Surgical Cooperative Group. Lancet 1996;347:995–999.
76. Maeta M, Yamashiro H, Saito H, et al. A prospective pilot study of extended (D3) and
1226
booksmedicos.org
superextended para-aortic lymphadenectomy (D4) in patients with T3 or T4 gastric cancer managed
by total gastrectomy. Surgery 1999;125:325–331.
77. Robertson CS, Chung SC, Woods SD, et al. A prospective randomized trial comparing R1 subtotal
gastrectomy with R3 total gastrectomy for antral cancer. Ann Surg 1994;220:176–182.
78. Siewert JR, Bottcher K, Stein HJ, et al. Relevant prognostic factors in gastric cancer: ten-year
results of the German Gastric Cancer Study. Ann Surg 1998;228:449–461.
79. Songun I, Putter H, Kranenbarg EM, et al. Surgical treatment of gastric cancer: 15-year follow-up
results of the randomised nationwide Dutch D1D2 trial. Lancet Oncol 2010;11:439–449.
80. Lee JS, Douglass HO Jr. D2 dissection for gastric cancer. Surg Oncol 1997;6:215–225.
81. Pacelli F, Doglietto GB, Bellantone R, et al. Extensive versus limited lymph node dissection for
gastric cancer: a comparative study of 320 patients. Br J Surg 1993;80:1153–1156.
82. Otsuji E, Yamaguchi T, Sawai K, et al. End results of simultaneous splenectomy in patients
undergoing total gastrectomy for gastric carcinoma. Surgery 1996;120:40–44.
83. Stipa S, Di Giorgio A, Ferri M, et al. Results of curative gastrectomy for carcinoma. J Am Coll Surg
1994;179:567–572.
84. Kunisaki C, Makino H, Suwa H, et al. Impact of splenectomy in patients with gastric
adenocarcinoma of the cardia. J Gastrointest Surg 2007;11:1039–1044.
85. Shchepotin IB, Chorny VA, Nauta RJ, et al. Extended surgical resection in T4 gastric cancer. Am J
Surg 1998;175:123–126.
86. Cuschieri A. Laparoscopic gastric resection. Surg Clin North Am 2000; 80:1269–1284, viii.
87. Ohtani H, Tamamori Y, Noguchi K, et al. A meta-analysis of randomized controlled trials that
compared laparoscopy-assisted and open distal gastrectomy for early gastric cancer. J Gastrointest
Surg 2010;14:958–964.
88. Huscher CG, Mingoli A, Sgarzini G, et al. Laparoscopic versus open subtotal gastrectomy for distal
gastric cancer: five-year results of a randomized prospective trial. Ann Surg 2005;241:232–237.
89. Kim HH, Hyung WJ, Cho GS, et al. Morbidity and mortality of laparoscopic gastrectomy versus
open gastrectomy for gastric cancer: an interim report–a phase III multicenter, prospective,
randomized Trial (KLASS Trial). Ann Surg 2010;251:417–420.
90. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradiotherapy after surgery compared with
surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med
2001;345:725–730.
resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20.
92. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy
versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal
junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687–
697.
93. Isaacson PG. Gastrointestinal lymphoma. Hum Pathol 1994;25:1020–1029.
94. Isaacson PG. Gastric lymphoma and Helicobacter pylori. N Engl J Med 1994;330:1310–1311.
95. Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N
Engl J Med 1994;330:1267–1271.
96. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, et al. Helicobacter pylori-associated gastritis and
primary B-cell gastric lymphoma. Lancet 1991;338:1175–1176.
97. Montalban C, Castrillo JM, Abraira V, et al. Gastric B-cell mucosa-associated lymphoid tissue
(MALT) lymphoma. Clinicopathological study and evaluation of the prognostic factors in 143
patients. Ann Oncol 1995;6:355–362.
98. Hussell T, Isaacson PG, Crabtree JE, et al. The response of cells from low-grade B-cell gastric
lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori. Lancet 1993;342:571–574.
99. Yoon SS, Coit DG, Portlock CS, et al. The diminishing role of surgery in the treatment of gastric
lymphoma. Ann Surg 2004;240:28–37.
100. Bayerdorffer E, Neubauer A, Rudolph B, et al. Regression of primary gastric lymphoma of mucosa-
associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study
Group. Lancet 1995;345:1591–1594.
1227
booksmedicos.org
101. Neubauer A, Thiede C, Morgner A, et al. Cure of Helicobacter pylori infection and duration of
remission of low-grade gastric mucosa-associated lymphoid tissue lymphoma. J Natl Cancer Inst
1997;89:1350–1355.
102. Pinotti G, Zucca E, Roggero E, et al. Clinical features, treatment and outcome in a series of 93
patients with low-grade gastric MALT lymphoma. Leuk Lymphoma 1997;26:527–537.
103. Stephens J, Smith J. Treatment of primary gastric lymphoma and gastric mucosa-associated
lymphoid tissue lymphoma. J Am Coll Surg 1998; 187:312–320.
104. Bartlett DL, Karpeh MS Jr, Filippa DA, et al. Long-term follow-up after curative surgery for early
gastric lymphoma. Ann Surg 1996;223:53–62.
105. Aviles A, Nambo MJ, Neri N, et al. The role of surgery in primary gastric lymphoma: results of a
controlled clinical trial. Ann Surg 2004;240:44–50.
106. Modlin IM, Kidd M, Latich I, et al. Current status of gastrointestinal carcinoids. Gastroenterology
2005;128:1717–1751.
107. Soga J. Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 reported cases.
Cancer 2005;103:1587–1595.
108. Landry CS, Brock G, Scoggins CR, et al. A proposed staging system for gastric carcinoid tumors
based on an analysis of 1,543 patients. Ann Surg Oncol 2009;16:51–60.
109. Gold JS, Dematteo RP. Combined surgical and molecular therapy: the gastrointestinal stromal
tumor model. Ann Surg 2006;244:176–184.
110. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus
approach. Hum Pathol 2002;33:459–465.
111. Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Hum
Pathol 2008;39:1411–1419.
112. Gold JS, Gonen M, Gutierrez A, et al. Development and validation of a prognostic nomogram for
recurrence-free survival after complete surgical resection of localised primary gastrointestinal
stromal tumour: a retrospective analysis. Lancet Oncol 2009;10:1045–1052.
113. Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in
gastrointestinal stromal tumors. J Clin Oncol 2006;24:4764–4774.
114. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT
mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer
Res 2006;12:1743–1749.
115. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of
localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled
trial. Lancet 2009;373:1097–1104.
116. Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable
gastrointestinal stromal tumor: a randomized trial. JAMA 2012;307:1265–1272.
1228
booksmedicos.org
SECTION F: SMALL INTESTINE
1229
booksmedicos.org
Chapter 48
Anatomy and Physiology of the Small Intestine

E. Ramsay Camp, Kevin F. Staveley-O’Carroll, Niraj J. Gusani, Jussuf T. Kaifi, and Eric T. Kimchi
Key Points
1 The normal adult anatomy of the small intestine is the result of a complex cascade of embryologic
events which result in 270 degrees of total rotation of the bowel around its axis. A failure of these
precise steps produces a spectrum of anatomical variants which are grouped together as malrotation
of the intestinal tract.
2 There is no clear anatomic boundary between the jejunum and ileum. The proximal two-fifths of the
small intestine distal to the ligament of Treitz have been arbitrarily defined as jejunum and the distal
three-fifths as ileum.
3 The enteric nervous system contains two major plexuses:
a. the myenteric (Auerbach) plexus, located between the longitudinal and circular muscle layers
b. the submucosal (Meissner) plexus
4 The small intestine is the largest endocrine organ in the human body. The secretion of numerous
hormones and neurotransmitters are specific to distinct anatomic zones within the small intestine.
5 The coordinated movement of the gastrointestinal tract is necessary for the proper digestion of food.
Well-timed contraction and relaxation patterns are initiated in gastrointestinal nervous system
causing coordinated electrical activity and muscular movements.
6 The lumen of the gastrointestinal tract is connected to the outside environment and comes in direct
contact with many potentially pathogenic microorganisms. Consequently, the small intestine needs a
complex defense mechanism to battle against these exposures in different ways.
7 The small intestine reabsorbs nearly 80% of the fluid that passes through it. This dynamic process is
accomplished by a rapid bidirectional movement of fluid in the intestinal lumen. This ebb and flow
of fluid in the intestinal lumen is critical in maintaining normal homeostasis. Minor changes in
intestinal permeability or rate of flow of the intestinal contents can result in net secretion and
diarrheal states.
8 While the exact mechanisms of many of the interactions between the gut microflora and the small
intestinal microenvironment are still speculative, it has become evident that a symbiotic
environment is present which, at least in part, is responsible for proper homeostasis of the small
intestine.
The small intestine’s intrinsic design serves to provide a maximum amount of surface area for
absorption of nutrients, water, and electrolytes. Specialized areas provide neurohormonal stimulation to
the digestive tract. Its structure and vast surface area also provide an important physical barrier to
potential pathogens and certain areas are critical in immune surveillance.
GROSS ANATOMY AND EMBRYOLOGY

1 The small intestine spans from the pylorus to the ileocecal valve, and includes three distinct regions:
the duodenum, the jejunum, and the ileum. These areas combined measure approximately 200 to 300
cm in a newborn and 5 to 7 m in an adult; comprising nearly 62% of the entire length of the alimentary
tract. The gastrointestinal tract is formed from the endodermal layer of the developing embryo. The
small intestine is derived from the distal foregut (proximal duodenum), midgut, and the adjacent
splanchnic mesenchyme. Epithelium and glands develop from the embryonic endoderm, while
connective tissue, muscle, and serosa develop from the mesoderm. During the 5th and 6th weeks of
development, the duodenal lumen is temporarily obliterated due to proliferation of its mucosal lining.
1230
booksmedicos.org
During the subsequent weeks, luminal vacuolization and degeneration of some of the proliferating cells
result in recanalization of the duodenal lumen. From the 4th to the 10th week of development, a large
portion of the midgut is herniated through the umbilicus. This may be due to the rapid growth of the
intestinal tract at this time in relation to the abdominal cavity. At approximately 8 weeks of gestation,
the midgut begins to rotate in a counterclockwise manner 90 degrees around the axis of the mesenteric
vasculature. The extra-abdominal portion of the gut returns to the abdominal cavity approximately 2
weeks later. Around this time point an additional 180-degree rotation occurs. These two rotations
provide 270 degrees of total rotation and result in the typical anatomy that is found in humans. A
failure of these precise steps produces a spectrum of anatomical variants which are grouped together as
malrotation of the intestinal tract.1
DUODENUM
The duodenum comprises the first portion of the small intestine and plays an important role in
connecting the foregut organs to the midgut. It anatomically begins at the duodenal bulb which is
immediately distal to the pylorus and terminates at the ligament of Treitz, where it joins the jejunum.
The duodenum is approximately 20 to 30 cm in length and is divided into four distinct areas.
The first portion of the duodenum is approximately 5 cm in length and is referred to as the bulb or
cap. This area is directly attached to the pylorus and extends laterally and cephalad. It serves as an
attachment for the hepatoduodenal ligament and traverses over the common bile duct, portal vein,
pancreatic head, and the gastroduodenal artery. The mucosal surface of the duodenal bulb is smooth
until its junction with the second portion of the duodenum, where the concentric Kerckring folds begin.
This portion of the duodenum is prone to ulceration, with approximately 90% of duodenal ulcers
occurring here. Unfortunately, due to its anatomic positioning, these ulcers may erode into the
gastroduodenal artery which lies directly posterior, causing potentially life-threatening bleeding.
The second portion of the duodenum (descending duodenum) extends from the origin of the
Kerckring folds to the beginning of the transverse duodenum and travels over the right renal
vasculature, the medial aspect of Gerota fascia, the inferior vena cava, and to the right of the L1 and L2
vertebra. It is approximately 10 cm in length and 3 to 5 cm in diameter. The Kerckring folds (plicae
circulares) are concentric mucosal folds which are 1 to 2 mm thick and 2 to 4 mm high and are
separated by 2 to 4 mm of smooth, flat mucosa. This portion of the duodenum serves as an entry point
for pancreatic and biliary secretions into the gastrointestinal tract. This is typically through the major
papilla (ampulla of Vater), which is a valvular structure arising in the midportion of the descending
duodenum, approximately 7 to 10 cm from the pylorus. Through this point, the confluence of the
common bile duct and the main pancreatic duct (duct of Wirsung) join the duodenum. The valvular
function of the papilla is regulated through the muscular sphincter of Oddi. The minor pancreatic duct
(duct of Santorini) enters through the minor papilla proximal to the ampulla of Vater in 50% to 60% of
patients and endoscopically appears as a 1- to 3-mm polypoid structure.
The second portion of the duodenum is important surgically as it represents the entry of the
duodenum into the retroperitoneum. Surgical evaluation of this part of the duodenum requires
mobilization from its posterior and lateral attachments, described as a Kocher maneuver. This allows for
further evaluation of the duodenum, pancreatic head, and bile duct.
The third (transverse) and fourth (ascending) portions of the duodenum complete the duodenal
sweep. The third portion of the duodenum is about 10 cm in length and courses transversely from right
to left, crossing the midline anterior to the spine, aorta, and inferior vena cava. This portion is closely
attached to the uncinate process of the pancreas. The superior mesenteric artery (SMA) and vein (SMV)
course anterior to the third portion of the duodenum to provide blood supply to the gut. The transition
between the third and fourth portions of the duodenum is marked by the passage of the SMA in front of
the duodenum. The SMA forms an acute angle as it originates from the aorta. An abnormally narrow
angle can result in obstruction of the duodenum at this location (SMA syndrome). The fourth portion of
the duodenum is approximately 5-cm long and courses upward and obliquely to reach the ligament of
Treitz, marking the end of the duodenum and the return of the small bowel to the peritoneal cavity.
1231
booksmedicos.org
Figure 48-1. Arterial blood supply to the duodenum.
Following its embryologic origins, the vascular supply to the duodenum arises from branches of the
celiac trunk for the foregut portion, whereas the distal (midgut origin) duodenum is supplied by
branches of the SMA (Fig. 48-1). Venous drainage includes a series of pancreaticoduodenal veins which
drain into the SMV–portal vein system. Lymphatic drainage follows the vascular supply with drainage to
the pancreaticoduodenal nodes. From here, lymph drains superiorly to the hepatic nodes or inferiorly to
the superior mesenteric nodes.
JEJUNUM AND ILEUM

2 Distal to the ligament of Treitz, the jejunum and ileum form the remainder of the small intestine. The
boundary between the two is arbitrarily determined such that 40% of the intraperitoneal small intestine
comprises jejunum and 60% comprises ileum. This portion of the bowel is suspended within the
peritoneal cavity by a thin, broad-based mesentery that is attached to the posterior abdominal wall. The
jejunum and ileum are freely mobile within the peritoneal cavity. The jejunum is the widest portion of
the small intestine, whose caliber progressively decreases as it approaches the ileocecal valve. The
mucosa of the jejunum has a thick lining and is characterized by prominent plicae circulares that
become shorter and less frequent in the ileum. The total length of jejunum and ileum varies, but is
usually between 5 and 7 m in length. The small intestine terminates in the right lower quadrant at the
ileocecal valve. The ileocecal valve exhibits motor characteristics separate from the terminal ileum and
colon, postulated to prevent reflux of fecal material from the colon into the small intestine.2
The arterial blood supply of the jejunum and the ileum arises from the SMA. The main vascular
branches form arcades within the mesentery. The vasa recta, intestinal arterial branches, enter into the
intestinal wall without anastamosing. The vasa recta of the jejunum are straight and long, in contrast to
the vasa recta of the ileum, which are shorter with greater arborization (Fig. 48-2). The venous and
lymphatic drainage follow the arterial supply. The main venous outflow is through the SMV which,
along with the splenic vein, becomes the portal vein.
1232
booksmedicos.org
Figure 48-2. The superior mesenteric artery supplies bloodflow into the small intestinal arteries (vasa recta) which branch within
the mesentery. In the jejunum (A), the vasa recta are straight and long, this is in contrast to the vasa recta within the ileum (B),
which are shorter with greater arborization.
MICROSCOPIC ANATOMY
General Considerations
3 The wall of the small intestine is composed of four distinct layers—mucosa, submucosa, muscle, and
serosa. The role of the mucosa is absorption and secretion. The luminal mucosal surface forms circular
folds known as plica circularis or valvulae conniventes in all segments of the small intestine distal to the
first portion of the duodenum. The submucosa contains an elaborate network of blood vessels,
lymphatics, and nerves. The muscular portion of the wall includes outer longitudinal and inner circular
muscle layers. Between the muscle layers lies the myenteric (Auerbach) plexus. The muscular layers are
responsible for coordinating peristaltic movements. The outermost layer, the serosa, is composed of a
thin layer of mesothelial cells overlying loose connective tissue. The serosa covers only the anterior
surface of the retroperitoneal segments of small bowel, but it completely covers the portions of small
bowel that are invested with mesentery.
Mucosa
The mucosa lines the luminal surface of the small intestine. It consists of three layers: epithelial cells,
lamina propria, and a narrow layer of smooth muscle, the muscularis mucosae. The basic structural unit
of the mucosa is the crypt and villus. Villi are finger-like projections of mucosa 0.5 to 1 mm high
extending into the intestinal lumen that have a columnar epithelial surface and a cellular connective
tissue core of lamina propria. Each villus contains a central lacteal (lymphatic), and a vascular network
consisting of a small artery, vein, and capillaries. Ninety percent of the cells of the villi are columnar
epithelial cells responsible for absorption and secretion. These cells are 22 to 25 μm high with basally
located nuclei. The apices of these cells have microvilli, produced by numerous folds in the apical
membrane, which account for the brush border appearance. Microvilli are approximately 1 μm long and
0.08 μm wide. Their surface is coated by glycoproteins rooted in the cell membrane. These glycoprotein
filaments are referred to as the glycocalyx and are essential for digestion and absorption.3 The lateral
membranes of neighboring enterocytes are connected by tight junctions, an apparent fusion of adjoining
plasma membranes just below the level of the brush border. Movement of ions and water can occur by
1233
booksmedicos.org
either a transmembrane or a paracellular route through tight junctions, which behave as selective pores.
Between the villi lie the crypts of Lieberkühn. Stem cells within the crypts of Lieberkühn are the
source of the four major types of differentiated cells: the absorptive enterocyte, goblet cells,
enteroendocrine cells, and Paneth cells. Absorptive enterocytes differentiate as they migrate from the
crypt compartment up toward the tip of the intestinal villus. Cells then undergo apoptosis and are shed
into the intestinal lumen. Most of the intestinal lining is renewed over a period of approximately 5 days.
Despite the rapid rate of cellular turnover, intestinal epithelial cells exhibit complex patterns of gene
expression that vary according to their location on the two main spatial axes of the gut, the vertical
(crypt-villus) and horizontal (proximal to distal) axes. For example, cells destined to become
enterocytes do not begin to express a variety of genes important in digestion and absorption until the
cells have migrated out of the crypt and up the villus. In addition, many epithelial cell genes are
selectively expressed in the proximal small intestine, whereas other genes are specifically expressed
only in the ileum.4
Several other cell types are present in the mucosa. Mucus-secreting goblet cells are present in both
the crypts and villi. Goblet cells have a narrow base containing the nucleus and a wide apical membrane
with a large number of granules containing mucin. Mucin is secreted in a merocrine fashion by the
goblet cell and functions as a lubricant and has a cytoprotective function.5
Paneth cells are pyramidal cells that reside in the crypt base. They contain large eosinophilic
secretory granules located at their apical surface. It is thought that Paneth cells play a role in host
defense based on their abundant expression of lysozyme and defensins, a family of small peptides that
are also found in human neutrophils and exhibit microbicidal activity toward many different bacterial
organisms in vitro. However, examination of the role of Paneth cells in the small intestine by lineage
ablation in transgenic mice revealed no alteration in host defense mechanisms, thus the actual function
of Paneth cells are yet to be delineated.6
Enteroendocrine (also referred to as amine precursor uptake and decarboxylation, or APUD) cells may
reside in either the crypts or the villi, depending on the particular neuroendocrine substance they
produce. Specific areas of the small intestine have higher concentrations of specific neuroendocrine
substances than other areas. These cells do not contact the intestinal lumen, unlike exocrine cells, and
their secretory granules are located below the nucleus near the basement membrane. This suggests that
these cells secrete their contents into the circulation rather than into the intestinal lumen.
Submucosa
The submucosa is a dense connective tissue layer with a rich network of blood vessels, nerves, and
lymphatics. The submucosa contains Meissner plexus and is the strongest layer of the intestinal wall.
Brunner glands are found in the submucosa of the duodenum and secrete mucus and bicarbonate into
the intestinal lumen. These secretions aid in the neutralization of the gastric acid load which enters the
duodenum. Peyer patches are localized collections of lymphoid follicles that are most prominent in the
submucosa of the ileum. These are typically 8 to 10 mm in diameter and are most abundant early in life,
gradually disappearing with age.
Physiology
4 The small intestine plays important physiologic roles in motility, blood flow, growth, digestion,
absorption, immune function, and endocrine secretion. In fact, the small intestine is the largest
endocrine organ in the human body.7 The secretion of numerous hormones and neurotransmitters are
specific to distinct anatomic zones within the small intestine (Fig. 48-3). There is no specific cell mass
which produces these hormones, but rather individual cells scattered along the gastrointestinal tract.
Gastrin is a peptide produced in the gastric antrum and in the duodenum by the G cells and secreted
into the circulation in response to gastric distension, vagal stimulation, amino acids, and hypercalcemia.
Gastrin exists in three functional forms (G-34, G-17, and G-14). Its release is inhibited by low
intraluminal pH, somatostatin, secretin, gastric inhibitory peptide (GIP), vasoactive intestinal peptide
(VIP), glucagon, and calcitonin. Gastrin binds to CCK2/gastrin receptors on ECL cells causing a release
of histamine which in turn stimulates the parietal cells in a paracrine fashion. Gastrin also causes an
increase in the gastric blood flow and the release of pepsinogen by the chief cells and pancreatic
enzymes from the pancreatic centroacinar cells.
1234
booksmedicos.org
Figure 48-3. Distribution of peptide hormones in the gastrointestinal tract.
Cholecystokinin (CCK) is produced in the proximal two-thirds of the small intestine by the I cells and
released into the gut lumen. It has 4 main forms (CCK-58, CCK-39, CCK-33, and CCK-8). It shares the
final five amino acids adjacent to the C-terminus with gastrin, and this accounts for its hormonal
activity. Stimulation of I cells by amino or fatty acids causes release of CCK, this in turn stimulates
contraction and emptying of the gallbladder, increases bile flow, causes relaxation of the sphincter of
Oddi, and stimulates pancreatic enzyme secretion. CCK also has trophic effects on the small intestinal
mucosa and pancreas.
Secretin, discovered as the first gastrointestinal hormone in 1902, is a 27 amino acid peptide
produced by the S cells of the duodenum and jejunum. Secretin is released into the circulation and
intestinal lumen in response to low intraluminal pH, fatty acids, and bile salts. Water and bicarbonate
are secreted by the pancreas in response to secretin. Bicarbonate is also released from the biliary ductal
epithelium and Brunner glands in response to secretin. In turn, pancreatic enzymes are released from
the pancreas. The increased pH and the presence of pancreatic enzymes aid in the digestion of lipids.
The increased pH also provides a negative feedback loop to inhibit further production of secretin.
Secretin produces a paradoxical release of gastrin in patients with gastrinomas, but does not produce
this effect on normal individuals.
Somatostatin is a peptide hormone consisting of 14 or 28 amino acids and is produced by D cells in
the pancreatic islets, gastric antrum, and duodenum. Its primary role is inhibition of other
gastrointestinal hormones and inhibition of pancreatic, biliary, and gastric secretion. In addition,
somatostatin decreases splanchnic and portal blood flow. Somatostatin is stimulated by the presence of
fat, proteins, acid, glucose, amino acids, and CCK. Octreotide, a long-acting synthetic somatostatin
analog, is used in the treatment of variceal bleeding, hormone secreting neuroendocrine tumors,
carcinoid syndrome, and enterocutaneous and pancreatic fistulas.8
Gastrin-releasing peptide, the mammalian homolog of bombesin, is a 27 amino acid peptide which is
produced by the small intestine and is released in response to vagal stimulation. It is a prostimulatory
molecule which causes the release of most gastrointestinal hormones, with the exception of secretin. It
also has a promotility effect and stimulates endothelial proliferation. Gastric inhibitory peptide or
glucose-dependent insulinotropic peptide (GIP) is a 42 amino acid peptide produced by the K cells of the
duodenum and jejunum. It is released in response to glucose, fat, protein, and adrenergic stimulation. It
stimulates secretion of insulin and inhibits gastric acid and pepsin production. Type 2 diabetics are
1235
booksmedicos.org
resistant to the effects of GIP.
Motilin is a 22 amino acid peptide produced by the enteroendocrine cells in the duodenum and
jejunum. Release of motilin occurs during the interdigestive and fasting periods. Release may also be
related to alkalinization of the duodenum. Motilin’s main function is to stimulate the migrating
myoelectric complex. Motilin agonists such as erythromycin, are used clinically as stimulants of
gastrointestinal motility.
VIP is a 28 amino acid peptide which is produced by gastrointestinal tract neurons. It serves as a
neurotransmitter stimulating pancreatic exocrine and intestinal secretion. Conversely, it has an
inhibitory effect on gastric acid secretion. VIP is a potent vasodilator and relaxant of smooth muscle.
Neurotensin is a 13 amino acid peptide that is produced by the N cells primarily in the ileum, but also
in the proximal small intestine and colon in response to the presence of intraluminal fat. It stimulates
pancreatic bicarbonate secretion and intestinal motility. Neurotensin also serves as a trophic factor on
the small intestinal mucosa and inhibits gastric secretion.
Pancreatic glucagon and enteroglucagon are 29 and 37 amino acid peptides produced by the α-islet
cells of the pancreas and the L cells of the small intestine, respectively. Pancreatic glucagon is released
in response to low serum glucose and subsequently induces glycogenolysis, lipolysis, gluconeogenesis,
and ketogenesis. Enteroglucagon is released in response to the presence of a mixed meal and inhibits
gastric emptying and small bowel motility.
Motility
5 The coordination of movements of the gastrointestinal tract is necessary for the proper digestion of
food. Well-timed contraction and relaxation patterns are initiated in gastrointestinal nervous system
causing coordinated electrical activity and muscular movements. This may be influenced by both
internal and external factors. The small intestine has motor functions which are distinct from the other
parts of the gastrointestinal tract. The intrinsic nerves (myenteric or Auerbach plexus) provide the basis
for coordinating the circular and longitudinal smooth muscles of the small intestine. Extrinsic
sympathetic (epinephrine) stimulation slows motility while parasympathetic (acetylcholine) stimulation
increases motility.
The intrinsic electrical activity of the small intestine is based on the intestinal smooth muscle normal
resting potential. This normally is –50 to –70 mV and is maintained by Na+-K+-ATPase activity.9 The
resting potential varies by 5 to 15 mV and results in a phasic depolarization which is referred to as slow
waves, basic electrical rhythm, or pacemaker potential. These depolarizations occur at regular intervals
of approximately 11 to 13 times per minute in the duodenum and decrease to 8 to 10 times in the ileum,
but do not directly lead to muscular contractions. The electrical activity is coupled to muscular
contraction at the level of gap junctions, which are low resistance cell-to-cell connections. These gap
junctions become less regular in the midjejunum and in the distal small intestine. This causes slowing of
the frequency of contractions distally, allowing for absorption of more slowly digested intestinal
contents, including fats and bile salts.
Spike potentials represent a second mode of electrical stimulation of the small intestine. Spike
potentials result in rapid depolarization of the membrane potential. Repeated bursts of spike potentials
cause a short area of contraction. In contrast to the always present slow waves, spike potentials occur at
discrete time intervals. The coordination of a slow wave and a spike potential leads to the initiation,
duration, and frequency of rhythmic migratory small intestinal contractions.
During the interdigestive period between feeding, the small intestine follows a well-defined rhythmic
pattern. This pattern consists of muscular contractions that migrate from the stomach or duodenum,
continue on to the terminal ileum, and are regulated by the migrating motor complex (MMC). This
pattern can be broken down into four distinct phases. Phase I is a period of relative quiescence; phase II
is a period of accelerated irregular electrical spiking and muscular activity; phase III is a series of high-
amplitude rapid electrical spikes corresponding to rhythmic gut contractions; and phase IV is a period of
subsiding activity. This process occurs over a period of 90 to 120 minutes and progresses from the
proximal small bowel and terminates in the ileum. Once the MMC reaches the terminal ileum, the
process starts over again in the proximal small bowel. The circular muscles provide segmental
contraction over a 1-cm length of small intestine. These contractions occur approximately 11 to 13 times
per minute in the duodenum and decrease to 8 to 10 times in the ileum. This creates functional
compartments where prolonged exposure to the mucosa and mixing of the intestinal chyme occurs,
aiding the process of digestion and absorption. The circular muscles are also responsible for the
peristaltic waves which propagate regularly at a rate of 1 to 2 cm/sec. These regular waves may be
1236
booksmedicos.org
interspersed with rushes of contractions followed by periods of no motor activity. This rate becomes
progressively slower in the distal small intestine. These peristaltic movements serve as a method of
propelling chyme through the length of the small intestine. The total transit time from the duodenum to
the terminal ileum is approximately 220 minutes (+/–53 minutes).10 Serum motilin levels have been
found to mirror the activity of the MMC. Exogenous motilin administration has been found to increase
MMC activity.
During and immediately following times of feeding, the intestinal movements are not rhythmic, with
complexes of peristaltic and antiperistaltic contractions. This is thought to be a disruption of the MMC
from bolus feeding. This seemingly random pattern of movements allows for effective mixing of chyme.
Hormonal changes are thought to play a role in this process. Physiologic doses of neurotensin, insulin,
gastrin, and CCK cause an alteration in the MMC similar to bolus feeding. Visual and olfactory feeding
cues can also cause a disruption of the MMC. The MMC is more significantly inhibited by fatty meals as
opposed to protein or carbohydrate meals of similar caloric value. The intrinsic nervous plexus or
Meissner plexus innervating the submucosa helps to regulate mucosal absorption and secretion, but has
no control on motility.
IMMUNOLOGY
Principles of Gut Immunology
6 The lumen of the gastrointestinal tract is connected to the outside environment and comes in direct
contact with many potentially pathogenic microorganisms. Lymphocytes, macrophages, polymorphic
granulocytes and other cells that take part in immune response are distributed throughout the whole
gut. The commensal microflora have many benefits to the host by supporting digestion and keeping the
appropriate balance among different microbial species.11 The immune system is highly effective at
responding selectively to invading pathogens, yet on the other hand tolerating a much larger number of
harmless food antigens and commensal organisms. Many bacteria, viruses and parasites are digested and
enter the small intestine every day.12 Consequently, the small intestine needs a complex defense
mechanism to battle against these exposures in different ways.13
While the immune system in the small intestine is important for host defense, other mechanisms
within the small intestine also participate in host defense. Proteolytic and lipolytic enzymes are
produced in high concentrations by extraintestinal cells in the pancreas and degrade different
pathogenic agents at an early phase of digestion. In addition, mucin is produced by the enterocytes
which is cytoprotective and inhibits bacterial growth. The small intestine can actively increase
peristalsis functions to mechanically get rid of pathogenic agents, which may be potentially dangerous
to the gut. In addition, tight junctions between epithelial cells prevent penetration of bacteria in
between cells. Potential pathogens vary greatly in size, from very small viruses that are nanometer in
size, to parasites such as helminths that are macroscopically visible and quite large. To put this into the
broader picture of evolution, a large range of defense mechanisms is essential for survival of each
individual.
The primary cellular barrier in the gut that prevents antigens from encountering the immune system
is the single layer of gut epithelium. The total surface area of the small intestine is 400 m2, due not only
to intestinal length but also due to the formation of millions of villi in the small bowel which contribute
significantly to the overall surface area.14 In the upper small intestine, the bulk of antigen exposure
comes from the diet, whereas in the ileum and colon, the additional antigenic load of an abundant and
highly complex commensal microflora is prevalent. The epithelial cells of the gut mucosa have
developed features that make the intestinal epithelium an active immunologic as well as anatomic
barrier. For example, these nonclassical immune cells express major histocompatibility complex (MHC)
class I and II molecules, consistent with their ability to participate in adaptive immune recognition of
pathogenic bacteria. Small intestinal epithelial cells also express toll-like receptors on their apical
surface that enables them to detect bacterial products and to initiate an innate immune response.
Antigen-presenting dendritic cells (DCs) also send processes between gut epithelial cells without
disturbing tight junction integrity and sample commensal and pathogenic gut bacteria.15,16 The gut
epithelial barrier therefore represents a highly flexible structure that limits antigens from entering the
systemic body.
The gut-associated immune system represents one of the largest immunologic compartments in the
body. Lymphoid tissue in the gastrointestinal tract is a major part of the whole-body immune system
1237
booksmedicos.org
and consists of both aggregated (lymphoid follicles, Peyer patches) and nonaggregated (luminal,
intraepithelial and in lamina propria) immune cells. Under physiologic circumstances, oral
administration of protein antigens induces systemic unresponsiveness when the same antigen is given
parenterally (a phenomenon known as oral tolerance). In animal models, oral tolerance appears to be a
specific consequence of the immune environment in the gut, which favors the generation of regulatory
T cells.
Nonaggregated and Aggregated Lymphoid Tissue

The gut epithelium and its mucous layer form a major barrier to trap pathogens which are then
eliminated when the gut epithelium is shed and replaced by new cells deriving from stem cells in the
crypts. Several different cell types face antigenic exposure present in the intestinal lumen and include
the epithelium, neutrophils, lymphocytes, and macrophages. These luminal cells represent an initial
effector mechanism in the first front directed toward an antigenic exposure. In addition, there are also
immigrated intraepithelial lymphocytes, which are found in between epithelial cells beneath the tight
junctions. Local defense depends in part on these T lymphocytes that are nestled among gut epithelial
cells. These T cells modulate homeostasis of the gut epithelium through local production of cytokines
and have cytolytic effects. In fact, the number of intraepithelial lymphocytes can increase dramatically
in response to inflammation or infection. After exposure to antigens, these cells reenter the circulation
to initiate a systemic immune response. The lamina propria contains nonaggregated, diffusely
distributed lymphoid tissue, including different types of immune cells (Fig. 48-4). B cells in the lamina
propria undergo cytokine-induced differentiation to become active producers of immunoglobulin A
(IgA) that is secreted into the gut lumen. T cells in the lamina propria may have a different role in a
helper-inducer function for immunoglobulin production rather than a cytolytic function. Mast cells and
eosinophils are also present in the lamina propria in small numbers. They exhibit an important role in
allergic and hypersensitivity reactions as well as defense against parasites. Parasites including worms
are recognized and tagged using the monovalent immunoglobulin E (IgE) which is mostly bound to host
cell surfaces. Actual parasite killing is depending on toxic proteins secreted by eosinophils.
There are also large aggregates of lymphoid tissue found in the small intestine. These so-called Peyer
patches are localized collections of lymphoid follicles that are most prominent and macroscopically
visible in the submucosa of the ileum. Peyer patches are most prominent in children and gradually
disappear with age. Along with the nonaggregated immune system, the enormous quantity and diversity
of antigens present within the gut are also processed via Peyer patches in the lamina propria and the
mucosa-associated lymphoid tissue (MALT), which in total contains about 70% of the body’s lymphoid
cells. Another often used term to describe the immune system within the small intestine is gut-
associated lymphoid tissue (GALT). Peyer patches do not have any villi, and so-called microfold (M)
cells concentrated within the epithelium allow the selective uptake of food antigens and microorganisms
(Fig. 48-5). M cells are specific cells in the intestinal epithelium over lymphoid follicles that endocytose
antigens. M cells transport them into the underlying tissue, where they are taken up by local DCs and
macrophages.17 DCs and macrophages that receive antigens from M cells present them to T cells in the
GALT, leading ultimately to appearance of IgA-secreting plasma cells in the mucosa. B-lymphocyte
precursors proliferate in germinal centers within the Peyer patches. DCs below the epithelium can also
take up luminal antigens by pushing pseudopods up between epithelial cells.
Immunoglobulin Secretion
At an early level of exposure at the gut epithelium, M cells take up antigen and transport it
transcellularly using an endocytic mechanism into the underlying lymphoid tissues of Peyer patches.
Lymphocyte activation ensues, and these activated lymphocytes migrate into afferent lymphatics, pass
through mesenteric lymph nodes, and enter the circulation through the thoracic duct. During this
process, the lymphocytes mature into B and T lymphoblasts with an enriched population of IgA-
producing B cells.18 Passage of viable bacteria from the intact gastrointestinal tract to the mesenteric
lymph node and beyond has been termed bacterial translocation, possibly explaining septic
complications and multiple organ failure in peritonitis, burn and trauma patients. The immunogenic
integrity of the mucosa is significantly damaged by systemic injury of different kinds. A major
protective mechanism of the intestinal immune system is synthesis and secretion of IgA. In the intestine,
IgA exists as a dimer that is linked with two additional molecules – the J chain – linking two IgA
molecules, and the polymeric immunoglobulin receptor, which transports the IgA complex across the
cell and allows release of the complex, termed secretory component, into the intestinal lumen. The
1238
booksmedicos.org
transmembranous immunoglobulin receptor is produced by the intestinal epithelial cell. It is thought
that the secretory component may prevent proteolytic degradation of the IgA molecule and may
stabilize the structure of the polymeric IgA complex in an environment containing numerous proteolytic
enzymes and bacteria that would otherwise rapidly degrade it. Unlike IgG and IgM, IgA does not
activate complement and does not promote cell-mediated opsonization. The major function of secretory
IgA in host defense is protection against bacteria, viruses, and luminal antigens. Secretory IgA inhibits
the adherence of bacteria to epithelial cells. It is well known that a breast-feeding mother transfers
secretory IgA to her nursing infant, protecting the infant from bacteria and viruses that were originally
present in the mother’s gastrointestinal tract.
Figure 48-4. Small intestinal villus with associated immunologic cells.
DIGESTION AND ABSORPTION

Absorption of Water and Electrolytes
7 An average person consumes approximately 1 to 1.5 L of water per day. An additional 5 to 10 L is
secreted by the gastrointestinal tract: 1 to 2 L of saliva, 2 to 3 L of gastric secretions, 0.5 L of biliary
secretions, 1 to 2 L of pancreatic juice, and 1 L of intestinal secretions. The small intestine reabsorbs
nearly 80% of the fluid that passes through it. This dynamic process is accomplished by a rapid
bidirectional movement of fluid in the intestinal lumen. This ebb and flow of fluid in the intestinal
lumen is critical in maintaining normal homeostasis. Minor changes in intestinal permeability or rate of
flow of the intestinal contents can result in net secretion and diarrheal states.
1239
booksmedicos.org
Figure 48-5. Epithelial anatomy in the area of Peyer patches.
The tonicity of the intraluminal contents determines the overall net movement of water. In general,
after a meal is consumed, the addition of large amounts of saliva, gastric juice, and hypotonic chime
enters the proximal small intestine. Acid gastric contents are neutralized by the secretion of bicarbonate,
creating NaCl and water, and decreasing the osmotic pressure. The jejunum is effective at passively
reabsorbing water in a paracellular fashion due to its relatively large intercellular pores. As the chyme
travels through the length of the small intestine, the intercellular channels become more tightly
arranged and the movement of water becomes dependent on the active transport of solutes into the
paracellular spaces. A total of 6 to 11 L of water enters the duodenum every day, of this, less than 1 L
enters the colon.
Sodium absorption occurs through several different processes. Simple electrogenic absorption,
nonelectrolyte-stimulated absorption, and electroneutral absorption are reliant on the Na+-K+-ATPase
pump on the basolateral membrane of the cell. This pump utilizes the hydrolysis of ATP to provide the
necessary energy to move 3 Na+ ions out of the cell while transporting 2 K+ ions into the cell against
an electrical gradient. This process maintains a negatively charged low Na+ intracellular environment,
allowing for several mechanisms of absorption at the apical membrane. Simple electrogenic absorption
of sodium is the process of an influx of Na+ ions from the sodium-rich intestinal lumen into the
negatively charged low-sodium intracellular environment. This process is indirectly energy dependent,
as it relies on the function of the Na+-K+-ATPase pump on the basolateral membrane to maintain the
low sodium environment and the negative intracellular charge. This process can be inhibited by oubain,
a Na+-K+-ATPase inhibitor.19
Nonelectrolyte-stimulated sodium absorption occurs when sodium is coupled with an organic solute,
such as glucose, amino acids, dipeptides, tripeptides, and bile acids. Sodium is preferentially transported
down its electrochemical gradient which is created by the Na+-K+-ATPase pump on the basolateral
membrane of the cell, providing the necessary energy to transport the organic solute against its gradient
(Fig. 48-6A). Electroneutral absorption of sodium chloride occurs through a process which couples two
neutral ion countertransport mechanisms. Na+ is exchanged for H+ and Cl− is exchanged for HCO3–,
resulting in no net change in intracellular charge. This process provides an influx of NaCl in exchange
for H+ HCO3– efflux. This electroneutral transfer of ions allows for intracellular pH regulation and for
sodium and chloride transport (Fig. 48-6B).
Figure 48-6. Mechanisms of sodium absorption in the small intestine: solute-coupled Na+ absorption (A) and electroneutral NaCl
absorption (B).
While the majority of chloride is absorbed by electroneutral transfer, chloride is also absorbed by
passive diffusion in a paracellular fashion. This is due to the slightly positive interstitium when
compared to the gut lumen, allowing the negatively charged chloride ions to be absorbed. An additional
important source of chloride transport involves the reabsorption of chloride ions contained within
gastric hydrochloric acid secretions. Chloride is a major determinant of the regulation of fluid secretion
into the small intestine and in intestinal hydration.20
Bicarbonate absorption occurs primarily in the jejunum and requires the formation of carbon dioxide
in the intestinal lumen from HCO3− and H+. This creates an increase in the partial pressure of carbon
1240
booksmedicos.org
dioxide in the intestinal lumen. Carbon dioxide subsequently diffuses back into the enterocyte and is
enzymatically cleaved into H+ and HCO3− by the action of carbonic anhydrase. HCO3− diffuses into the
interstitium and H+ is resecreted in exchange for other cations, predominantly Na+. In the duodenum
and ileum, HCO3− is secreted in exchange for Cl−. This efflux of HCO3− provides a mechanism to
neutralize gastric acid entering into the duodenum. HCO3− secretion in the ileum most likely helps
maintain acid–base equilibrium, although this process is not well understood.21
Approximately 90 mEq/d of potassium is ingested in a normal diet of which 90% is absorbed. An
equal amount of potassium is excreted in the urine as is absorbed in the intestine, allowing maintenance
of potassium homeostasis. The majority of absorption occurs in the small intestine mainly through
passive mechanisms.22 This process is thought to occur through intercellular pores or through an H+-K+
exchange pathway facilitated by the intracellular electrochemical gradient which is created
predominantly by the basolateral ATPase pump. Intracellular K+ then diffuses across the basolateral
membrane by a K+ channel or carrier.
Mineral Absorption
Mineral absorption is necessary for the proper form and function of the human body. These inorganic
elements are responsible for approximately 4% to 6% of a person’s mass. Calcium accounts for
approximately 50% of this mass, phosphate provides an additional 25%, and a variety of other minerals
constitute the remaining 25%. Many of these minerals are best absorbed in their ionized forms, which is
aided by the presence of hydrochloric acid in the gastric lumen. Calcium, phosphate, magnesium, sulfur,
sodium, chloride, and potassium are considered macrominerals, with daily requirements exceeding 100
mg/d. Microminerals (trace minerals) include iron, zinc, copper, manganese, iodine, selenium, fluoride,
molybdenum, chromium, and cobalt with daily requirements of less than 15 mg/d.
Approximately 1 g of calcium is consumed per day, mainly from dairy products. Once in its ionized
form, calcium is primarily absorbed in the duodenum, although this process occurs throughout the
length of the small intestine. When calcium is present intraluminally at low levels, it is transported
across the apical membrane of the enterocyte by carrier-mediated facilitated diffusion. Once calcium is
in the cytoplasm, it is bound to calcium-binding proteins and delivered to the basal membrane. Calcium
is then transferred into the interstitium by a Ca2+-ATPase pump. This process is indirectly regulated by
parathyroid hormone (PTH). PTH in low-calcium states promotes conversion of vitamin D to its active
form 1,25-(OH)2 vitamin D. This activated form of Vitamin D causes an increase in the expression of
both calcium-binding proteins and Ca2+-ATPase, causing an increase in the absorption of calcium by the
small intestine.23,24 When intraluminal calcium is in excess of its capacity to be actively transferred by
the apical membrane’s carrier-mediated mechanism, passive paracellular calcium absorption occurs in
the distal small intestine.
Absorbable dietary sources of iron are typically either contained within a protein, such as heme, or as
a ferrous (Fe2+) ion. Iron-containing proteins are usually from ingested meats, whereas ferrous forms
are typically present in vegetables, grains, and fruits. Vitamin C (ascorbic acid) increases iron
absorption by reducing the ferric (Fe3+) ion into the more soluble ferrous state. Absorption of iron is
facilitated by carrier-mediated translocation across the apical membrane of the enterocyte in the
duodenum and proximal jejunum. Once in the cytoplasm, the ferrous ion is released by enzymatic
cleavage. Ferrous ions may be stored intracellularly by ferritin or transported into the circulation by
transferrin. The process of iron absorption is regulated in the enterocyte by hypoxia-inducible factor
signaling and iron-regulatory proteins. Systemically, the central iron regulatory hormone is hepatic
hepcidin. Hepatic hepcidin regulates iron absorption and mobilization from systemic stores by inhibiting
ferroportin, a cellular iron exporter.25
Carbohydrate Digestion and Absorption

Carbohydrates are a staple in many diets and provide a major source of daily caloric intake. In Western
diets, 400 g of carbohydrates are consumed by the average adult daily, providing 1,600 kcal (4 kcal/g
of carbohydrate). Carbohydrates are present in three main digestible forms: complex starches,
disaccharides, and simple sugars. Complex starches account for approximately 60% of daily
carbohydrate intake. The most common form is amylopectin which consists of glucose linked in a linear
fashion with α(1,4)-glycosidic bonds with branch points consisting of α(1,6)-glycosidic linkages
occurring after approximately every 20 to 26 glucose moieties. Amylose is a long linear grouping of
glucose molecules connected with α(1,4)-glycosidic bonds without branch points. Disaccharides, mainly
sucrose and lactose, are the next most common source of dietary carbohydrates, representing nearly a
1241
booksmedicos.org
third of daily intake. Sucrose disaccharides are comprised of glucose–fructose dimers, whereas lactose
disaccharides consist of glucose–galactose dimers.
The complex starches, amylopectin and amylose, are digested with the aid of salivary and pancreatic
amylase. Salivary amylase contributes a small amount to this process as it is inactivated by gastric acid,
leaving the remainder of this process to be completed by pancreatic amylase. This process yields
maltose, which are glucose dimers with α(1,4)-glycosidic bonds, and maltotriose, which are glucose
trimers with α(1,4)-glycosidic bonds. In addition, α-dextrins are produced with an average of 6 glucose
moieties with α(1,4)-glycosidic bonds and side branches linked by α(1,6)-glycosidic bonds. This
digestive process is usually completed before the carbohydrate bolus leaves the duodenum. These small
oligosaccharides along with ingested disaccharides, typically sucrose and lactose, are then further
digested by the brush border saccharidases in the jejunum.
The brush border of the small bowel contains specific enzymes which through catalytic reactions
hydrolyze these oligo- and disaccharides into their component monosaccharide moieties, such as
glucose, galactose, and fructose. Once broken down into their basic subunits, these monosaccharides can
be transported across the apical cell membrane. A sodium-dependent hexose transporter (SGLUT-1) is
required for the transport of glucose and galactose as they utilize the same carrier mechanism. The
cotransportation of these monosaccharides with sodium is dependent on the Na+-K+-ATPase pump on
the basolateral membrane to maintain a sodium gradient allowing for this influx. Fructose is transported
in a carrier mediated diffusion dependent manner by GLUT5 and does not require sodium as a
cotransporter (Fig. 48-7). The movement of monosaccharides into the cellular cytoplasm provides an
additional gradient by which water is absorbed by the enterocytes from the intestinal lumen. The
monosaccharides are then transported across the basolateral membrane by GLUT2. This hexose
transporter allows for the diffusion of all three monosaccharides into the extracellular space and
ultimately into the portal blood flow. A small portion of these monosaccharides may be used by the
enterocyte, but the majority is transported through the cell.
Nondigestible carbohydrates (dietary fiber) such as cellulose are thought to be an important part of a
normal diet even though they do not provide dietary calories. Dietary fiber is present in grains,
vegetables, and pulpy fruits. Dietary fiber helps decrease bowel transit time by absorbing water in the
intestinal lumen. In addition, fiber can absorb organic materials such as lipids and bile salts and
inorganic minerals such as zinc, calcium, and magnesium. These actions of fiber are thought to play a
role in preventing carcinogenesis and in helping to maintain normal serum lipid profiles. Unfortunately,
fiber is underrepresented in most Western diets.
Protein Digestion and Absorption

Protein consumption is essential to the daily diet. An average adult requires 0.75 g/kg of protein per
day, although this requirement may be significantly increased during childhood, pregnancy, and times
of significant illness. Protein provides an important caloric energy source as well as the essential
building blocks for production of new proteins. A nearly equal amount of protein is ingested daily from
dietary sources (70 to 100 g) as is provided by endogenous proteins (50 to 60 g of protein per day) in
the small intestine from secreted enzymes, desquamated cells, and plasma protein leakage. Nearly 90%
of this protein load is metabolized in a similar fashion to dietary proteins.
The initial digestion of protein begins with the activation of pepsinogen to pepsin in the acid
environment of the stomach. Pepsin hydrolyzes protein into its component amino acids; however this
action only represents a small part of overall protein digestion. The majority of protein digestion occurs
in the small intestine by pancreatic peptidases and proteases. Pancreatic enzymes flow into the
duodenum, initiating this phase of protein digestion. These pancreatic proteases are initially released as
proenzymes (zymogens). These zymogens are inactive and require a further catalytic process to occur
for their activation. This is initiated by the brush border enzyme enteropeptidase (enterokinase) in the
duodenum. Endopeptidase cleaves trypsinogen into the active enzyme trypsin. Trypsin in turn activates
the other zymogens into their active endopeptidases (trypsin, chymotrypsin, and elastase) which
hydrolyze internal peptide bonds. Additional protein digestion is performed by exopeptidases
(caroxypeptidase A and B) which are able to cleave amino acids from the C-terminal ends of proteins.
Seventy percent of the process results in short oligopeptides of 2 to 6 amino acids and the remaining
30% produces single amino acids.
1242
booksmedicos.org
Figure 48-7. Digestion and absorption of carbohydrates.
Short oligopeptides are further digested by enzymes in the brush border of the small intestine or
within the cell cytoplasm. Single amino acids, dipeptides, and tripeptides are able to diffuse through the
apical membrane into the cytoplasm. Single amino acids are cotransported into the cytoplasm with
sodium along an electrochemical gradient. This electrochemical gradient is maintained by the Na+-K+-
ATPase pump on the basolateral cell membrane. At least four separate transport mechanisms exist for
the various electrochemical properties of amino acids which are transported (neutral, dibasic, acidic,
and imino). Peptides greater than 3 amino acids in length are broken down into smaller peptides by
enzymes in the brush border. The resultant dipeptides and tripeptides are then moved into the
cytoplasm along with H+ by a cotransporter PepT1, where they are hydrolyzed by specific peptidase
into their component amino acids. Transport of amino acids into the cytosol provides an osmotic
gradient by which water is further absorbed from the intestinal lumen. A small portion of the processed
amino acids are utilized by the enterocyte, and the vast majority is shuttled into the portal blood flow
via amino acid transporters on the basolateral membrane.
Fat Digestion and Absorption

Forty percent of the average daily caloric intake (60 to 90 g) in a Western diet is in the form of fat.
Ninety percent of these ingested fats are triglycerides, while the remainder is comprised of cholesterol,
phospholipids, and fat-soluble vitamins. The initiation of lipid digestion occurs when CCK is stimulated
by the presence of fatty acids on the duodenal mucosa. CCK in turn stimulates pancreatic secretion of
lipase and its cofactor colipase. Lipase hydrolyzes triglycerides at the 1 and 3 positions of the glycerol
backbone, yielding two fatty acids and a monoglyceride (a fatty acid esterified to glycerol). Cholesterol
and fat-soluble vitamins are hydrolyzed by pancreatic cholesterol esterase and phospholipids by
phopholipase A2. The products of lipolysis interact with bile salts to form water soluble micelles. Mixed
micelles are 50 to 400 Å in diameter and are a combination of fatty acids, bile salts, and
monoglycerides. The structure of a micelle is composed of an inward facing hydrophobic region and a
hydrophilic region facing outward toward the aqueous environment of the intestinal lumen. Due to the
hydrophobic core, cholesterol, phospholipids, and fat-soluble vitamins can reside within the micelle
structure. Micelles are able to interact with the mucosal cells and empty their contents into the
cytoplasm. This occurs by the process of dissolution of the micelles into the lipid bilayer of the mucosal
cell. Once this is completed, the components of the micelle are ready to reform with new lipid
components to repeat this process. There is no energy consumed directly in the transfer of lipids into
the cell cytoplasm.
Once in the cytoplasm, long-chain fatty acids and β-monoglycerides are carried by cytosolic fatty
acid–binding proteins to the smooth endoplasmic reticulum (SER). In the SER, resynthesis of
triglycerides occurs. These triglycerides are further processed in the Golgi apparatus where a
phospholipid and an apoprotein coat are added to form a chylomicron. Chylomicrons are 90%
triglyceride; the remaining 10% is composed of phospholipid, cholesterol, and protein. These large
1243
booksmedicos.org
particles are 750 to 6,000 Å in diameter. Before exiting the Golgi apparatus, the chylomicrons are
packaged into secretory vesicles. They exit the cell membrane by exocytosis and enter the central
lacteal of the villus and the intestinal lymphatic system. In addition, enterocytes also produce smaller
lipoprotein particles, very low density lipoproteins, which contain a higher cholesterol/triglyceride ratio
and provide the major route of entry for dietary cholesterol into the lymphatic system.
Short chain fatty acids contain less than 8 carbon atoms and are water soluble. This allows these
molecules to enter and exit the enterocyte by simple diffusion independent of bile micelles or
chylomicrons. Medium chain triglycerides consist of 6 to 12 carbon atoms and can be absorbed by
simple diffusion or through the previously mentioned process of transport of long chained fatty acids
via the formation of bile micelles and chylomicrons. Both short and medium chain fatty acids may enter
the portal circulation without entering into the lymphatics. The majority of dietary fat is processed and
absorbed in the duodenum and upper jejunum.
Absorption of Bile Salts

Approximately 95% of the bile salts secreted into the intestine are reabsorbed and returned to the liver
through the portal circulation. Once in the liver, these bile salts are reprocessed and secreted and stored
in the gallbladder in preparation for the next meal. This process of recycling of bile salts is referred to
as the enterohepatic circulation. This reabsorption occurs by both passive and active means. A small
amount of bile salts are passively reabsorbed along the entire length of the small intestine. The majority
of bile salts, however, are reabsorbed though an active Na+-dependent transport mechanism in the
terminal ileum. Bile, which is not reabsorbed, passes into the colon where it is deconjugated by
bacteria. This process increases the solubility of the bile and promotes further passive absorption. High
concentrations of bile salts within the colon inhibit sodium and water reabsorption, resulting in
diarrhea. Patients who have undergone resection of their ileum may suffer from diarrhea due to this
process. These patients may be treated with the bile-binding resin, cholestyramine, to help alleviate
their symptoms.
Vitamin Absorption
Fat-soluble vitamins (A, D, E, and K) are incorporated into micelles along with fats in order to pass into
the enterocyte. These vitamins are then processed and packaged into chylomicrons so that they can exit
into the lymphatic system. Water-soluble vitamins are absorbed in the jejunum and ileum through a
variety of mechanisms. Vitamin C (ascorbic acid), biotin, and niacin are transported by Na+-dependent
mechanisms. Folate, vitamin B1 (thiamine), and vitamin B2 (riboflavin) are absorbed by Na+-
independent mechanisms and vitamin B6 is absorbed by passive diffusion.25
Vitamin B12 (cobalamin) absorption is dependent on the presence of intrinsic factor, a glycoprotein
produced by the gastric parietal cells. One molecule of intrinsic factor binds two molecules of cobalamin
to form a complex which attaches to a specific membrane receptor in the terminal ileum. Unbound
cobalamin cannot be absorbed. Cobalamin becomes unbound from its complex in the enterocyte and
exits from the cell into the portal circulation with the aid of B12-binding proteins called transcobalamins.
Cobalamin is essential for DNA synthesis and a deficiency usually presents with megaloblastic anemia.
Inability to absorb sufficient amounts of cobalamin may be due to lack of intrinsic factor after proximal
or total gastrectomy, autoimmunity to gastric parietal cells or intrinsic factor, or atrophic gastritis. In
addition, cobalamin-intrinsic factor complexes may fail to be absorbed due to distal ileal disease or
resection, and cobalamin deficiency may occur from bacterial overgrowth due to bacterial
overconsumption of cobalamin.
Small Intestinal Microbiota

8 The importance of the microbiota of the small intestine on metabolism and its impact on health and
disease processes are increasingly being realized. The small intestine is not highly populated by bacteria
due to its relatively inhospitable environment, which is comprised of a variety of antimicrobial proteins,
immunoglobulins, and a low pH. Bacterial populations of the small intestine have been estimated at
103/g in the duodenum to 108/g in the distal ileum, but despite these relatively low populations there is
evidence that there is interplay between the microbes and the intestinal lining that may directly affect
intestinal health.26 The role of microbes and bile acid metabolism is relatively well understood, but new
findings about the regulation of bile acid conjugation are cited as possible factors in irritable bowel
disease and inflammatory bowel disease.27 Metabolism of fatty acids, dietary fiber, and amino acids
1244
booksmedicos.org
alter the production of microbial anti-inflammatory and proinflammatory factors and is thought to play
an important role in mucosal integrity and translocation, as well as, hepatic function and may have a
role in the pathogenesis of nonalcoholic fatty liver disease.28–32 While the exact mechanisms of many of
the interactions between the gut microflora and the small intestinal microenvironment are still
speculative, it has become evident that a symbiotic environment is present which, at least in part, is
responsible for proper homeostasis of the small intestine.
References
1. Kluth D, Jaeschke-Melli S, Fiegel H. The embryology of gut rotation. Semin Pediatr Surg
2003;12(4):275–279.
2. Cohen S, Harris LD, Levitan R. Manometric characteristics of the human ileocecal junctional zone.
Gastroenterology 1968;54(1):72–75.
3. Holmes R, Lobley RW. Intestinal brush border revisited. Gut 1989;30(12):1667–1678.
4. Rubin DC. Spatial analysis of transcriptional activation in fetal rat jejunal and ileal gut epithelium.
Am J Physiol 1992;263(6 Pt 1):G853–G863.
5. Trier JS. Studies on small intestinal crypt epithelium. I. The fine structure of the crypt epithelium of
the proximal small intestine of fasting humans. J Cell Biol 1963;18:599–620.
6. Garabedian EM, Roberts LJ, McNevin MS, et al. Examining the role of Paneth cells in the small
intestine by lineage ablation in transgenic mice. J Biol Chem 1997;272(38):23729–23740.
7. Englander E, Greeley J. Postpyloric Gastrointestinal Peptides. San Diego: Elsevier; 2005.
8. Weckbecker G, Lewis I, Albert R, et al. Opportunities in somatostatin research: biological, chemical
and therapeutic aspects. Nat Rev Drug Discov 2003;2(12):999–1017.
9. Casteels R. Membrane potential in smooth muscle cells. In Bulbring E, Brading A, Jones A, eds.
Smooth Muscle: An Assessment of Current Knowledge. Austin, TX: University of Texas Press;
1981:105–126.
10. Ofori-Kwakye K, Fell JT, Sharma HL, et al. Gamma scintigraphic evaluation of film-coated tablets
intended for colonic or biphasic release. Int J Pharm 2004;270(1–2):307–313.
11. Xavier RJ, Podolsky DK. Microbiology. How to get along–friendly microbes in a hostile world.
Science 2000;289(5484):1483–1484.
12. Kraehenbuhl JP, Corbett M. Immunology. Keeping the gut microflora at bay. Science
2004;303(5664):1624–1625.
13. Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science
2005;307(5717):1920–1925.
14. Hayday A, Viney JL. The ins and outs of body surface immunology. Science 2000;290(5489):97–
100.
15. Niess JH, Reinecker HC. Lamina propria dendritic cells in the physiology and pathology of the
gastrointestinal tract. Curr Opin Gastroenterol 2005;21(6):687–691.
16. Pasare C, Medzhitov R. Toll-like receptors: Balancing host resistance with immune tolerance. Curr
Opin Immunol 2003;15(6):677–682.
17. Niess JH, Brand S, Gu X, et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and
bacterial clearance. Science 2005;307(5707):254–258.
18. Macpherson AJ, Uhr T. Induction of protective IgA by intestinal dendritic cells carrying commensal
bacteria. Science 2004;303(5664):1662–1665.
19. Charney AN, Donowitz M. Functional significance of intestinal Na+-K+-ATPase: In vivo ouabain
inhibition. Am J Physiol 1978;234(6):E629–E636.
20. Barrett KE, Keely SJ. Chloride secretion by the intestinal epithelium: molecular basis and
regulatory aspects. Annu Rev Physiol 2000;62:535–572.
21. Minhas BS, Sullivan SK, Field M. Bicarbonate secretion in rabbit ileum: electrogenicity, ion
dependence, and effects of cyclic nucleotides. Gastroenterology 1993;105(6):1617–1629.
22. Agarwal R, Afzalpurkar R, Fordtran JS. Pathophysiology of potassium absorption and secretion by
the human intestine. Gastroenterology 1994;107(2):548–571.
23. Cai Q, Chandler JS, Wasserman RH, et al. Vitamin D and adaptation to dietary calcium and
1245
booksmedicos.org
phosphate deficiencies increase intestinal plasma membrane calcium pump gene expression. Proc
Natl Acad Sci U S A 1993; 90(4):1345–1349.
24. Walters JR. Calbindin-D9k stimulates the calcium pump in rat enterocyte basolateral membranes.
Am J Physiol 1989;256(1 Pt 1):G124–D128.
25. Said HM. Recent advances in carrier-mediated intestinal absorption of water-soluble vitamins. Annu
Rev Physiol 2004;66:419–446.
26. Leser TD, M⊘lbak L. Better living through microbial action: the benefits of the mammalian
gastrointestinal microbiota on the host. Environ Microbiol 2009;11(9):2194–2206.
27. Joyce SA, Gahan CG. The gut microbiota and the metabolic health of the host. Curr Opin
Gastroenterol 2014;30(2):120–127.
28. Elamin EE, Masclee AA, Dekker J, et al. Ethanol metabolism and its effects on the intestinal
epithelial barrier. Nutr Rev 2013;71(7):483–499.
29. Everard A, Cani PD. Diabetes, obesity and gut microbiota. Best Pract Res Clin Gastroenterol
2013;27(1):73–83.
30. Keshavarzian A, Fields JZ, Vaeth J, et al. The differing effects of acute and chronic alcohol on
gastric and intestinal permeability. Am J Gastroenterol 1994;89(12):2205–2211.
31. Wang HB, Wang PY, Wang X, et al. Butyrate enhances intestinal epithelial barrier function via up-
regulation of tight junction protein Claudin-1 transcription. Dig Dis Sci 2012;57(12):3126–3135.
32. Willemsen LE, Koetsier MA, van Deventer SJ, et al. Short chain fatty acids stimulate epithelial
mucin 2 expression through differential effects on prostaglandin E(1) and E(2) production by
intestinal myofibroblasts. Gut 2003;52(10):1442–1447.
1246
booksmedicos.org
Chapter 49
Ileus and Bowel Obstruction

David I. Soybel and Ariel P. Santos
Key Points
1 Peritoneal adhesions account for more than half of small bowel obstruction (SBO) cases.
2 In simple obstruction the intestinal lumen is partially or completely occluded without compromise of
intestinal blood flow. Simple obstructions may be complete, meaning that the lumen is totally
occluded, or incomplete, meaning that the lumen is narrowed but permitting distal passage of some
fluid and air. In strangulation obstruction, blood flow to the obstructed segment is compromised and
tissue necrosis and gangrene are imminent.
3 Four key symptoms that are associated with acute mechanical bowel obstruction include abdominal
pain, vomiting, distention, and obstipation; abdominal pain out of proportion to physical findings
should raise concern about rapidly evolving closed-loop obstruction and the need for urgent
resuscitation and operation.
4 Use of water-soluble contrast may be both diagnostic and therapeutic.
5 Increasingly, computed tomography (CT) is the “go-to” imaging modality to detect and identify the
likely site and source of obstruction.
6 Conservative management consisting of intravenous hydration, nasogastric decompression, and
restoration of electrolyte balance is a cornerstone of initial management of any patient suspected of
having intestinal obstruction.
7 Open exploratory laparotomy is the gold standard in treating unresolved SBO but laparoscopic
management should be considered in select group of patients. Types of intestinal obstruction that are
more likely to lead to strangulation and the need for urgent/emergent operation include closed-loop
obstructions, obstruction that occurs without a prior history of operation, and obstructions that occur
after laparoscopic procedures.
8 Ileus denotes underlying alterations in motility of the gastrointestinal tract, leading to functional
obstruction.
9 Postoperative ileus (POI) can be differentiated from SBO with the use of contrast CT and
enteroclysis imaging techniques.
10 POI is often self-limiting; less frequent interventions are required for prolonged POI, if proper
precautions have been taken during surgery.
INTRODUCTION AND HISTORICAL PERSPECTIVE

The purpose of this chapter is to provide an overview of the pathophysiology, natural history, diagnosis,
and management of acute obstruction and ileus of the small and large intestines. The development of
the modern approach to intestinal obstruction and ileus paralleled the development of techniques for
safe abdominal surgery. Chief among these accomplishments were the discovery of safe general
anesthetics, the popularization of aseptic methods in the operating rooms and management of wounds,
and the development of techniques for intestinal resection, intestinal anastomosis, and colostomy. The
foundations of the recognition and management of intestinal obstruction and ileus are attributed to
Frederick Treves.1–3 In 1884, he published a detailed discussion of the etiologies (including adhesions)
and surgical management of mechanical intestinal obstruction.1 Treves also distinguished mechanical
from nonmechanical (i.e., paralytic) causes of intestinal distention, classifying the latter causes under
the term ileus. From 1880 to 1925, proximal intestinal decompression was recognized to provide relief
from the symptoms of mechanical obstruction or ileus.3 In 1933, Wangensteen and Paine reported the
efficacy of gastrointestinal intubation in relieving symptoms of intestinal distention caused by intestinal
obstruction or from the ileus that resulted from laparotomy.4,5 Subsequently, Wangensteen and Rea
1247
booksmedicos.org
provided experimental evidence that the source of gaseous distention in cases of obstruction or ileus
was swallowed air.6 The value of intravenous fluid resuscitation in experimental models of intestinal
obstruction was recognized as early as 19127 and became a principle of care of the patients with
intestinal obstruction in the late 1920s. By 1920, plain abdominal radiographs were used in diagnosis of
intestinal obstruction.3 Thus, the principles of early diagnosis, rapid intravenous fluid resuscitation,
gastrointestinal decompression, and early operation to avoid intestinal gangrene and peritonitis, were
established well before the advent of antibiotic therapy, invasive hemodynamic monitoring, and
parenteral nutrition.8 These early developments were most important in reducing morbidity and
mortality of mechanical intestinal obstruction and ileus.9
MECHANICAL OBSTRUCTION OF THE INTESTINES

Terminology and Classification
The term mechanical obstruction means that luminal contents cannot pass through the gut tube because
the lumen is blocked. This obstruction is in contrast with neurogenic or functional obstructions in which
luminal contents are prevented from passing because of disturbances in gut motility that prevent
coordinated peristalsis from one region of the gut to the next. This latter form of obstruction is
commonly referred to as ileus in the small intestine and pseudo-obstruction in the large intestine. In
simple obstruction the intestinal lumen is partially or completely occluded without compromise of
intestinal blood flow. Simple obstructions may be complete, meaning that the lumen is totally occluded
(Fig. 49-1), or incomplete, meaning that the lumen is narrowed but permitting distal passage of some
fluid and air. In strangulation obstruction, blood flow to the obstructed segment is compromised and
tissue necrosis and gangrene are imminent. Strangulation usually implies that the obstruction is
complete, but some forms of partial obstruction can also be complicated by strangulation.
Figure 49-1. Schematic illustration of different forms of simple mechanical obstruction. Simple obstruction is most often due to
adhesion (A), groin hernia (B), or neoplasm (C). The hernia can act as a tourniquet, causing a closed-loop obstruction and
strangulation.
1248
booksmedicos.org
1 The various forms of mechanical intestinal obstruction can be classified according to different but
overlapping schemes. Most commonly, obstruction is classified according to etiology. As detailed in
Table 49-1, distinctions are drawn between intraluminal obturators such as foreign bodies or gallstones,
intramural lesions such as tumors or intussusceptions, and extrinsic or extramural lesions such as
adhesions. Adhesions are the most common cause of intestinal obstruction, accounting for more than
half of all cases. In order to highlight the pathophysiology, presentation, and natural history, however,
it is useful to classify obstruction according to the location of the obstructing lesion. Proximal or “high”
obstructions involve the pylorus, duodenum, and proximal jejunum. Intermediate levels of obstruction
involve the intestine from the midjejunum to the midileum. Distal levels of obstruction arise in the
distal ileum, ileocecal valve, and proximal colon whereas the most distant or “low” obstructions would
arise in regions beyond the transverse colon. As shown in Table 49-2, clinical symptoms and signs of
obstruction (pain, vomiting, abdominal distention, and gas pattern on abdominal radiographs) vary with
the level of obstruction.
It is also important to distinguish between open-loop and closed-loop obstructions. An open-loop
obstruction occurs when intestinal flow is blocked but proximal decompression is possible through
vomiting. A closed-loop obstruction occurs when inflow to the loop of bowel and outflow from the loop
are both blocked. This obstruction permits gas and secretions to accumulate in the loop without a means
of decompression, proximally or distally. Examples of closed-loop obstructions are torsion of a loop of
small intestine around an adhesive band (Fig. 49-2), incarceration of the bowel in a hernia, volvulus of
the cecum or colon, or development of an obstructing carcinoma of the colon with a competent ileocecal
valve. The primary symptoms of a closed-loop obstruction of the small intestine are sudden, severe
midabdominal pain and vomiting whereas symptoms of the large intestine are pain and sudden
abdominal distention. This pain often occurs before associated findings of localized abdominal
tenderness or involuntary guarding. When signs of peritoneal irritation or frank peritonitis develop,
there is a high level of suspicion that the viability of the bowel is compromised.
Table 49-1 Classification of Adult Mechanical Intestinal Obstructions
Pathophysiology of Intestinal Obstruction

Local Effects of Bowel Obstruction
When a loop of bowel becomes obstructed, intestinal gas and fluid accumulate. Stasis of luminal content
favors bacterial overgrowth, alters intestinal fluid transport properties and motility, and causes
variations in intestinal perfusion and lymph flow. Luminal contents and volume, bacterial proliferation,
and alterations in motility and perfusion work in concert to determine the rate at which symptoms and
complications develop. Each of these factors merits discussion in some detail.
Intestinal Gas. Approximately 80% of the gas seen on plain abdominal radiographs is attributable to
swallowed air.6 Approximately 70% of the gas in the obstructed gut is inert nitrogen.10 Oxygen accounts
for 10% to 12%, CO2 for 6% to 9%, hydrogen 1%, methane 1%, and hydrogen disulfide 1% to 10%. In
the setting of acute pain and anxiety, patients with intestinal obstruction may swallow excessive
amounts of air. Passage of such swallowed air distally is prevented by nasogastric suction.
1249
booksmedicos.org
Intestinal Flora. An important contribution to normal digestive function comes from its bacterial
population.11 In patients with normal gastric acid secretion, the chyme entering the duodenum is sterile.
The small numbers of bacteria that are found in stomach and proximal intestine are aerobic, gram-
positive species found in the oropharynx. Distally, in the ileum and colon, gram-negative aerobes are
present and anaerobic organisms predominate. Total bacterial counts in normal feces reach 1011
organisms per gram of fecal matter. Control of the bacterial populations depends on intact motor
activity of the intestines and the interactions of all species present. This ecology can be disturbed by
antibiotic therapy or by surgical reconstructions that result in stasis within intestinal segments.
Intestinal bacteria serve several functions, including metabolism of fecal sterols, releasing the small-
chain fatty acids that are an important food source for colonocytes; metabolism of fecal bile acids, fat-
soluble vitamins (e.g., vitamin K) and vitamin B12; and breakdown of complex carbohydrates and
organic matter, leading to formation of CO2, H2, and CH4 gases.9 Considerable evidence suggests that
the normal flora may contribute to baseline levels of intestinal secretion and, perhaps, normal intestinal
motility. Under baseline conditions, the small intestines in germfree animals are frequently dilated, fluid
filled, and without peristalsis.12,13
Table 49-2 Symptoms and Signs of Bowel Obstruction
Figure 49-2. Schematic illustration of a closed-loop obstruction. The small intestine twists around its mesentery, compromising
inflow and outflow of luminal contents from the loop. Also, the vascular supply to the loop may be compromised due to the
twisting of the mesentery. The risk of strangulation is high.
In recent years, the role of bacterial toxins in mediating the mucosal response to obstruction has
received increasing attention. In germfree dogs, luminal accumulation of fluid is not observed and
absorption continues.13 In addition, it is well recognized that bacterial endotoxins can stimulate
secretion, possibly via release or potentiation of activity of neuroendocrine substances and
prostaglandins.12 Finally, since a substantial part of systemic microvascular and hemodynamic responses
to endotoxemia appear to be attributable to heightened synthesis of nitric oxide,14,15 it seems likely that
mucosal response to local inflammation and endotoxin release will also be altered by conditions
1250
booksmedicos.org
modifying the synthesis or activity of nitric oxide. The role of nitric oxide in mucosal fluid and
electrolyte movements is currently under active investigation.16,17
Intestinal Fluid. Classical experimental studies established that fluid accumulates intraluminally with
open- or closed-loop small intestinal obstruction.9,11,18 Factors contributing to the accumulation of fluid
include intraluminal distention and pressure, release of prosecretory and antiabsorptive hormones and
paracrine substances, changes in mesenteric circulation, and elaboration and luminal release of bacterial
toxins. Experimental studies and clinical investigation19,20 demonstrated that elevation of luminal
pressures above 20 cm H2O inhibits absorption and stimulates secretion of salt and water into the lumen
proximal to an obstruction. In closed-loop obstructions, luminal pressures may exceed 50 cm H2O and
may account for a substantial proportion of luminal fluid accumulation.21 In simple, open-loop
obstructions, distention of the lumen by gas rarely leads to luminal pressures higher than 8 to 12 cm
H2O.22 In open-loop obstructions, the contributions of high luminal pressures to hypersecretion may not
be important.
The release of endocrine/paracrine substances remains relatively uncharacterized in states of
mechanical bowel obstruction.23,24 Suggestions have been made that vasoactive intestinal polypeptide
(VIP) may be released from the submucosal and myenteric plexuses within the gut wall, promoting
epithelial secretion and inhibiting absorption.24,25 Use of prostaglandin synthesis inhibitors has also
implicated excess release of prostaglandins.23 Further work may be expected to focus on the role of
luminal factors such as irritative bile acids, proinflammatory agents such as endotoxin and platelet-
activating factor,26–28 and messengers such as nitric oxide29,30 in coordinating responses of mucosal
secretory and absorptive functions during intestinal obstruction.
Intestinal Blood Flow. Microvascular responses to intestinal obstruction may also play an important
role in determining the hydrostatic gradients for fluid transfer across the mucosa into the lumen. In
response to heightened luminal pressure, total blood flow to the bowel wall may initially increase.31
The breakdown of epithelial barrier structures and enzymatic breakdown of stagnant intestinal contents
leads to increased osmolarity of luminal contents. In addition to secretory stimulation and absorptive
inhibition of the mucosa, the simultaneous changes in hydrostatic and osmotic pressures on the blood
and lumen sides of the mucosa favor flow of extracellular fluid into the lumen. Perfusion is then
compromised as luminal pressures increase, bacteria invade, and inflammation leads to edema within
the bowel wall.11
Intestinal Motility. Obstruction of the intestinal lumen does not simply block distal passage of luminal
contents. The accumulation of fluid and gas in the obstructed lumen also elicit changes in myoelectrical
function of the gut, proximal and distal to the obstructed segment. In response to this distention, the
obstructed segment itself may dilate, a process known as receptive relaxation.32 Such changes ensure that,
despite accumulation of air and fluid, intraluminal pressures do not amplify easily to the point of
compromising blood flow to the intestinal mucosa. At sites proximal and distal to the obstruction,
changes in myoelectrical activity are time dependent. Initially, there may be intense periods of activity
and peristalsis. Subsequently, myoelectrical activity is diminished and the interdigestive migrating
myoelectrical complex pattern, is replaced by ineffectual and seemingly disorganized clusters of
contractions.33–35 Similar alterations have been observed in experimental models of large bowel
obstruction. Subsequent patterns of myoelectrical quiescence may correspond to increasing
accumulation of fluid and air proximally and the attempt to prevent luminal pressures from rising. It is
likely that many factors contribute to the rate at which these changes in myoelectrical activity occur.36
These factors would include neurohumoral milieu, bacterial products, and luminal constituents.
Complications and Systemic Effects of Bowel Obstruction

Closed-Loop Obstructions. The complications of closed-loop obstructions evolve rapidly. The reasons
for this rapid evolution are best understood by considering the simplest and most common form of
closed-loop obstruction, appendicitis. When a fecalith obstructs the blind-ended appendix, secretion of
mucus and enhanced peristalsis represent the initial attempt to clear the blockage. Intense crampy
abdominal pain focused at the umbilicus results. Nausea and vomiting are not uncommon as a result of
luminal obstruction but as a reflexive response to hyperperistalsis and stretching of the mesentery. Over
the next 8 to 18 hours, continued secretion of mucus to high intraluminal pressures, stasis, bacterial
overgrowth, mucosal disruption, and elevation of luminal pressures convert intermittent cramps to
constant and worsening pain. When luminal pressure exceeds mural venous pressure and then capillary
1251
booksmedicos.org
perfusion pressures, inflammatory cells are recruited from surrounding peritoneal structures. This
sequence of events leads to intense inflammation, release of exudate in the area of the appendix and the
first localization of pain from the umbilicus to the area of peritoneum lying nearest the inflamed
appendix. Peritoneal findings (localized tenderness, involuntary guarding, rebound, or referred
tenderness) and fevers appear. Subsequently, 20 to 24 hours into the illness, the blood supply of the
appendix is compromised. Gangrene and perforation follow and, if not contained by surrounding
structures, free perforation leads to a rigid abdomen. Toxins from necrotic tissue and bacterial
overgrowth are released into the systemic circulation and shock ensures. Torsion of a loop of small
intestine around an adhesive band or inside a hernia leads to a similar pattern of events. As discussed
below, torsions of the large bowel are usually accompanied by massive distention of the loop by air and
feces, but the compromise of intestinal wall perfusion and evolution into peritonitis, systemic toxicity,
and shock are similar.
Open-Loop Obstructions. Complications in open-loop obstructions do not necessarily evolve as rapidly

as in closed-loop obstructions. Not uncommonly, an open-loop obstruction located in the proximal
jejunum can be decompressed by the patient’s ability to vomit. Proximal obstruction is characterized by
vomiting and loss of gastric, pancreatic, and biliary secretions, with resulting electrolyte disturbances.
These disturbances include dehydration, metabolic alkalosis, hypochloremia, hypokalemia, and usually
hyponatremia. In contrast, obstructions of the distal ileum may lead only to a slowly progressing
distention of the small intestine, with accommodation by intestinal myoelectrical function and minor
alterations in fluid and electrolyte balances. Open-loop obstructions located in the midgut are often
complicated by events similar to those seen in closed-loop obstructions or combinations of events seen
in high and low obstructions (Table 49-2). Patients with distal jejunal obstruction tend to present with a
combination of complications resulting from loss of intestinal contents from vomiting, as well as
distention and compromise of intestinal wall perfusion.
2 In simple or uncomplicated obstruction, the intestinal lumen is partially or completely occluded
without compromise of intestinal blood flow. Simple obstructions may be complete, meaning that the
lumen is totally occluded, or incomplete, meaning that the lumen is narrowed but permitting distal
passage of some fluid and air. In strangulation obstruction, blood flow to the obstructed segment is
compromised and tissue necrosis and gangrene are imminent.
Clinical Presentation and Differential Diagnosis

3 The four key symptoms associated with acute mechanical bowel obstruction include abdominal pain,
vomiting, distention, and obstipation. When bowel obstruction is the most likely diagnosis, “abdominal
pain out of proportion to physical findings” represents a surgical emergency. Colon obstruction is
usually accompanied by varying levels of pain with massive abdominal distention and obstipation. As
noted earlier, the signs and symptoms of acute but simple small intestinal obstructions are related to the
level of the obstruction and the closed- or open-loop nature of the obstruction. Other abdominal
conditions, such as appendicitis, diverticulitis, perforated peptic ulcer, cholecystitis, or
choledocholithiasis can usually be distinguished from SBO, by clinical examination and basic laboratory
data. It should be emphasized that bowel obstruction can complicate any of these abdominal conditions.
The presence of another abdominal process does not exclude the complication of SBO.
Over the years, numerous attempts have been made to use groupings of clinical criteria to establish
the diagnosis of complete and irreversible intestinal obstruction, as distinguished from partial intestinal
obstruction that might improve without operative intervention or other abdominal pathology. In recent
studies, computer-assisted analysis has been used to identify such criteria.37 Key factors in the history
and clinical examination38 include previous abdominal surgery, quality of pain (colic/intermittent
versus steady), abdominal distention, and hyperactivity of bowel sounds. Not surprisingly, the use of
such computer-assisted algorithms confirms that the most important clues to the diagnosis of simple
obstruction of the small intestine are obtained in a complete and careful history and physical
examination. As discussed below, the role of plain abdominal radiographs and other imaging studies is
to confirm the clinical diagnosis of simple obstruction. It should be emphasized that, in simple
obstruction, laboratory studies do not play a direct role in diagnosis, but aid in understanding the extent
of complications such as dehydration, strangulation, and sepsis.
Strangulation obstruction is accompanied by symptoms and signs suggesting peritonitis, large fluid
shifts, or systemic toxicity. These symptoms and signs include abdominal tenderness or involuntary
guarding localized to the area of the strangulated loop of bowel, decreasing urine output, fever, and
1252
booksmedicos.org
tachycardia. There have been attempts to use common clinical and laboratory test criteria to identify
the likelihood that the obstruction is associated with strangulation. Stewardson et al.39 observed that the
risk of strangulation was low in patients with partial (i.e., incomplete) or complete SBO if fever,
tachycardia, localized abdominal tenderness, or leukocytosis were not present. These authors suggested
that, in a setting consistent with bowel obstruction, any one of these four cardinal signs indicated a
small risk for strangulation. The presence of any two of these signs increased the risk of strangulation so
high as to warrant immediate surgery. These authorities and others have stressed, however, that when
complete obstruction is present, no satisfactory clinical criteria are available to reliably exclude the
possibility of strangulation.39–43
Different laboratory tests have been advocated for early detection of strangulated intestine. Metabolic
(i.e., lactic) acidosis and increases in serum amylase, inorganic phosphate, hexosaminidase, intestinal
fatty acid–binding protein, and serum D-lactate levels have all been associated with intestinal
ischemia.44,45 Such laboratory abnormalities may be helpful in diagnosing established strangulation in a
small group of patients where the diagnosis of necrotic bowel is not clear. However, a noninvasive and
rapid test has not yet been developed that can provide information to suggest that tissue necrosis is
imminent but not yet established.43
Radiographs and Imaging

Plain Films
The role of plain abdominal radiographs and imaging studies is to confirm the diagnosis of bowel
obstruction, locate the site of obstruction, and gain insight into the lesion responsible for the
obstruction. On plain radiographs of the abdomen, the key findings of SBO reflect the accumulation of
air and fluid proximal, and clearance of fluid and air distal to the point of obstruction. Dilated loops of
small intestine are defined as those greater than 3 cm in diameter. Free air represents perforation of a
viscus and mandates immediate operation. Such findings include dilated loops of small bowel on the flat
plate (Fig. 49-3) and multiple air–fluid levels located at different levels on the upright film or lateral
decubitus film (Fig. 49-4). Based on these criteria plain abdominal radiography is diagnostic in 67% to
80% of patients.46,47 Plain radiographs, however are only accurate in 46% to 85% of the time and can
miss SBO in patients without air–fluid levels because of fluid-filled distended loops.48 In complete
obstruction of the small intestine, the colon loops and rectum do not contain air. If there is air in the
colon, the obstruction may be complete, but early, or it may be incomplete.
In the colon, tight closed-loop obstructions (i.e., volvulus of the cecum, transverse colon, or sigmoid
colon) are accompanied by distention of the obstructed segment (Fig. 49-5). The proximal colon is
considered dilated when it reaches 8 to 10 cm; the sigmoid colon is considered dilated at 4 to 5 cm. In
contrast, obstruction by carcinoma or diverticulitis presents with massive distention of the entire colon
from the point of obstruction to the ileocecal valve. From this standpoint, any large bowel obstruction
may represent a “closed loop” if the ileocecal valve is competent. Although plain film findings can be
used to differentiate obstruction of the small bowel from that of the large bowel, they are not
consistently accurate in localizing the specific site of obstruction.
Figure 49-3. Plain supine abdominal film of a patient with small-intestinal obstruction. Note the multiple dilated loops of small
1253
booksmedicos.org
intestine (black arrow) in the left upper quadrant, characterized by complete markings of the plicae. Also note the absence of air in
colon and rectum.
Figure 49-4. Plain upright abdominal film of a patient with small-intestinal obstruction. Note the air–fluid levels in the stomach
and multiple dilated loops of small intestine (black arrows), and absence of air in the colon or rectum.
Figure 49-5. Plain upright abdominal film of a patient with sigmoid volvulus. The dilated centrally located sigmoid loop is seen
(arrowheads). The proximal colon is dilated and gas filled. T, transverse colon; D, descending colon.
Contrast Studies
The diagnosis of bowel obstruction can generally be made by considering the clinical history, physical
examination, laboratory, and plain radiograph findings. Contrast studies (i.e., small bowel follow-
through, enteroclysis, and contrast enema) may provide specific localization of the point of obstruction
and the nature of the underlying lesion. When obstruction of the small intestine is not progressing or
resolving, a small bowel follow-through may be performed to confirm the presence and location of the
obstruction. Also, even under acute circumstances, diagnosis and management of colonic obstructions
are generally enhanced by the use of a contrast enema. Under some circumstances, however, contrast
studies are unnecessary and may be contraindicated. For example, in the classic setting of abdominal
pain, nausea, vomiting, and a plain film indicating multiple air–fluid levels in the small intestine and
colonic collapse, the diagnosis of acute obstruction can be made clinically. Failure to improve in a short
period of time will mandate operation and contrast studies are unnecessary. When strangulation or
perforations are strongly suspected, contrast studies are contraindicated.
4 The choice of contrast materials includes water-insoluble suspensions of barium and water-soluble
agents such as Gastrografin® or Hypaque®. Barium studies provide the clearest images, in both small
bowel studies where the contrast is given from above and colon/rectum studies in which the contrast is
1254
booksmedicos.org
given by enema. If barium leaks into the peritoneum, it elicits intense peritonitis. If there is any
possibility of bowel perforation or gangrene, barium should not be used. Water-soluble agents such as
sodium amidotrizoate/meglumine amidotrizoate oral solution (Gastrografin®) or diatrizoate
sodium/diatrizoate meglumine (Hypaque®) are hyperosmotic and can elicit fluid translocation into the
gut. When the obstruction of the small intestine is incomplete the use of these agents may facilitate
resolution. Gastrografin is hyperosmolar (1,900 mOsm/L). Its administration permits mobilization of
fluid into the bowel lumen which decreases edema of the intestinal wall and increases the pressure
gradient across obstructive site. It is thought that these fluid and pressure shifts can contribute to
resolution in cases of incomplete obstruction. The 2013 Bologna guidelines for diagnosis and
management of adhesive SBO recommended a dosage of 50 to 150 mL of Gastrograffin administered
either orally or via NGT immediately on admission or after an attempt of conservative treatment for 48
hours.49 The appearance of contrast in the colon within 4 to 24 hours after administration had a
sensitivity of 96% and specificity of 98% in predicting resolution of SBO.50 A prospective randomized
trial confirmed that gastrograffin significantly reduced the need for surgery by 74%.51 Some studies
showed that water-soluble contrast medium reduces hospital stay but does not reduce need for
surgery52,53 but recent meta-analysis showed that it is effective in reducing the need for surgery and
shortening length of stay.50 Use of water-soluble contrast may thus be both diagnostic and can be
therapeutic.
Computed Tomography and Other Imaging Modalities

5 The potential benefits of computed tomography (CT) scanning in diagnosis of bowel obstruction include
the following.54–57 First, using radiographic contrast, the obstructing segment may be localized and
characterized as complete or incomplete. Second, the nature of the obstructing lesion, especially if it is
malignant, can be established. Third, additional abdominal pathology (e.g., metastases, ascites,
parenchymal liver abnormalities) may be identified. Fourth, anatomic information obtained from the CT
can be used in operative planning. There is also evidence that, in special circumstances, CT may
improve preoperative detection of strangulation.42,56 Coronal and sagittal reconstruction improve the
ability to identify transition point and IV contrast with delayed imaging should be considered to assess
for venous occlusion or delayed bowel wall enhancement.58 CT findings indicating the site of
obstruction and impending ischemia include beak-like narrowing, mesenteric edema, vascular
engorgement, moderate to severe intestinal wall thickening (greater than 2 mm) (Fig. 49-6). In
addition, high attenuation of bowel wall on unenhanced CT scans, low or reduced attenuation of bowel
wall on intravenous contrast CT scans, and presence of intramural air (pneumatosis) or portal venous
gas are CT findings suggestive of strangulation. Attenuation reflects increased energy absorption,
scattering, beam divergence, and other causes of energy loss. Thus, areas of high attenuation appear
darker than areas of low attenuation. CT scan has a 96% sensitivity and 93% specificity with a negative
predictive value of 99% in diagnosing intestinal strangulation.59 Although CT scan need not be routinely
performed unless history, physical examination, and plain films are not conclusive for SBO diagnosis,60
it is increasingly the “go-to” study for confirmation.
1255
booksmedicos.org
Figure 49-6. Axial (A) and coronal (B) images of a closed-loop obstruction with strangulated small bowel secondary to a volvulus
from an adhesive band. Distended fluid-filled loops of small bowel (B) in a radial distribution converge toward the point of
torsion (white arrows). There is edema within the mesentery (M). Shown in (C) is a coronal view of vascular engorgement and
mesenteric edema in a closed-loop obstruction.
Ultrasound has a very limited use in diagnosing SBO and visualization can be obscured by the
intraluminal air but it has been suggested that real-time abdominal sonography could aid in the
diagnosis of strangulation obstruction. In studies conducted in two different institutions, Ogata and
colleagues61,62 demonstrated that the presence of significant amounts of peritoneal fluid and of an
akinetic and dilated loop of bowel were strongly associated with the presence of strangulation. In
patients who had strangulation, but were thought to have simple obstruction only, these findings helped
to make the preoperative diagnosis of infarction.
Magnetic resonance imaging (MRI) has the sensitivity comparable to CT scan in diagnosing
obstruction but limitations include lack of availability after hours, poor definition of mass lesion, and
poor visualization of colonic obstructions.63 The use of MRI should be limited to patients who have
contraindications to CT or are allergic to contrast material.49
It should be emphasized that when the clinical picture suggests strangulation, unnecessary imaging
studies should not delay resuscitation or expeditious movement to the operating room. Such studies will
not necessarily be helpful when clinical criteria and basic abdominal radiographs have indicated the
presence of a simple and complete obstruction. By itself, this diagnosis mandates urgent exploration and
the information sought should be weighed against the risk of delay in going to the operating room. In
fact, in most studies evaluating the impact of imaging on diagnosis and timing of intervention, clinical
diagnosis is seldom incorrect – it is highly specific when multiple clinical signs (tenderness, peritoneal
signs, leukocytosis, and profound dehydration) of strangulation are present. However, such a picture
represents advanced disease and use of CT scan may detect strangulation before such signs are manifest.
These findings reinforce the dictum that when there are clinical signs of strangulation, surgery should
be performed without delaying for additional imaging studies. In patients with equivocal findings or
uncertain clinical diagnosis, CT can be highly useful in confirming the diagnosis, localizing the site and
detecting the cause of intestinal obstruction and strangulation.56
General Considerations in Management of the Patient with Bowel Obstruction
1256
booksmedicos.org
Patients with obstruction of the large bowel present with abdominal pain, distention, and obstipation.
Vomiting and electrolyte imbalances are sometimes prominent, though usually delayed. Elderly
patients, in particular, are prone to dehydration. The presentation of SBO depends on level of
obstruction, open- or closed-loop nature, and interval since onset of symptoms. Symptoms and signs of
pain, vomiting, obstipation, and distention are present in variable degrees. The overall picture,
however, is usually one of a patient with abdominal symptoms that are evolving and getting worse. In
the settings described previously, the following questions must be addressed as expeditiously as
possible:
1. Is the abdominal pain disproportionate to the physical findings and laboratory studies?
2. How rapidly the symptoms and signs are evolving: minutes, hours, or less acutely?
3. Does the patient suffer from dehydration, electrolyte imbalance and acid–base disturbance?
4. Is the obstruction complete or incomplete?
5. Is there a possibility of strangulation?
Clinical data and basic laboratory studies will provide reliable information to answer the first three
questions. Answering questions 4 and 5 will often depend on close clinical observation and
reexamination in the first hours or days after presentation. Abdominal radiographs and imaging studies
are frequently used to provide additional information to help answer these latter questions, as well as
providing information to identify the obstructing lesion.
Summarized in Table 49-3 are thumbnail sketches of different, but typical, kinds of patients
presenting with symptoms and signs consistent with obstruction of the small intestine. The principles of
diagnosis and management of each of these patients begins with clinical information that indicates the
likelihood of a bowel obstruction. Laboratory studies and plain abdominal films are used to confirm the
diagnosis of obstruction and determine the extent of physiologic impairment. The patient’s history and
clinical course in the first few hours of observation are used to determine the likelihood of
strangulation. Indications for surgery include rapid evolution of symptoms and signs and the diagnosis
that the obstruction is complete. Contrast or imaging studies are used only when symptoms are not
evolving rapidly and when identification of the underlying lesion might alter the operative strategy (see
specific lesions later).
Table 49-3 Diagnosis and Decisions in Bowel Obstruction in Three Hypothetical

Patients
6 The initial management of all patients with suspected bowel obstruction includes designating the
patient “NPO” and starting intravenous fluids comprised of isotonic Ringers or normal saline solutions.
Restoration of fluid and electrolyte balance is a priority, often requiring frequent evaluation of serum
electrolytes and pH. In rapidly evolving cases or patients with significant dehydration, an indwelling
1257
booksmedicos.org
urinary catheter should be placed to monitor urine output. Invasive hemodynamic monitoring (e.g., a
Swan–Ganz catheter) may be necessary to monitor the response to fluid resuscitation in patients with
severe cardiac, pulmonary, or renal insufficiency.
Nasogastric decompression is indicated in most cases. The nasogastric tube, typically a 16- or 18-Fr
sump tube, serves to prevent distal passage of swallowed air and minimizes the discomfort of refluxing
intestinal content. The use of longer tubes has been advocated in certain settings, especially for patients
with chronic but intermittent obstruction arising from Crohn disease, peritoneal carcinomatosis,
radiation enteritis, or many previous laparotomies for obstruction. The underlying rationale is that
advancement of the tip of the long tube to the obstructed loop would permit more effective
decompression, perhaps resulting in relaxation of the loop and relief of the obstruction. A number of
studies have failed to document benefits in the use of long tubes64,65 in helping to resolve partial
intestinal obstruction or prolonged ileus. Recently. A more possibly effective version of the long tube
has been described, the ileus tube (Create Medic, Tokyo), which is made of silicon is 300 cm in length,
is 16 Fr wide and has three channels. This tube is advanced with endoscopic guidance and has been
reported in one study to be more effective (89.6 vs. 46.7%) compared to NGT group, specifically with
respect to the intervals to resolution of symptoms and radiographic findings.66 Caution should be
undertaken on the potential risk of development of pneumonia and respiratory failure in routine use of
NGT.67
A randomized controlled trial suggested that resolution of partial SBO could be accelerated with the
use of a regimen of oral adjunctive therapy that included magnesium oxide (500 mg), simethicone (40
mg) and Lactobacillus acidophilus (0.3 g tablet) given three times daily via NGT was effective in
hastening the resolution of the conservatively treated partial adhesive SBO and shortening the hospital
stay with no difference in complication rate and recurrence. Magnesium oxide was used due to its
laxative side effects. Simethicone, a defoaming agent, was used because it alters surface tension of gas
bubbles and causes them to coalesce, thereby accelerating the passage of gas through the intestinal
tract. Lactobacillus, a probiotic, may have multiple benefits, including improved digestion and
prevention of overgrowth of pathogenic bacterial species.67a
Recent study showed the potential beneficial effects of hyperbaric oxygen (HBO) therapy at a
pressure of 2.0 atmospheres absolute with 100% oxygen given once a day up to 7 days. HBO therapy
was associated with earlier resumption of oral intake (4.7 days vs. 5.6 days; p = 0.001), shorter
hospital stay (10.3 days vs. 14.1; p = 0.001) and lower operative rate (7.4% vs. 14.8%).68 It is
postulated that intestinal edema is decreased through the osmotic effect of oxygen. Oxygenation under
high pressure enhances inert gas diffusion from the closed intestinal lumen into the blood. Relaxation of
the distended intestinal loop improves the compromised microcirculation and oxygenation of hypoxic
intestinal tissue which leads to preservation of intestinal viability and recovery of motility. This
modality may be an option in the management of patients with high anesthesiologic risk.69 A current
study (HOT Trial) is underway to find out the clinical value of HBO therapy in obstruction due to
radiation-induced fibrosis (ISRCTN 86894066).
The use of intravenous antibiotics in the initial management of bowel obstruction should be discussed
as well. Clinically, it has been recognized that antibiotics can ameliorate the evolution of symptoms and
signs of strangulation in closed-loop obstruction and appendicitis. Studies in humans have demonstrated
that, even in simple obstruction, bacterial counts in succus rise from under 106 organisms/L to over 109
organisms/L70 and are not necessarily reduced with short-term administration of antibiotics.71
Moreover, experimental studies indicate that bacteria can translocate across the intestinal mucosa,
passing into lymph channels.72 Further studies have demonstrated that germfree animals can survive
strangulation obstruction longer than normal animals and that luminal fluid taken from obstructed
segments in germ-free animals is much less toxic than fluid taken from normal animals.73,74
For all these reasons, it is a well-established practice to administer antibiotics perioperatively, in
order to reduce wound infection and abdominal sepsis rates in patients undergoing operation to relieve
intestinal obstruction, simple or strangulated. Once the decision has been made to proceed with surgery,
broad-spectrum antibiotics, covering gram-negative aerobes and anaerobes should be given. A second-
generation cephalosporin or a combination of a first-generation cephalosporin and metronidazole is a
rational practice for perioperative coverage in both simple and strangulation obstruction. Nevertheless,
the use of antibiotics in patients who have not yet been committed to operation has not been evaluated
systematically. Giving antibiotics to patients who are being observed can obscure the underlying process
and, in the end, delay optimal therapy.
The decision to perform abdominal exploration to relieve intestinal obstruction should be made
1258
booksmedicos.org
expeditiously, but not in the absence of critical information or before adequate resuscitation (Algorithm
49-1). Indications for surgery are outlined in Table 49-3, for each of the thumbnail vignettes. It should
be emphasized that once a diagnosis of complete obstruction is made, simple or strangulated, the
operation should proceed without undue delay. It is reasonable to commit the patient to a period of
observation when the diagnosis is uncertain (i.e., there is a possibility of a nonsurgical diagnosis or that
the obstruction is not complete). A practical point is that obstruction occurring in a patient without a
previous history of laparotomy is not likely to be caused by peritoneal adhesions. This is known as de
novo obstruction and whatever the underlying cause will not usually resolve without operation.
Specific Types of Bowel Obstruction

Chronic Adhesions
As noted previously, peritoneal adhesions account for more than half of SBO cases. Lower abdominal
procedures such as appendectomy, hysterectomy, colectomy, and abdominoperineal resection are
common precursor operations to adhesive obstruction. Adhesions form after any abdominal procedure,
however, including cholecystectomy, gastrectomy, and abdominal vascular procedures. In long-term
follow-up, about 5% of patients undergoing laparotomy will develop adhesive obstruction; of these,
10% to 30% will suffer from additional episodes.75,76 Up to 80% episodes of SBO due to adhesions may
resolve nonoperatively.39,40,53,64 However, an index episode and three recurrences indicate a likelihood
of over 80% that there will be more recurrences.75 Surgical management of an acute episode appears to
reduce subsequent recurrence rates from ∼15% to ∼6%,76 but no studies have been able to establish
whether the immediate benefit of laparotomy for any given episode of simple adhesive obstruction
outweighs the overall benefit of expectant management and operation only for serial recurrences. Thus,
a previous history of a laparotomy simply provides a reasonable basis for expectant management of
patients in whom it is not yet possible to diagnose a complete obstruction. Ultimately, patients who
present with signs and symptoms of bowel obstruction are managed according to the CT findings and
clinical course.
Algorithm 49-1. Algorithm for the management of adhesive small bowel obstruction.
The pathobiology of adhesion formation has been the subject of considerable investigation.11
Histologic examination of chronic adhesions reveals foreign body reaction, usually to talc, starch, lint,
intestinal content, or suture. Talc and starch are found less commonly now than previously, because of
1259
booksmedicos.org
improvements in techniques of manufacture and sterilization of surgical gloves. Mesothelial cells are the
presumed origin of tissue plasminogen activator (TPA). TPA binds fibrin and plasminogen, thereby
preventing adhesion formation. In early studies, inflammatory cells, including mast cells,77 were
implicated in the process that produces adhesions. Recent studies78,79 have emphasized the role of
various cytokines in exacerbating or inhibiting adhesion formation in different animal models.
Biologically active substances that might prove useful in preventing postoperative adhesions include
transforming growth factor beta (TGF-beta) and vascular endothelial growth factor (VEGF), both of
which may be targeted for inhibition without less fear of compromising the response to bacterial
infection.78,79
Current strategies to prevent adhesions after a first laparotomy include targeting the fibrinolytic
system, which enhances rapid healing and appears to minimize formation of peritoneal adhesions.78
Attempts to minimize or prevent adhesion formation have resulted in development of hyaluronic acid–
carboxymethylcellulose membrane (Seprafilm, Genzyme, Cambridge, MA). This compound mechanically
prevents adhesion formation by physically separating adjoining tissues. It is absorbed by the body in 7
days and thus is present only during the phase of fibrosis, and not as a persistent foreign body.
Randomized trials have suggested that this compound prevents, minimizes severity, and decreases
density and vascularity of adhesions.78,80 Other trials and review of 17 RCT corroborate decreased
incidence, extent, severity, density, and vascularity of adhesions but not total prevention of adhesions
or reduction of the incidence of subsequent bowel obstruction,81 and caution not be placed on
anastomosis due to increased rate of anastomotic leak.82 Seprafilm and similar barriers have been
advocated for use in patients in whom a second abdominal procedure is planned or significant adhesions
anticipated (e.g., Hartmann procedure, ileal pouch anal anastomosis with protecting ileostomy, pelvic
surgery, gynecologic procedures, staged hepatic surgery and colon surgery) – though it has been
proposed for all surgeries by the manufacturers. The largest randomized, single blind, controlled study
on Seprafilm showed that the incidence of adhesive small bowel requiring reoperation was significantly
lower for Seprafilm patient with absolute reduction rate of 1.6% and relative reduction rate of 47%.83
The Prevention of Postoperative Adhesion (POPA) study uses 2,000 icodextrin 4% solution before
abdominal closure and follow-up upto 10 years showed that it is safe and reduces intra-abdominal
adhesion formation and the risk of reobstruction (2.19% vs. 11.1%).84 Small trials showed the potential
use of hydrogen adhesion barrier spray85 and lyophilized human peritoneal membrane.86
More important than pharmacologic approaches, however, are the efforts of the surgeon to pay
meticulous attention to hemostasis and surgical technique, the avoidance of excessive tissue dissection,
and careful search and removal of any extraneous material. The use of laparoscopic approaches, when
feasible, should lower the likelihood of pathological adhesions as well.87
Early Postoperative Adhesions

Obstruction in the immediate period following abdominal surgery is uncommon but may occur in up to
1% of patients in the 4 weeks following laparotomy. Adhesions are responsible for approximately 90%
of such cases and hernias for approximately 7%.88 Intussusception, internal herniation, inflammation,
abscess, intramural intestinal hematoma or technical errors may be responsible for the remainder of
cases.89–91 Most cases occur after surgery of the colon, especially abdominoperineal resections, or
operations in the lower abdomen. It is rare for upper abdominal surgery to cause such obstructions. A
common scenario is that a patient will undergo colectomy uneventfully, pass flatus and have bowel
sounds by postoperative day 3. On the fourth postoperative day the patient suddenly becomes distended
and uncomfortable, and stops passing flatus and stool. Patients with acutely evolving symptoms and
signs represent complete obstruction and should be managed as such. In this latter setting, the mortality
may be as high as 15% due to delays in recognition and operative intervention. The loss of bowel
sounds after a short period of normal or hyperactive activity is worrisome for ischemia of the
obstructed segment. The vast majority of such cases may be treated as partial intestinal obstruction;
nasogastric suction and intravenous fluids will help resolve symptoms within a few days (Algorithm 49-
2). When the clinical course does not demand earlier intervention, a nonoperative approach may be
tried for 10 to 14 days and will resolve the obstruction in over 75% of such cases.88,90,92 It is recently
noted that patients who experienced early postoperative adhesions may have a higher risk of developing
adhesive SBO (26.5% vs. 7.5% at 5 years; p < 0.001).91
Bowel Obstruction after a Bariatric Procedure

The obesity epidemic sees the growth in the number of bariatric procedures which includes gastric
banding, sleeve gastrectomy, gastric plication, roux-en-y gastric bypass, and biliopancreatic diversion
1260
booksmedicos.org
with or without duodenal switch. Band slippage can occur in 15% to 20% of patients and typically
presents with a history of upper abdominal symptoms of reflux, regurgitation, and dysphagia. Upper GI
study is the preferred method of diagnosing band slippage showing the evidence of malposition of the
band and proximal pouch dilatation with obstruction. The initial management is urgent band deflation
using Huber needle and if this is unsuccessful or patient is acutely unwell, necrosis, abscess, or erosion
must be considered which may require surgery. Intestinal obstruction occurs in 4.4% after roux-en-y
gastric bypass. The etiology of obstruction includes internal hernia (53%), roux limb compression due to
scarring (20%), adhesion (14%), stricture at gastrojejunal anastomosis, kinking of the alimentary limb,
incisional hernia, and intestinal intussusception. The most common site of internal herniation is
mesojejunal mesenteric window, followed by Petersen window and the mesocolic window.93 It is
paramount to differentiate bariatric from nonbariatric patients presenting with SBO since there are
significant differences in their management. Nonoperative management was successful in 72% of non-
postbariatric patients but surgery was performed in about 62% of postbariatric surgery patients with
SBO. Also, the bariatric group is most likely to undergo laparoscopy (5% vs. 2%), abdominal wall
reconstruction (38% vs. 9%) and is less likely to require colostomy (1% vs. 13%). The bariatric group
underwent surgery sooner within an average of 24 hours compared to 3.3 days in non-postbariatric
patients.94
Algorithm 49-2. Approach to the management of malignant bowel obstruction.
1261
booksmedicos.org
Figure 49-7. Computed tomography images of an inguinal hernia. Axial (A) and coronal (B) CT scan images showing incarcerated
right inguinal hernia with air- and fluid-filled loop of small bowel (arrowhead) in the right inguinal canal (arrow) causing small
bowel obstruction with dilated loops of proximal small bowel (B).
Hernia
Hernias of all types are second only to adhesions as the most frequent causes of obstruction in Western
countries. External hernias such as inguinal (Fig. 49-7) or femoral hernias may present with the
symptoms of obstruction and will not be diagnosed unless sought.95 Femoral hernias are particularly
prone to incarceration and bowel necrosis due to the small size of the hernia inlet.95 Other hernias such
as umbilical, incisional, paracolostomy, or lumbar hernias are obvious. Still others, such as internal
hernias are usually diagnosed at laparotomy for obstruction. These include obturator hernias,
paraduodenal hernias (Fig. 49-8), and hernias through the foramen of Winslow or mesenteries. When
hernia has been identified as the cause of the obstruction, the patient is quickly resuscitated, given
antibiotics, and taken to the operating room. The hernia is then reduced and the viability of the bowel
assessed. If viable, the bowel is left alone; if not, it is resected. The hernia defect is then repaired. One
important consideration is the Richter hernia (Fig. 49-9).96 In this variant, only a portion of the wall of
the bowel is incarcerated and thus incarceration and strangulation may not be associated with complete
obstruction. These most frequently occur in association with femoral or inguinal hernias. Complete
obstruction can occur if more than half of the bowel circumference is incarcerated.
For external (abdominal wall) hernias, it may be possible to perform taxis, that is, the manual
reduction of an incarcerated/irreducible hernia. Reduction (taxis) of the hernia is usually successful.
Occasionally taxis results in reduction of the contents of the hernia sac en mass (still obstructed),
reduction of strangulated bowel resulting in generalized peritonitis, or reduction of an obstructed
Richter hernia.97–101 This is one reason for using circumspection in relying on taxis as a mode of
treatment for incarcerated inguinal, femoral, and incisional hernias. In general, taxis should be followed
expeditiously by operative repair.
Gallstone Ileus
As a result of intense inflammation surrounding a gallstone, a fistula may develop between the biliary
tree and the small or large intestine. Most fistulae develop between the gallbladder fundus and
duodenum. If the stone is greater than 2.5 cm in diameter, it can lodge in the narrowest portion of the
terminal ileum, which is just proximal to the ileocecal valve. This complication is rare, accounting for
less than 6 in 1,000 cases of cholelithiasis and no more than 3% of cases of intestinal obstruction.
Typically, the patient is elderly female and presents with intermittent symptoms over several days, as
the stone tumbles distally toward the ileum. The classic findings on plain radiographs include those of
intestinal obstruction, a stone lying outside the right upper quadrant, and air in the biliary tree (Fig. 49-
10). Treatment includes removal of the stone and resection of the obstructed segment only if there is
evidence of tissue necrosis. The risk of a recurrent gallstone ileus is about 5% to 10%.102,103 Such
recurrences usually occur within 30 days of the initial episode and are usually due to stones in the small
1262
booksmedicos.org
intestine that were missed at the original operation.
The difficult decisions in management of gallstone ileus focus on the fistula. The arguments in favor
of disconnecting the fistula and removing the gallbladder have been the possibility of recurrence of
gallstone ileus and the risk of cholangitis due to reflux of intestinal content into the biliary tree. When
the latter operation is included, the mortality may be doubled as compared to simple removal of the
gallstone. It is used selectively in good-risk patients. The long-term incidence of biliary tract infections
has not been common enough to warrant the more aggressive approach at the initial operation. Some
authors have advocated cholecystectomy at a second operation, especially if the patient is young and fit.
The consensus is that cholecystectomy should not be performed at the initial operation for gallstone
ileus, except in highly selected patients. A careful search of the entire intestine should be performed to
exclude the possibility of additional large stones which can occur in up to 25% of patients.102–104
Figure 49-8. Paraduodenal hernia. A: Plain film of closed-loop obstruction with neck of the closed loop in the right upper
abdomen. B: Computed tomography scan showing slippage of the jejunum behind the stomach, with dilatation and obstruction of
the duodenum. C: Schematic diagram showing relationships of the paraduodenal fossa and transverse mesocolon.
Figure 49-9. Richter hernia. A: Computed tomography scan showing contrast and air in the incarcerated segment within the left
1263
booksmedicos.org
groin. B: Schematic diagram showing Richter hernia, in which the antimesenteric border (but not the whole wall) of the intestine
is incarcerated.
Figure 49-10. A: Plain radiograph of a patient with gallstone ileus, showing obstructed loops of small intestine (black arrow) in the
abdomen and a gallstone (white arrow) in the pelvis (gallstone was initially misinterpreted as an EKG lead [black arrow]). B:
Computed tomography (CT) scan showing a cholecystoduodenal fistula (black arrow) with air in the biliary tree (D, duodenum). C:
CT scan showing gallstone (white arrow) in the distal ileum and fecalization of luminal content adjacent to the stone.
Intussusception
About 5% of intussusceptions occur in adults. An intussusception occurs when one segment of bowel
telescopes into an adjacent segment, resulting in obstruction and ischemic injury to the intussuscepting
segment (Fig. 49-11) and the obstruction may become complete, particularly if tissue inflammation and
necrosis occur. Of adult cases, 90% are associated with pathologic processes.105,106 Tumors, benign or
malignant, act as the lead point of intussusception in more than 65% of adult cases. A significant
proportion of cases have been reported to occur after abdominal surgery for lesions other than
neoplasm. In cases not associated with neoplasm, Sarr et al.106 reported that approximately 20% were
related to the suture line, approximately 30% to adhesions, and approximately 60% to intestinal tubes.
Intussusception related to long tubes can occur when the tube is withdrawn, but most frequently occurs
with the tube in place. Perioperative intussusception frequently subsides without intervention.
Four types of intussusception are recognized: enteric (Fig. 49-12), ileocolic, ileocecal, and colonic. In
the ileocolic form, the ileum telescopes into the colon past a fixed ileocecal valve. In the ileocecal form,
the valve itself may be the lead point of the intussusception. Radiographic features of intussusception
are not specific. Plain films reveal evidence of partial or complete obstruction. Occasionally, a sausage-
shaped soft tissue density will be seen, outlined by two strips of air. Recently, in both pediatric and
adult cases, it has been suggested that sonography may be useful in diagnosis. Nevertheless, the
mainstays of diagnosis are contrast studies or CT scan. Because of the high incidence of tumors, surgery
has generally been recommended. Reduction by hydrostatic pressure, which is the standard of care in
pediatric cases, is not usually attempted in adults. Honjo et al. described preoperative reduction in
31.8% and 31.8% intraoperative reduction of adult intussusceptions. Preoperative reduction serves
several functions including avoidance of emergency surgery, allowing radical surgery for cancer,
reducing the extent of intestinal resection, and allows time for preoperative predation of the bowel.
This may shift the paradigm in management of adult intussusception.107 Clear indications for operation
include long length and wide diameter of the intussusception, presence of a lead point, or evidence of
bowel obstruction.105 Recent studies have called into question the need to operate in all cases detected
on sensitive imaging studies such as CT scan, arguing that a number of these patients can be safely
managed without operation.105 However, in the opinion of these authors, it is difficult to advise
1264
booksmedicos.org
expectant management except in unusual circumstances.
Figure 49-11. Anatomy of intussusception. The intussusceptum is the segment of bowel that invaginates into the intussuscipiens.
Figure 49-12. Axial (A) and coronal CT scan (B) images of an ileocolic intussusception secondary to colon carcinoma (M) as a lead
point. Intussusceptum (long arrows) and intussuscipiens (arrowhead). Mesenteric vessels and fat (white arrowhead) accompany the
intussusceptum.
Crohn Disease
Indications for surgery in Crohn disease are discussed elsewhere in this book. In this disease, obstruction
occurs under two different sets of circumstances.108 When the disease has flared acutely, the lumen may
be narrowed by a reversible inflammatory process. The result is an open-loop obstruction that may
respond, first to intravenous hydration and nasogastric decompression, and ultimately to therapy with
corticosteroids or other anti-inflammatory regimens. Alternatively, obstruction may occur in the setting
of a chronic stricture. Such strictures will not respond to conservative measures and, once diagnosed,
operative therapy should not be delayed. One important clinical point is that about 7% of strictures in
the colon, and an uncertain proportion of those in the small intestine, are malignant.108 Extent of
resection is thus based on intraoperative findings, that is, to margins beyond visibly diseased bowel and
does not necessarily include enlarged lymph nodes in the mesentery. If there is suspicion for
malignancy, a lymphadenectomy is performed.
1265
booksmedicos.org
A second clinical point is that Crohn-affected bowel may not be dilated proximal to the obstruction
but can be complicated by a small perforation. Such a microperforation may not be large enough to be
associated with free air on plain films. The patient may thus present with significant abdominal pain and
tenderness. A CT scan is likely to be the most sensitive imaging modality for obtaining evidence that
differentiates conditions that require immediate surgery (closed-loop obstruction and microperforation)
from simple obstruction that would otherwise be observed. In the absence of clinical progression of
symptoms and signs, however, extended conservative management is warranted before the patient is
committed to surgery.
Malignant Obstruction
Obstruction can complicate malignancies of the small and large bowel in a number of settings. Studies
have documented that 10% to 28% of patients with colorectal cancer and 20% to 50% of patients with
ovarian cancer will present with a malignant bowel obstruction at some point during the course of their
disease.109 Most commonly, a primary lesion such as an adenocarcinoma or lymphoma will enlarge until
the lumen of the intestine is blocked. The lesion then presents with symptoms and signs associated with
the level of obstruction and are managed accordingly.
A second setting involves a patient who previously has undergone surgery for malignancy and now
returns with evidence of bowel obstruction. The likelihood that the obstruction is due to recurrent
disease is based on several factors, including the origin of the primary malignancy, the stage of the
primary malignancy, and the designation of the original surgery as curative or palliative. Gastric and
pancreatic carcinomas often present with or are subsequently complicated by peritoneal carcinomatosis
and thus the subsequent obstruction is most likely due to malignancy. With respect to colon and rectal
carcinomas, as many as 50% of cases presenting with obstruction after resection of the primary may be
due to adhesions and not recurrent malignancy.109,110 In addition, even if the obstruction is now due to
unresectable disease, significant palliation can be obtained through bypass or enterostomy in up to 75%
of patients (Fig. 49-13). However, the underlying diagnosis of cancer in this patient population
mandates careful attention be paid to patient selection prior to any surgical intervention and risk factors
for poor outcome (Table 49-4, Algorithm 49-2). In patients presenting with gastroduodenal and
colorectal obstructing lesions who are not candidates for surgical bypass or enterostomy, endoscopic
management options including percutaneous endoscopic gastrostomy (PEG) tube placement and self-
expanding metallic stent (SEMS) placement, are available (Algorithm 49-2). These options have been
associated with symptomatic relief in greater than 75% of patients.109
Figure 49-13. Significant palliation can be achieved in a patient with obstructing but unresectable malignancy. Enteroenterostomy
is performed to bypass the obstructing segment.
Management of incurable malignant obstruction may require an approach that moves away from
classical surgical teaching of nil by mouth, nasogastric tube, intravenous fluids, and serial
radiographs.111 Patients with advanced malignant obstruction in the absence of a solitary or correctable
obstructing lesion are generally managed without surgery (Algorithm 49-2). Patients are managed
without a nasogastric tube if possible. They are encouraged to eat as soon as obstructive symptoms
resolve using a low-fiber diet. Antiemetics and opioids via continuous subcutaneous infusions are used
to manage nausea, vomiting, and colic, respectively. In addition, octreotide, a somatostatin analog, is
used in palliation of refractory malignant intestinal obstruction by improving intestinal mucosal
absorption, improving motility, reducing gastrointestinal hormone levels and intestinal secretions, and
having a direct antineoplastic effect on the obstructing tumor.112 This allows true palliative care outside
a hospital setting saving patients the pain, discomfort, and complications of hospitalization and
1266
booksmedicos.org
unproductive surgery.111
Volvulus
The term volvulus indicates that a loop of bowel is twisted more than 180 degrees about the axis of its
mesentery. Volvulus has been reported for the cecum, transverse colon, splenic flexure, and sigmoid
colon. A special variant of volvulus, complicating a condition known as Chilaiditi syndrome, can occur
when redundant loops of the transverse colon slip between the liver and diaphragm and then undergo
torsion.113 Generally, the condition is asymptomatic, but when associated with volvulus must be
relieved surgically.
Table 49-4 Results of Management of Malignant Obstructions: Risk Factors for

Unfavorable Outcome
The most common site for volvulus is the sigmoid colon, accounting for 65% of cases.114 By
definition, a volvulus is a form of closed-loop obstruction of the colon. Air is always present in the colon
and rectum, and thus volvulus of any segment of the colon is associated with abdominal distention and,
usually, severe abdominal pain. As shown in Figure 49-5, the most common radiographic feature is the
“bent inner tube” appearance of the sigmoid, which is located in the upper abdomen. The preferred
method of management involves endoscopic decompression. A rigid or flexible proctosigmoidoscope is
advanced gently into the rectum until a rush of air and feces indicates that the loop has been untorsed.
A rectal tube is then advanced well into the loop as a stent to prevent retorsion. Gangrene of the colon
does not usually complicate the picture if the patient is seen and treated promptly. This conservative
approach resolves the volvulus in 85% to 90% cases and elective resection or fixation of the redundant
segment can then be planned. Following endoscopic decompression, recurrence of the volvulus is higher
than 60%.115 Thus, an operation to remove the sigmoid should be performed if the patient is fit for
surgery.116 However, a majority of these patients are elderly and infirm and approximately 15% have a
history of psychiatric disorder. As a result, the patient may present with peritoneal findings, sepsis, and
shock. In this setting, rapid resuscitation followed by urgent resection and colostomy is warranted.
Other forms of volvulus generally cannot be detorsed without operation. Fixation of the torsed segment
(e.g., via cecostomy or cecopexy) is generally a less satisfactory solution than resection of the involved
segment and is not generally recommended.114
Radiation Enteritis
After asymptomatic periods lasting at least 10 years, chronic intestinal obstruction can result. Radiation
injury elicits an underlying vasculitis and fibrosis that lead to chronic, recurring low-grade partial
obstruction of the small intestine or stricturing and bleeding in the colon and rectum. Operation is
indicated for incapacitating symptoms and obstruction not resolved by conservative management.117
Recurrence of the original tumor as a cause of obstruction should be considered and excluded. However,
the diffuse nature of the injury and pathologic responses can lead to massive resections that leave the
patient with short-bowel syndrome. Attempts to suture scarred loops can also result in chronic
inflammation and formation of interloop abscesses and fistulae. The incidence of suture line leak is
high.118 There are several experimental therapies used in the treatment and prevention of radiation
enteritis which includes pentoxifylline–tocopherol combination, sulfasalazine, methylprednisolone,
HBO, intraperitoneal octreotide, cysteine, triamcinolone, and amifostine.119,120
Role of Laparoscopy in Management of Small Bowel Obstruction
1267
booksmedicos.org
Open surgery is the preferred method in the management of strangulating SBO after failed conservative
management but since the advent of laparoscopy for general abdominal surgery, a number of
investigators have reported the feasibility of laparoscopic approaches to small and large bowel
obstruction. Such approaches have been used, with varying degrees of success, to manage obstruction
from a number of different etiologies (Table 49-5).121–123 Laparoscopic management of bowel obstruction
provides many potential benefits including quicker recovery of bowel function, shorter hospital stay,
less postoperative pain, reduced recovery time and early return to full activity, and fewer postoperative
complications including a decreased incidence of wound infection and pneumonia. Additionally, as
suggested by both clinical and experimental studies in animal models, laparoscopy is associated with
decrease in incidence, extent and severity of intra-abdominal adhesions compared with open
surgery.124,125 Thus laparoscopic management of bowel obstruction may result in a decreased lifetime
risk for recurrent bowel obstruction. According to a systematic review and meta-analysis, laparoscopic
adhesiolysis was associated with reduced overall complication rate with no significant difference in the
occurrence of intraoperative injury to bowel and overall mortality.126
Table 49-5 Results for Outcome of Laparoscopic Management of Intestinal

Obstruction: Favorable Attributes
In adults, the most common etiology for which laparoscopic versus open surgical management of
bowel obstruction has been evaluated is adhesive bowel obstruction.123,127–136 Studies of laparoscopic
lysis of adhesions for SBO indicate that it is feasible, with acceptable operative times, length of hospital
stay, as well as conversion and complication rates (Table 49-6). Studies directly comparing laparoscopic
to open surgical management of adhesive SBO highlight the benefits of the laparoscopic approach as
indicated by statistically significant decreases in complication rates, time to return of bowel function,
length of hospital stay, and even overall cost (Table 49-7).
Despite these benefits, laparoscopic management of bowel obstruction should be approached with
caution and individualized to specific clinical situations.137 Laparoscopy is discouraged when the
surgeon is uncomfortable with the technique or in patients presenting with peritonitis, hemodynamic
instability, severe comorbid conditions, complete and distal obstruction, or when contraindications to
pneumoperitoneum exist. Recent advancement and improvement in tools and skill in laparoscopy have
paved the way for its increased use in the surgical management of SBO. Recently, consensus guidelines
have been published emphasizing its role in selected group of patients.138 Laparoscopically assisted lysis
of adhesions may be attempted in case of first episode of SBO or anticipated single-band lesion. While it
may be problematic to use a laparoscopic approach in managing obstruction in patients who have
previously undergone extensive and open intra-abdominal procedures, it is safe to use a laparoscopic
approach in managing obstruction in patients who have previously undergone laparoscopic procedures,
especially focused procedures such as appendectomy and cholecystectomy.
Under these circumstances, success in using laparoscopy to confirm the diagnosis of obstruction is
between 60% and 100%; its success in therapeutic resolution of the obstruction is lower, perhaps 40% to
80%. The predictive factors for a successful laparoscopic adhesiolysis are less than 2 previous
laparotomies, nonmedian previous laparotomy, appendectomy as previous surgical treatment, unique
band adhesion as phatogenetic mechanism of SBO, early laparoscopic management within 4 hours from
onset of symptoms, no signs of peritonitis on physical examination, and experience of surgeon.139 There
should be a low threshold for open conversion. The usual reasons for converting to open adhesiolysis
are inadequate laparoscopic control due to intestinal distention, extensive adhesions, iatrogenic
perforations, bleeding, and resection of necrotic segments.140 Operative technique plays a paramount
1268
booksmedicos.org
role in the success of laparoscopic approach. In obtaining laparoscopic access, an open access (Hasson)
technique, entry to the left upper quadrant and ultrasound-guided site entry were recommended.49,138
Although recent studies suggest that laparoscopic approaches are safe, effective and beneficial,
prospective randomized studies evaluating laparoscopic management of SBO are required to definitively
document its benefits over the traditional open approaches. It is also important to point out the need for
adhesion quantification in future research. Coccolini et al. proposed a peritoneal adhesion index ranging
from 0 to 30, providing a more precise and standardized system for describing findings at operation.141
Such standardization would enable integration of the results of different studies, permitting a better
understanding of circumstances where treatments may be standardized and those where
individualization is important.
Table 49-6 Outcomes and Complications of Laparoscopic Operations for

Obstruction of the Small Intestine Due to Adhesions
Table 49-7 Outcomes, Complications, and Costs in Laparoscopic Management of

Intestinal Obstruction Due to Adhesions
7 Open exploratory laparotomy is the gold standard in treating unresolved SBO, but laparoscopic
management should be considered in select group of patients. Types of intestinal obstruction that are
more likely to lead to strangulation and the need for urgent/emergent operation include closed-loop
obstructions, obstruction that occurs without a prior history of operation, and obstructions that occur
after laparoscopic procedures.
ILEUS AND PSEUDO-OBSTRUCTION

Ileus
Etiologic Factors
1269
booksmedicos.org
8 An ileus or “eileos” (Greek for “twisting”) reflects a loss of forward peristalsis and coordination of the
motility of the different regions of the gastrointestinal tract causing a functional obstruction.142
Clinically, bowel sounds, passage of flatus, and bowel movements have been used to signal the return of
bowel function and coordination of peristalsis. Liquid contrast and radiolabeled marker studies suggest
that effective duration of ileus varies in different regions of the alimentary tract.143,144 A POI may last
for 0 to 24 hours in the small intestine, 24 to 48 hours in the stomach, and 48 to 72 hours in the large
bowel.145,146 The type of surgery and the wide variety of endpoints used to measure gut recovery often
decide the duration of ileus. There is no consensus as to which one is most clinically meaningful.
Duration of ileus is therefore primarily dependent on the return of colonic motility and its coordination
with other regions of the gastrointestinal tract. A typical period of ileus is thus self-limited and easily
tolerated. Factors implicated in ileus (Table 49-6) are outlined below:
Neurohumoral Peptides. Increases in endogenous neuromuscular inhibitors of the bowel include

norepinephrine, corticotropin-releasing hormone (CRH), nitric oxide, somastostatin, glucagon, gastric
inhibitory peptide, opioids and other peptides such as calcitonin gene-related peptide, motilin, substance
P, VIP_ and substance P, have all been established as inhibitory neurotransmitters in the intrinsic gut
nervous system. Antagonists to VIP, substance P and inhibitors of NO synthesis improve postoperative
bowel motility.147,148 Calcitonin gene–related peptide inhibits postoperative gastric emptying and
gastrointestinal transit.149,150 The use of anticholinergic medications delays recovery of an ileus.151
One group of neurohumoral substances that are particularly important in this regard are the opioids,
both synthetic and endogenous. Opioids are established neurotransmitters in central and peripheral
nervous systems, and it is well established that their use delays gastric emptying and promotes
nonpropulsive smooth muscle contraction with an increase in intraluminal pressure throughout the
entire gastrointestinal tract.152,153 Over the years, a series of experimental studies have indicated that
recovery of ileus is accelerated during administration of specific antagonists to kappa or mu opioid
receptors,154,155 suggesting that endogenous opioid release modulates recovery from ileus.
Inflammation. A relatively recent series of experimental and clinical investigations have focused
attention on the role of inflammatory cells and mediators of inflammation in the development of
prolonged ileus. Surgical intervention results in elevated levels of interleukin-6 (IL-6), cyclooxygenase
isoform COX-2, and inducible nitric oxide synthetase (iNOS), all mediators of inflammation from
macrophages.156,157 In experimental animals, focal manipulation of the bowel may result in a pan-
enteric inflammation and ileus.157 In experimental animals and human subjects, activated macrophages
have been found in the muscularis of the small bowel, as early as 3 hours after laparotomy.158 Increased
COX-2 expression leads to prostaglandin release. Jejeunal contractility appears to be impaired, an effect
blocked in COX-2 knockout mice and by the administration of selective COX-2 inhibitors. In related
studies both in experimental animals and human subjects, Kalff et al. found that NO synthesis is
stimulated in activated macrophages in the muscular layer of the small intestine following surgical
intervention. More recently, degranulation of mast cells has also been implicated in the pathogenesis of
ileus after laparotomy. In this regard, it has been shown that surgical manipulation of intestines
activates quiescent macrophages as well as mast cells, and that mast cell destabilizers can prevent
mechanically induced intestinal inflammation and dysmotility.159,160 Bowel wall edema from
inflammation or intravenous fluid overload is another mechanism of impairment of GI motility.161
Table 49-8 Etiologies of Prolonged Ileus After Abdominal Operations
1270
booksmedicos.org
Inhibitory Neural Reflexes. Noxious spinal afferent signals are thought to increase inhibitory
sympathetic activity in the gastrointestinal tract.162 Blockade of spinal afferents with epidural local
anesthetics or with topical capsaicin has been shown to accelerate resolution of ileus in experimental
studies.149,150 In clinical studies of patients undergoing complex abdominal operations through
conventional laparotomy incisions, it appears that conventional intramuscular injections are less likely
to be associated with prolonged ileus than strategies utilizing patient-controlled intravenous
injection.163,164 Moreover, utilization of epidural analgesia tends to decrease recovery times from ileus
in this group of patients,165–167 suggesting that autonomic pathways coursing through spinal cord may
serve as control points for ileus. Recent studies also provide evidence that carbon monoxide, derived
from the activity of heme oxygenase-2 in myenteric plexus of the intestine, may play a role in
modulating smooth muscle activity and its regulation by enteric nervous system.168–170
Central responses have also been observed as a result of laparotomy162 and have been linked to
activation of afferent pathways in the vagus nerve and a general response of the organism to stress and
release of corticotrophin-releasing factor.171 Very recently, the efferent pathways in the vagus have also
been implicated as possible modulators or control points for the inflammatory response. A series of
experimental studies172,173 has suggested that the vagus participates in suppression of certain
macrophage activities, leading to earlier resolution of intestinal ileus.173 These observations offer the
possibility of a multidimensional understanding of ileus, both in individuals who are recuperating
normally and in those who have protracted ileus but no specific risk factors for it (e.g., undrained
sepsis, overuse of narcotics, spinal cord injury, severe pelvic fractures, and retroperitoneal
inflammation).
Diagnosis
It is important to distinguish between a normal POI and a paralytic ileus. The distinction is
predominantly one of time since operation and based on circumstance. POI is less severe, self-limiting
(lasts 2 to 3 days vs. 3 to 5 days) and is usually an indicator of colonic dysmotility rather than a
paralytic ileus which represents inhibition of small bowel activity. A prolonged POI (PPOI) occurs with
protracted signs or symptoms of abdominal distention, bloating, diffuse and persistent abdominal pain,
nausea, vomiting, and inability to pass flatus or tolerate an oral diet.
It is also important to distinguish between a PPOI from a mechanical SBO. Clinically, the presence of
intense colicky pain, feculent emesis, or rapidly progressing pain or distension is more suggestive of
SBO than PPOI. Localized tenderness, fever, tachycardia, and peritoneal signs suggest bowel ischemia or
perforation, necessitating emergent surgical intervention.10
A variety of clinical circumstances and laboratory tests may also increase suspicion for prolonged
ileus and lessen concern for mechanical obstruction and associated complications. In addition to opiates,
a number of medications have been associated with slow recovery of intestinal motor function (Table
49-8). Isolated metabolic disturbances such as ketoacidosis, hypomagnesemia, hypercalcemia, and
hypokalemia can prolong ileus. Ileus can be caused and perpetuated by systemic inflammatory
responses to sepsis, abscess, pneumonia, and pancreatitis.
9 When the patient’s POI has extended beyond the expected period, plain films of the abdomen
reveals gas in segments of both small and large bowel (Fig. 49-14). At this point, the patient may begin
to experience some discomfort and distention, as swallowed air fills loops that do not have effective
peristalsis. Bowel sounds may be present, if hypoactive. The differential diagnosis now includes the
possibility of mechanical obstruction from early postoperative adhesions (see earlier). To differentiate
early postoperative obstruction from ileus, contrast studies or CT scans are helpful. The latter may be
useful if other abdominal pathology such as an abscess could be contributing to the clinical picture. CT
with oral contrast has a sensitivity and specificity of 90% to 100% in distinguishing ileus from a complete
postoperative SBO.174 However, it is less reliable in distinguishing ileus from a partial SBO.174 If the
diagnosis is uncertain after CT, upper GI contrast studies (enteroclysis) with water-soluble radio-opaque
contrast material (e.g., Gastrograffin) are especially helpful in distinguishing ileus from partial SBO
(which more closely mimics ileus than complete SBO) and in identifying the severity of partial
obstruction.174
1271
booksmedicos.org
Figure 49-14. Plain supine abdominal radiograph of a patient with ileus. Air–fluid levels are present in the small intestine (thin
arrow). Gas is seen in the colon (thick arrowhead). These findings are characteristic of, but not specific for, ileus. Surgical drains in
the pelvis and skin staples (short arrow).
Management
10 A normal POI is usually self-limiting. Nevertheless, there are a number of interventions that are
effective in reducing the duration of a normal postlaparotomy ileus (Table 49-9). Midthoracic epidurals
with neuraxial local anesthetics has been shown to hasten the return of bowel function compared to
systemic or epidural opioids.165–167 Midthoracic local anesthetic epidurals block nociceptive afferent
signals from the surgical site as well as sympathetic efferent outflow; this is useful for 48 to 72 hours
postoperatively.
The goals in management in the normal period of postoperative ileus are to prevent uncomfortable
distension, vomiting, and aspiration. Classic studies6,10 indicate that flatus and the air accumulating
during intestinal distension is derived largely from swallowing. Under normal circumstances, flatus is
passed as early as 30 minutes after a “test bolus” of air is administered by tube into the stomach. Thus,
passage of flatus is used, in reliable patients, as the index indicating coordination of all segments of the
gastrointestinal tract and resolution of ileus.
For many years, the mainstay of therapy was the use of nasogastric suction to prevent accumulation
of swallowed air and secreted fluids in an alimentary tract not yet coordinating flow distally.
Subsequent studies have demonstrated that the putative benefit does not compensate for risks of
aspiration and discomfort of the tube. Thus, in routine abdominal cases such as colectomy, nasogastric
tubes are used selectively175,176 in patients who are felt to be at risk of complications of ileus, based on
the surgeon’s judgments about intraoperative findings or manipulations – prolonged handling and
packing of the bowel, anticipation of intensive use of narcotics or other antikinetic agents, presence of
sepsis or peritonitis, or extensive blood loss. Otherwise, a nasogastric tube is used for a short
postoperative period or never placed, with the expectation that a small percentage of patients will
require placement for symptoms.176 In these patients, the patient is allowed nothing more than sips or
ice chips until there is evidence (by listening for bowel sounds or the patient’s report of “rumbles”) that
ileus is likely resolving. Intravenous fluids are necessary until the patient can be advanced to full intake
of their requirements, usually after flatus is passed.
Table 49-9 Treatment for Postoperative Ileus
1272
booksmedicos.org
In addition correctable conditions such as electrolyte disturbances or uremia are investigated and
rectified. Mobilization has other benefits in reducing morbidity.177,178 Early feeding is thought to
stimulate gastrointestinal hormones, secretions and motility, and coordinated propulsive activity. In
addition early feeding may improve immune function, reduce179 infectious and catabolic
complications.142,180 Despite the use of laxatives with prokinetic agents, no controlled trial exists to
assess the possible beneficial effects of laxatives on POI.142
One treatment, gum chewing, has attracted attention as a simple and inexpensive method of
accelerating return of bowel function. Mastication stimulates the cephalic vagal cholinergic pathways
that increases gastrointestinal hormone secretion such as gastrin, pancreatic polypeptide, and
neurotensin which affects gastrointestinal motility.181,182 Since the initial publication of one small and
underpowered study,183 a number of prospective randomized trials have been conducted to test the
hypothesis that gum chewing results in earlier passage of flatus and bowel movement in patients
undergoing laparoscopic colectomy.184,185 No conclusive evidence has been obtained to demonstrate a
clear benefit of gum chewing, although subgroup analysis suggests some patients may benefit.185 At the
same time, prospective randomized studies continue to be performed, arguing one conclusion or the
other.186–190 According to one hypothesis sorbitol and other hexitols, the key gradients of “sugar-free”
chewing gums may also play a role in the earlier recovery of POI.191 A recent study192 argued that
nicotine gum might accelerate resolution of postoperative ileus through enhancement of vagal
activation.
Salt and water disturbances in the body also may influence return of bowel function following
laparotomy. In one study, patients undergoing colectomy received a restricted perioperative fluid
resuscitation regimen or a standard, more liberal fluid resuscitation. The “restricted” group had a
quicker passage of flatus and moved their bowels earlier, leading in part to shorter hospital stays.193
Subsequent studies194,195 have not uniformly suggested that recovery from ileus is faster with
temperance in fluid resuscitation; or have indicated that there is a benefit from fluid restriction
protocols but have not reported return of gastrointestinal function as an endpoint.196 However, this
benefit, as well as others, may be more clearly observed when fluid therapy is directed by physiologic
assessments of volume status, such as esophageal Doppler monitoring of the great vessels and heart
chambers.197,198 A double-blind, randomized controlled clinical trial showed that Doppler-guided
intraoperative fluid management decreases postoperative nausea, vomiting, ileus and wound
infection.199
Experimental evidence of pharmacologic interventions specifically directed at abnormal surges of
1273
booksmedicos.org
neurotransmitters or hormones that might prolong ileus have provided a useful insight into the
pathophysiology of POI. Opioid antagonists, somatostatin analogs, sympatholytics, injection of local
anesthetics into mesenteric nerve roots, or nonsteroidal anti-inflammatory agents, such as ketorolac,
appear to promote faster recovery to normal myoelectric activity and intestinal transit times.151,200,201
The peripherally acting, selective μ-opioid receptor antagonist alvimopan (EnteregTM) has been reported
to reduce GI recovery time and to facilitate hospital discharge for both open and laparoscopic colorectal
surgery cases,202 after gynecologic surgery,203 after bowel resection, and after radical cystectomy.204
Importantly, in one study, the effect of alvimopan accelerated recovery after open abdominal surgery as
an independent influence in an accelerated recovery program205 from colectomy.
Prokinetic agents such as metoclopramide, cisapride (presently not approved by U.S. Food and Drug
Administration), and erythromycin have been evaluated for their efficacy in shortening the duration of
POI. For ileus following upper gastrointestinal procedures (e.g., pancreaticoduodenectomy), such
medications may be effective in promoting gastric emptying.206–211 For general abdominal procedures
involving the small intestine, colon, and retroperitoneal structures such as the aorta, there has been
limited success in using such agents to shorten recovery times.179 In multiple controlled studies,
metoclopramide did not have significant impact on the duration of ileus.212–214 In other studies, no
benefit was observed when patients were given erythromycin. Promising results have been observed
with cisapride and related agents,179,206,208 which significantly reduced the duration of ileus. The results
would depend on the route of its administration. However, this medication is no longer approved for
use in the United States due to the occurrence of potentially fatal arrhythmias.215 In a Cochrane review
of fifteen systemically acting prokinetic drugs, the conclusion was that erythromycin has no effect and
there are insufficient evidence to recommend cholecystokinin-like drugs, cisapride, dopamine
antagonist, propranolol, or vasopressin. IV lidocaine and neostigmine might show a potential effect but
more evidence is needed.179 Mosapride, a selective 5-hydroxytryptamine 4 receptor agonist has been
shown to reduce the duration of POI in animal and human studies.216 Escin, a natural mixture of
triterpene saponins extracted from dried seeds of horse chestnut (Aesculus hippocastanum or chinensis)
also may shorten time to recovery of gastrointestinal motility.217
Along with pharmacologic measures, it should be emphasized that, in otherwise routine laparotomy
or laparoscopy, gentle handling of tissues, meticulous attention to hemostasis, and applications of sound
principles of wound management are likely to have the greatest impact on optimizing recovery from
ileus and minimizing the incidence of prolonged ileus. Efforts to reduce incision size and time spent
handling the intestines through the use of laparoscopic approaches clearly improves recovery from ileus
in some if not all patients undergoing standardized intra-abdominal procedures such as
appendectomy,218 and colectomy.219 Even in open procedures,220 standardization of management and
effective communication help expedite clinical fast-track pathways and facilitate earlier recovery of
bowel function and discharge from hospital.142,198,221 Currently proposed measures to minimize the
prolongation of ileus are summarized in Table 49-10.
Table 49-10 Measures to Prevent Prolongation of Ileus
Colonic Pseudo-Obstruction (Ogilvie Syndrome)

Etiologic Factors
Acute pseudo-obstruction of the colon, also known as Ogilvie syndrome,222 is a paralytic ileus of the large
bowel, characterized by rapidly progressive abdominal distention, often painless.223 Although the
1274
booksmedicos.org
distention of the colon is not due to mechanical obstruction, the wall of the bowel, particularly that of
the cecum, can become sufficiently distended so that its blood supply is compromised. Gangrene,
perforation, peritonitis, and shock can follow. In 95% of the cases there are underlying diseases.223,224
Less than 5% of the cases occur in the absence of other conditions.
Major risk factors for development of Ogilvie syndrome include traumatic injury (11%), infections
such as pneumonia, sepsis (10%); obstetric/gynecologic conditions (10%); myocardial infarction and
congestive heart failure (10%); abdominal and pelvic surgery (9%); neurologic conditions such as
Parkinson disease, spinal cord injury, multiple sclerosis, and Alzheimer disease (9%); orthopedic
procedures (7%); other medical conditions including metabolic imbalances, for example, hypokalemia,
hypocalcemia, hypomagnesemia (32%); and other surgical conditions (12%).222,224 Evidence suggests
that Ogilvie syndrome is thought to be related, at least in part to sympathetic nervous overactivity or
interference with sacral parasympathetic efferents, although there is little direct experimental evidence
for this.223 It is postulated that the distal colon becomes atonic on interruption of the S2 to S4
parasympathetic nerve fibers. Other theories about the pathophysiologic causes include autonomic
dysfunction, reduced colonic ganglion cells, and loss of intrinsic nitric oxide activity but the cause
remains unknown.225
Diagnosis
This syndrome is commonly encountered in patients hospitalized over 3 to 7 days, often in men more
than 60 years of age. Primary manifestations variably include gastrointestinal symptoms such as nausea,
vomiting, abdominal pain, constipation, and diarrhea.223,224 Labored breathing, caused by abdominal
distention, may be observed as part of the clinical picture. Other than distension, there are no
characteristic physical or laboratory findings for this syndrome. On percussion the abdomen is resonant
due to the presence of air in dilated segments of small intestine and colon. Sounds from the small
intestine are present and may not be high pitched, as they are in intestinal obstruction.
Laboratory findings associated with this syndrome may include hypokalemia, hypocalcemia,
hypomagnesemia, and hypophosphatemia, which are implicated as etiologic factors. Leukocytosis,
elevation of sedimentation rate or c-reactive protein is also present if low-grade systemic inflammation
is present or perforation is impending.
The diagnosis is usually apparent from plain film radiographs of the abdomen which may reveal air in
the small bowel and distention of discrete segments of the colon (i.e., cecum or transverse colon often
up to splenic flexure) or the entire abdominal colon. Haustral markings disappear with increasing
distension. In doubtful cases and when bowel necrosis is not a significant worry, a hypaque contrast
enema can establish the nonmechanical nature of the dilatation. Alternatively, colonoscopy can be
diagnostic as well as therapeutic. Features suggesting the complication of bowel ischemia may include
localized tenderness, worsening leukocytosis, metabolic acidosis, evidence of sepsis, or a rapidly
deteriorating clinical course.
It is important to differentiate this syndrome from toxic megacolon and mechanical obstruction before
establishing a final diagnosis. Mechanical obstruction of the colon, occurring in volvulus or obturator
obstructions from cancer or diverticular disease, presents with acute pain along with distension. In
contrast, pseudo-obstruction is less often associated with acute pain and more likely to present with
discomfort due to distention. However, lack of pain in postoperative patients on opiates or elderly
patients cannot exclude mechanical obstruction. In plain x-rays, the pathognomonic signs of mechanical
obstruction such as lack of gas in the distal colon or rectum, and air–fluid levels in small intestine on x-
ray can also be seen in Ogilvie syndrome. CT scan is currently the standard method for identifying colon
pseudo-obstruction and excluding other forms of obstruction.223 Patients with toxic megacolon may
manifest typically with symptoms such as fever, tachycardia, abdominal tenderness, bloody diarrhea or
other manifestations of chronic inflammatory bowel disease along with “thumb printing” on the
appearance of the abdomen on plain x-ray film in upright posture. Flexible sigmoidoscopy is
contraindicated if toxic megacolon is thought to be likely, but it or contrast enemas223 can be useful
diagnostically and therapeutically if toxic megacolon is thought unlikely.
Management
Initial management includes resuscitation and correction of any underlying metabolic or electrolyte
imbalances (Table 49-11). Patients should have physical examination and plain abdominal radiographs
serially to correlate colonic diameters in order to determine which case needs colonoscopic
decompression or surgery. If the patient is not very uncomfortable and the colonic distension is no
greater than 12 cm, conservative treatment can be continued for 1 to 2 days. It may be helpful to place
1275
booksmedicos.org
the patient in a prone position or at the knee chest position with hips held high, alternating right and
left lateral decubitus position each hour. A nasogastric tube is helpful if the patient is vomiting and will
prevent swallowed air from passing distally. When bowel ischemia is suspected, surgery is indicated. If
bowel necrosis is found, the affected segment is resected and an ileostomy or colostomy should be
performed. If the bowel is viable, a cecostomy is placed to vent the colon and prevent distention.
If, initially, the distention is painless and the patient shows no signs of toxicity or bowel ischemia,
expectant management is successful in about 50% of cases.223,226 The risk of spontaneous perforation is
approximately 3%, with attendant mortality of 50%. In most patients acute colonic pseudo-obstruction
usually resolves within 3 days.223,227 If worsening and cecal diameter increases beyond 10 to 12 cm or if
it persists for more than 48 hours, intervention is recommended. The duration of distention may be
more important than the absolute size of the cecum with respect to spontaneous perforation.
Colonoscopy should only be performed by experienced endoscopists. Endoscopic decompression is
successful in 60% to 90% of cases, but the condition can recur in up to 40%. This rate of recurrence may
be decreased by placement of a decompressive tube. Recurrence would require repeated colonoscopic
decompression in approximately 40% of cases after initial successful decompression. The placement of a
decompression with the aid of a guidewire at the time of colonoscopy may reduce the need for repeated
colonoscopic decompression. Rectal tubes are ineffective as primary modalities in managing distention
of the proximal colon. Such tubes may be useful in promoting passage of air and feces after colonoscopy
but should not be used as a substitute for colonoscopic decompression. Percutaneous endoscopic left-
sided colostomy (PEC), a minimally invasive technique, can be used to treat pseudo-obstruction
provided these cases are carefully selected in the hands of a skilled endoscopist because of a high failure
rate caused by infection.228
Table 49-11 Treatment for Pseudo-Obstruction
In anecdotal reports, prokinetic agents such as cisapride and erythromycin have been used to treat
Ogilvie syndrome with some success. Erythromycin acts by binding to motilin receptors in the small
intestine, causing intestinal smooth muscle contraction and perhaps better coordination with colonic
motor function. Anecdotal reports have suggested the success of erythromycin treatment on either
intravenous route for 3 days or oral route for 10 days.229,230 However, the relative paucity of motilin
receptors in colon smooth muscle may explain why erythromycin is only anecdotally effective in
relieving colonic pseudo-obstruction. Successful resolution of pseudo-obstruction has been reported with
sympatholytic agents or spinal sympathetic block. The efficacies of these modalities have not been
systematically evaluated.223,231
Neostigmine, a parasympathomimmetic, is used in the treatment of acute colonic pseudo-obstruction.
The decompression with this drug has been achieved in 80% to 100% with a recurrence rate of 5%.223
Neostigmine may be a viable alternative to colonoscopy in pregnant women, provided mechanical
obstruction is properly excluded. The administration of a polyerthylene glycol electrolyte balanced
solution after initial resolution of colonic dilation may reduce the recurrence rate with use of
neostigmine.232
Neostigmine has expected cardiovascular side effects such as bradycardia, hypotension, and dizziness;
and is excreted via the kidneys. The few relative contraindications to its use in treatment of acute
colonic pseudo-obstruction are a baseline heart rate of less than 60 beats per minute or systolic blood
pressure of less than 90 mm Hg; active bronchospasm requiring medication; a history of colon cancer or
1276
booksmedicos.org
partial colonic resection; active gastrointestinal bleeding; pregnancy; or a serum creatinine
concentration of more than 3 mg/dL (265 μmol/L). Other side effects would include mild to moderate
crampy abdominal pain, excessive salivation and vomiting. Side effects such as increasing airway
secretions and bronchospasm, can be reduced by concomitant use of glycopyrrolate without reduction of
colonic response.233,234 Ponec et al.235 recommend use of neostigmine prior to colonoscopy, based on its
easy administration, lower expense, and superior results in comparison to colonoscopy. Reported rates
of response to treatment with neostigmine are 91% (single administration) and 100% (second
administration) in a group of 21 randomized patients.223,235 Colonoscopy is associated with morbidity of
3% and mortality of 1%. Further studies of this combination therapy are warranted. It should be
emphasized however, that patients should undergo immediate exploration if they exhibit signs of
clinical deterioration or bowel perforation (peritoneal signs on physical examination or free air on
radiographs).
Surgery is reserved for patients not responding to medical and endoscopic management and for
patients who develop signs of peritonitis or perforation. Percutaneous endoscopic cecostomy can also be
performed if case conservative measures fail.236 Cecostomy tubes are often poorly tolerated because of
issues related to skin breakdown; in the authors opinion, this approach is advisable only when more
extensive surgical procedures are considered too risky. Procedures such as total colectomy, ileostomy,
and Hartmann procedure are taken into consideration in case of perforation.223
References
1. Treves F. Intestinal Obstruction: Its varieties, with Their Pathology, Diagnosis, and Treatment.
Philadelphia, PA: H.C. Lea’s Son and Co; 1884.
2. Ballantyne GH. The meaning of ileus. Its changing definition over three millennia. Am J Surg
1984;148(2):252–256.
3. Welch JP. History. In: Bowel Obstruction: Differential Diagnosis and Clinical Management. 1990,
Philadelphia, PA: W.B. Saunders Co; 3–27.
4. Wangensteen OH, Paine JH. Treatment of acute intestinal obstruction by suction with a duodenal
tube. JAMA 1933;101:1532.
5. Paine JR, Carlson HA, Wangensteen OH. Postoperative control of distension, nausea and vomiting;
clinical study with reference to employment of narcotics, cathartics, and nasal catheter suction-
siphinage. JAMA 1933;100(1910).
6. Wangensteen OH, Rea CE. The distension factor in simple intestinal obstruction: an experimental
study with exclusion of swallowed air by cervical esophagostomy. Surgery. 1939;5(327).
7. Hartwell HJ, Hoguet JP. Experimental intestinal obstruction in dogs with special reference to the
cause of death and the treatment by large amounts of normal saline solution. JAMA 1912;59(82).
8. Milamed DR, Hedley-Whyte J. Contributions of the surgical sciences to a reduction of the mortality
rate in the United States for the period 1968 to 1988. Ann Surg 1994;219(1):94–102.
9. Wangensteen OH. Intestinal Obstructions. 3rd ed. Springfield: Charles C. Thomas; 1955.
10. Ellis H. Intestinal Obstruction. New York: Appleton Crofts; 1982:11–21.
11. Dayton MT, Dempsey DT, Larson GM, et al. New paradigms in the treatment of small bowel
obstruction. Curr Probl Surg 2012;49(11):642–717.
12. Roscher R, Oettinger W, Beger HG. Bacterial microflora, endogenous endotoxin, and prostaglandins
in small bowel obstruction. Am J Surg 1988;155(2):348–355.
13. Heneghan JB, Robinson JW, Menge H, et al. Intestinal obstruction in germ-free dogs. Eur J Clin
Invest 1981;11(4):285–290.
14. Stark ME, Szurszewski JH. Role of nitric oxide in gastrointestinal and hepatic function and disease.
15. Caplan MS, Hedlund E, Hill N, et al. The role of endogenous nitric oxide and platelet-activating
factor in hypoxia-induced intestinal injury in rats. Gastroenterology 1994;106(2):346–352.
16. Barry MK, Aloisi JD, Pickering SP, et al. Nitric oxide modulates water and electrolyte transport in
the ileum. Ann Surg 1994;219(4):382–388.
17. Kubes P. Nitric oxide modulates epithelial permeability in the feline small intestine. Am J Physiol
1992;262(6 Pt 1):G1138–G1142.
1277
booksmedicos.org
18. Shields R. The absorption and secretion of fluid and electrolytes by the obstructed bowel. Br J Surg
1965;52(10):774–779.
19. Wright HK, O’Brien JJ, Tilson MD. Water absorption in experimental closed segment obstruction of
the ileum in man. Am J Surg 1971;121(1):96–99.
20. Sung DT, Williams LF Jr. Intestinal secretion after intravenous fluid infusion in small bowel
obstruction. Am J Surg 1971;121(1):91–95.
21. Ruf W, Suehiro GT, Suehiro A, et al. Intestinal blood flow at various intraluminal pressures in the
piglet with closed abdomen. Ann Surg 1980;191(2):157–163.
22. Ohman U. Studies on small intestinal obstruction. I. Intraluminal pressure in experimental low
small bowel obstruction in the cat. Acta Chir Scand 1975;141(5):413–416.
23. Ohman U. The effects of luminal distension and obstruction on the intestinal circulation. In:
Shepherd AP, Granger DN, eds. Physiology of the Intestinal Circulation. New York, NY: Raven Press;
1984:321.
24. Basson MD, Fielding LP, Bilchik AJ, et al. Does vasoactive intestinal polypeptide mediate the
pathophysiology of bowel obstruction? Am J Surg 1989;157(1):109–115.
25. Nellgard P, Bojo L, Cassuto J. Importance of vasoactive intestinal peptide and somatostatin for fluid
losses in small-bowel obstruction. Scand J Gastroenterol 1995;30(5):464–469.
26. Fevang J, Ovrebo K, Svanes K, et al. Endotoxin and cytokine release in strangulation obstruction
and in partial occlusion of the mesenteric artery in pigs. Eur Surg Res 1999;31(1):26–38.
27. Fevang J, Ovrebo K, Ostgaard G, et al. Release of endothelin-1 in strangulation obstruction of the
small bowel in pigs. J Surg Res 1998;79(1):77–84.
28. Fevang J, Ovreb⊘ K, Myking O, et al. Role of endothelin in the circulatory changes associated with
small bowel strangulation obstruction in pigs: effects of the endothelin receptor antagonist
bosentan. J Surg Res 2001;96(2):224–232.
29. Ozbek E, Ilbey YO, Cekmen M, et al. Bacterial translocation to kidney in rats with intestinal
obstruction and the role of nitric oxide. Arch Ital Urol Androl 2009;81(1):56–58.
30. Palasthy Z, Kaszaki J, Lázár G, et al. Intestinal nitric oxide synthase activity changes during
experimental colon obstruction. Scand J Gastroenterol 2006;41(8):910–918.
31. Enochsson L, Nylander G, Ohman U. Effects of intraluminal pressure on regional blood flow in
obstructed and unobstructed small intestines in the rat. Am J Surg 1982;144(5):558–561.
32. Fondacaro J. Intestinal blood flow and motility. In: Shepherd AP, Granger DN, eds. Physiology of the
Intestinal Circulation. New York, NY: Raven Press; 1984:107.
33. Frank JW, Sarr MG, Camilleri M. Use of gastroduodenal manometry to differentiate mechanical and
functional intestinal obstruction: an analysis of clinical outcome. Am J Gastroenterol
1994;89(3):339–344.
34. Camilleri M. Jejunal manometry in distal subacute mechanical obstruction: significance of
prolonged simultaneous contractions. Gut 1989;30(4):468–475.
35. Summers RW, Yanda R, Prihoda M, et al. Acute intestinal obstruction: an electromyographic study
in dogs. Gastroenterology 1983;85(6):1301–1306.
36. Deloose E, Janssen P, Depoortere I, et al. The migrating motor complex: control mechanisms and
its role in health and disease. Nat Rev Gastroenterol Hepatol 2012;9(5):271–285.
37. Eskelinen M, Ikonen J, Lipponen P. Contributions of history-taking, physical examination, and
computer assistance to diagnosis of acute small-bowel obstruction. A prospective study of 1333
patients with acute abdominal pain. Scand J Gastroenterol 1994;29(8):715–721.
38. Taylor MR, Lalani N. Adult small bowel obstruction. Acad Emerg Med 2013;20(6):528–544.
39. Stewardson RH, Bombeck CT, yhus LM. Critical operative management of small bowel obstruction.
Ann Surg 1978;187(2):189–193.
40. Sarr MG, Bulkley GB, Zuidema GD. Preoperative recognition of intestinal strangulation obstruction.
Prospective evaluation of diagnostic capability. Am J Surg 1983;145(1):176–182.
41. Pain JA, Collier DS, Hanka R. Small bowel obstruction: computer-assisted prediction of
strangulation at presentation. Br J Surg 1987;74(11):981–983.
42. Jancelewicz T, Vu LT, Shawo AE, et al. Predicting strangulated small bowel obstruction: an old
problem revisited. J Gastrointest Surg 2009;13:93–99.
1278
booksmedicos.org
43. van Oudheusden TR, Aerts BA, de Hingh IH, et al. Challenges in diagnosing adhesive small bowel
obstruction. World J Gastroenterol 2013;19(43):7489–7493.
44. Gollin G, Marks WH. Early detection of small intestinal ischemia by elevated circulating intestinal
fatty acid binding protein (I-FABP). Surg Forum 1991;42 118–120.
45. Murray MJ, Barbose JJ, Cobb CF. Serum D(-)-lactate levels as a predictor of acute intestinal
ischemia in a rat model. J Surg Res 1993;54(5):507–509.
46. Silen W, Hein MF, Goldman L. Strangulation obstruction of the small intestine. Arch Surg
1962;85:121–129.
47. Maglinte DD, Balthazar EJ, Kelvin FM, et al. The role of radiology in the diagnosis of small-bowel
obstruction. AJR Am J Roentgenol 1997; 168(5):1171–1180.
48. Furukawa A, Yamasaki M, Furuichi K, et al. Helical CT in the diagnosis of small bowel obstruction.
Radiographics 2001;21(2):341–355.
49. Di Saverio S, Coccolini F, Galati M, et al. Bologna guidelines for diagnosis and management of
adhesive small bowel obstruction (ASBO): 2013 update of the evidence-based guidelines from the
world society of emergency surgery ASBO working group. World J Emerg Surg 2013;8(1):42.
50. Branco BC, Chew MH, Eu KW. Systematic review and meta-analysis of the diagnostic and
therapeutic role of water-soluble contrast agent in adhesive small bowel obstruction. Br J Surg
2010;97(4):470–478.
51. Choi HK, Chu KW, Law WL. Therapeutic value of gastrografin in adhesive small bowel obstruction
after unsuccessful conservative treatment: a prospective randomized trial. Ann Surg. 2002;236:1–6.
52. Abbas SM, Bissett IP, Parry BR. Meta-analysis of oral water-soluble contrast agent in the
management of adhesive small bowel obstruction. Br J Surg 2007;94(4):404–411.
53. Assalia A, Schein M, Kopelman D, et al. Therapeutic effect of oral Gastrografin in adhesive, partial
small-bowel obstruction: a prospective randomized trial. Surgery 1994;115(4):433–437.
54. Balthazar EJ, George W. Holmes lecture. CT of small-bowel obstruction. AJR Am J Roentgenol
1994;162(2):255–261.
55. Frager D, Medwid SW, Baer JW, et al. CT of small-bowel obstruction: value in establishing the
diagnosis and determining the degree and cause. AJR Am J Roentgenol 1994;162(1):37–41.
56. Mallo RD, Salem L, Lalani T, et al. Computed tomography diagnosis of ischemia and complete
obstruction in small bowel obstruction: a systematic review. J Gastrointest Surg 2005;9:690–694.
57. Barnett RE, Younga J, Harris B, et al. Accuracy of computed tomography in small bowel
obstruction. Am Surg 2013;79(6):641–643.
58. Santillan CS. Computed tomography of small bowel obstruction. Radiol Clin North Am
2013;51(1):17–27.
59. Zalcman M, Sy M, Donckier V, et al. Helical CT signs in the diagnosis of intestinal ischemia in
small-bowel obstruction. AJR Am J Roentgenol 2000;175(6):1601–1607.
60. Tresallet C, Lebreton N, Royer B, et al. Improving the management of acute adhesive small bowel
obstruction with CT-scan and water-soluble contrast medium: a prospective study. Dis Colon Rectum
2009;52(11):1869–1876.
61. Ogata M, Imai S, Hosotani R, et al. Abdominal ultrasonography for the diagnosis of strangulation in
small bowel obstruction. Br J Surg 1994;81(3):421–424.
62. Ogata M, Mateer JR, Condon RE. Prospective evaluation of abdominal sonography for the
diagnosis of bowel obstruction. Ann Surg 1996;223:237–241.
63. Diaz JJ Jr, Bokhari F, Mowery NT, et al. Guidelines for management of small bowel obstruction. J
Trauma 2008;64(6):1651–1664.
64. Brolin RE, Krasna MJ, Mast BA. Use of tubes and radiographs in the management of small bowel
obstruction. Ann Surg 1987;206(2):126–133.
65. Fleshner PR, Siegman MG, Slater GI, et al. A prospective, randomized trial of short versus long
tubes in adhesive small-bowel obstruction. Am J Surg 1995;170(4):366–370.
66. Chen XL, Ji F, Lin Q, et al. A prospective randomized trial of transnasal ileus tube vs nasogastric
tube for adhesive small bowel obstruction. World J Gastroenterol 2012;18(16):1968–1974.
67. Fonseca AL, Schuster KM, Maung AA, et al. Routine nasogastric decompression in small bowel
obstruction: is it really necessary? Am Surg 2013;79(4):422–428.
1279
booksmedicos.org
67a. Chen SC, Yen ZS, Lee CC, et al. Nonsurgical management of partial adhesive small-bowel
obstruction with oral therapy: a randomized controlled trial. CMAJ 2005;173(10):1165–1169.
68. Fukami Y, Kurumiya Y, Mizuno K, et al. Clinical effect of hyperbaric oxygen therapy in adhesive
postoperative small bowel obstruction. Br J Surg 2014;101(4):433–437.
69. Ambiru S, Furuyama N, Kimura F, et al. Effect of hyperbaric oxygen therapy on patients with
adhesive intestinal obstruction associated with abdominal surgery who failed to respond to more
than 7 days of conservative treatment. Hepatogastroenterology 2008;55(82–83):491–495.
70. Sykes PA, Boulter KH, Schofield PF. The microflora of the obstructed bowel. Br J Surg 1976;63:721–
725.
71. Elmes ME, Howells CH, Lowe GH. Mucosal flora of the small intestine and the effect of pre-
operative antibiotics. J Clin Pathol 1984;37:1272–1275.
72. Deitch EA. Simple intestinal obstruction causes bacterial translocation in man. Arch Surg
1989;124(6):699–701.
73. Cohn I Jr, Floyd CE, Dresden CF, et al. Strangulation obstruction in germfree animals. Ann Surg
1962;156:692–702.
74. Amundsen E, Gustafsson BE. Results of experimental intestinal strangulation obstruction in
germfree rats. J Exp Med 1963;117:823–832.
75. Fevang BT, Fevang J, Lie SA, et al. Long-term prognosis after operation for adhesive small bowel
obstruction. Ann Surg 2004;240:193–201.
76. Duron JJ, Silva NJ, du Montcel ST, et al. Adhesive postoperative small bowel obstruction: incidence
and risk factors of recurrence after surgical treatment: a multicenter prospective study. Ann Surg
2006;244:750–757.
77. Liebman SM, Langer JC, Marshall JS, et al. Role of mast cells in peritoneal adhesion formation. Am
J Surg 1993;165(1):127–130.
78. Attard JA, MacLean AR. Adhesive small bowel obstruction: epidemiology, biology and prevention.
Canad J Surg 2007;50:291–300.
79. Cahill RA, Redmond HP. Cytokine orchestration in post-operative peritoneal adhesion formation.
World J Gastroenterol 2008;14:4861–4866.
80. Beck DE. The role of Seprafilm bioresorbable membrane in adhesion prevention. Eur J Surg Suppl
1997;(577):49–55.
81. Vrijland WW, Tseng LN, Eijkman HJ, et al. Fewer intraperitoneal adhesions with use of hyaluronic
acid-carboxymethylcellulose membrane: a randomized clinical trial. Ann Surg 2002;235(2):193–199.
82. Robb WB, Mariette C. Strategies in the prevention of the formation of postoperative adhesions in
digestive surgery: A systematic review of the literature. Dis Colon Rectum 2014;57(10):1228–1240.
83. Fazio VW, Cohen Z, Fleshman JW, et al. Reduction in adhesive small-bowel obstruction by
Seprafilm adhesion barrier after intestinal resection. Dis Colon Rectum 2006;49(1):1–11.
84. Catena F, Ansaloni L, Di Saverio S, et al; World Society of Emergency Surgery. P.O.P.A. study:
prevention of postoperative abdominal adhesions by icodextrin 4% solution after laparotomy for
adhesive small bowel obstruction. A prospective randomized controlled trial. J Gastrointest Surg
2012;16(2):382–388.
85. Tjandra JJ, Chan MK. A sprayable hydrogel adhesion barrier facilitates closure of defunctioning
loop ileostomy: a randomized trial. Dis Colon Rectum 2008;51(6):956–960.
86. Keller DS, Champagne BJ, Stein SL, et al. Pilot study evaluating the efficacy of AlloMEM for
prevention of intraperitoneal adhesions and peritoneal regeneration after loop ileostomy. Surg
Endosc 2013;27(10):3891–3896.
87. O’Leary DP, Coakley JB. The influence of suturing and sepsis on the development of postoperative
peritoneal adhesions. Ann R Coll Surg Engl 1992;74(2):134–137.
88. Ellozy SH, Harris MT, Bauer JJ, et al. Early postoperative small-bowel obstruction: a prospective
evaluation in 242 consecutive abdominal operations. Dis Colon Rectum 2002;45:1214–1217.
89. Stewart RM, Page CP, Brender J, et al. The incidence and risk of early postoperative small bowel
obstruction. A cohort study. Am J Surg 1987;154(6):643–647.
90. Sajja SB, Schein M. Early postoperative small bowel obstruction. Br J Surg 2004;91:683–691.
91. Lee SY, Park KJ, Ryoo SB, et al. Early postoperative small bowel obstruction is an independent risk
1280
booksmedicos.org
factor for subsequent adhesive small bowel obstruction in patients undergoing open colectomy.
World J Surg 2014; 38(11):3007–3014.
92. Pickleman J, Lee RM. The management of patients with suspected early postoperative small bowel
obstruction. Ann Surg 1989;210(2):216–219.
93. Hamdan K, Somers S, Chand M. Management of late postoperative complications of bariatric
surgery. Br J Surg 2011;98(10):1345–1355.
94. Martin MJ, Beekley AC, Sebesta JA. Bowel obstruction in bariatric and nonbariatric patients: major
differences in management strategies and outcome. Surg Obes Relat Dis 2011;7(3):263–269.
95. Ihedioha U, Alani A, Modak P, et al. Hernias are the most common cause of strangulation in
patients presenting with small bowel obstruction. Hernia 2006;10:338–340.
96. Skandalakis PN, Zoras O, Skandalakis JE, et al. Richter hernia: Surgical anatomy and technique of
repair. Am Surg 2006;72:180–184.
97. Ravikumar H, Babu S, Govindrajan M, et al. Reduction en-masse of inguinal hernia with
strangulated obstruction. Biomed Imaging Interv J 2009;5(4):e14.
98. Wu SC, Wang CC, Sheen-Chen SM. Intestinal obstruction caused by intraoperative mass reduction
of an incarcerated inguinal hernia–report of a case. Int J Surg 2008;6(6):e103–e105.
99. Magnus R. Late bowel obstruction due to kinking of the damaged loop following reduction of a
strangulated hernia. Br J Surg 1965;52:121–122.
100. Gallagher WB, Segnitz RH. Intestinal obstruction due to incarcerated external hernia, with notes on
non-operative reduction and interim elective herniorrhaphy. Am J Surg 1957;93(5):771–777.
101. Walsham WJ. Auto-reduction of hernia “en masse” as a cause of abdominal obstruction. Br Med J
1901;1(2099):691–692.
102. Reisner RM, Cohen JR. Gallstone ileus: a review of 1001 reported cases. Am Surg 1994;60(6):441–
446.
103. Vagefi PA, Ferguson CM Hall JF. Recurrent gallstone ileus: third time is the charm. Arch Surg
2008;143:1118–1120.
104. Halabi WJ, Kang CY, Ketana N, et al. Surgery for gallstone ileus: a nationwide comparison of
trends and outcomes. Ann Surg 2014;259(2):329–335.
105. Rea JD, Lockhart ME, Yarbrough DE, et al. Approach to management of intussusception in adults: a
new paradigm in the computed tomography era. Am Surg 2007;73:1098–1105.
106. Sarr MG, Nagorney DM, McIlrath DC. Postoperative intussusception in the adult: a previously
unrecognized entity? Arch Surg 1981;116(2):144–148.
107. Honjo H, Makio Mike, Hiroshi Kusanagi, et al. Adult intussusception: a retrospective review. World
J Surg 2014;39:134–138.
108. Strong SA, Koltun WA, Hyman NH, et al; Standards Practice Task Force of The American Society of
Colon and Rectal Surgeons. Practice parameters for the surgical management of Crohn’s disease. Dis
Colon Rectum 2007;50:1735–1746.
109. Ripamonti CI, Easson AM, Gerdes H. Management of malignant bowel obstruction. Eur J Cancer
2008;44:1105–1115.
110. Soybel DI, Bliss DP Jr, Wells SA Jr. Colon and rectal carcinoma. Curr Probl Cancer 1987;11(5):257–
356.
111. Glare PA, Dunwoodie D, Clark K, et al. Treatment of nausea and vomiting in terminally ill cancer
patients. Drugs 2008;68:2575–2590.
112. Mystakidou K, Tsilika E, Kalaidopoulou O, et al. Comparison of octreotide administration vs
conservative treatment in the management of inoperable bowel obstruction in patients with far
advanced cancer: a randomized, double- blind, controlled clinical trial. Anticancer Res
2002;22:1187–1192.
113. Saber AA, Boros MJ. Chilaiditi’s syndrome: what should every surgeon know? Am Surg
2005;71:261–263.
114. Oren D, Atamanalp SS, Aydinli B, et al. An algorithm for the management of sigmoid colon
volvulus and the safety of primary resection: experience with 827 cases. Dis Colon Rectum
2007;50:489–497.
115. Wertkin MG, Aufses AH Jr. Management of volvulus of the colon. Dis Colon Rectum 1978;21(1):40–
1281
booksmedicos.org
45.
116. Peoples JB, McCafferty JC, Scher KS. Operative therapy for sigmoid volvulus. identification of risk
factors affecting outcome. Dis Colon Rectum 1990;33(8):643–646.
117. Regimbeau JM, Panis Y, Gouzi JL, et al; French University Association for Surgical Research.
Operative and long term results after surgery for chronic radiation enteritis. Am J Surg
2001;182:237–242.
118. Meissner K. Late radiogenic small bowel damage: guidelines for the general surgeon. Digestive Surg
1999;16:169–174.
119. Harb AH, Abou Fadel C, Sharara AI. Radiation enteritis. Curr Gastroenterol Rep 2014;16(5):383.
120. Cetin E, Ozturk AS, Orhun H, et al. Role of triamcinolone in radiation enteritis management. World
J Gastroenterol 2014;20(15):4341–4344.
121. Franklin ME, Gonzalez JJ Jr, Miter DB, et al. Laparoscopic diagnosis and treatment of intestinal
obstruction. Surg Endosc 2004;18:26–30.
122. Kirshtein B, Roy-Shapira A, Lantsberg L, et al. Laparoscopic management of acute small bowel
123. Levard H, Boudet MJ, Msika S, et al; French Association for Surgical Research. Laparoscopic
treatment of acute small bowel obstruction: a multicentre retrospective study. ANZ J Surg
2001;71:641–646.
124. Gutt CN, Oniu T, Schemmer P, et al. Fewer adhesions induced by laparoscopic surgery? Surg Endosc
2004;18:898–906.
125. Tittel A, Treutner KH, Titkova S, et al. Comparison of adhesion reformation after laparoscopic and
conventional adhesiolysis in an animal model. Langenbecks Arch Sur 2001;386(2):141–145.
126. Li MZ, Lian L, Xiao LB, et al. Laparoscopic versus open adhesiolysis in patients with adhesive small
bowel obstruction: a systematic review and meta-analysis. Am J Surg 2012;204(5):779–786.
127. Pekmezci S, Altinli E, Saribeyoglu K, et al. Enteroclysis-guided laparoscopic adhesiolysis in
recurrent adhesive small bowel obstructions. Surg Laparosc Endosc Percutan Tech 2001;12:165–170.
128. Sato Y, Ido K, Kumagai M, et al. Laparoscopic adhesiolysis for recurrent small bowel obstruction:
Long-term follow-up. Gastrointest Endosc 2001;54:476–479.
129. Suter M, Zermatten P, Halkic N, et al. Laparoscopic management of mechanical small bowel
obstruction: are there predictors of success or failure? Surg Endosc 2000;14:478–483.
130. Al-Mulhim AA. Laparoscopic management of acute small bowel obstruction. Experience from a
Saudi teaching hospital. Surg Endosc 2000;14:157–160.
131. Chosidow D, Johanet H, Montariol T, et al. Laparoscopy for acute small-bowel obstruction
secondary to adhesions. J Laparoendosc Adv Surg Tech A 2000;10:155–159.
132. Strickland P, Lourie DJ, Suddleson EA, et al. Is laparoscopy safe and effective for treatment of
acute small-bowel obstruction? Surg Endosc 1999;13:695–698.
133. Leon E, Metzger A, Tsiotos GG, et al. Laparoscopic management of small bowel obstruction:
indications and outcomes. J Gastrointest Surg 1998;2:132–140.
134. Bailey IS, Rhodes M, O’Rourke N, et al. Laparoscopic management of acute small bowel
obstruction. Br J Surg 1998;85:84–87.
135. Navez B, Arimont JM, Guiot P. Laparoscopic approach in acute small bowel obstruction. A review
of 68 patients. Hepatogastroenterology 1998;45:2146–2150.
136. Ibrahim IM, Wolodiger F, Sussman B, et al. Laparoscopic management of acute small bowel
137. Ghosheh B, Salameh JR. Laparoscopic approach to acute small bowel obstruction: review of 1061
cases. Surg Endosc 2007;21:1945–1949.
138. Vettoretto N, Carrara A, Corradi A, et al. Laparoscopic adhesiolysis: consensus conference
guidelines. Colorectal Dis 2012;14(5):e208–e215.
139. Farinella E, Cirocchi R, La Mura F, et al. Feasibility of laparoscopy for small bowel obstruction.
World J Emerg Surg 2009;4:3.
140. Grafen FC, Neuhaus V, Schöb O, et al. Management of acute small bowel obstruction from
intestinal adhesions: indications for laparoscopic surgery in a community teaching hospital.
Langenbecks Arch Surg 2010;395(1):57–63.
1282
booksmedicos.org
141. Coccolini F, Ansaloni L, Manfredi R, et al. Peritoneal adhesion index (PAI): Proposal of a score for
the “ignored iceberg” of medicine and surgery. World J Emerg Surg 2013;8(1):6.
142. Kehlet H. Postoperative ileus–an update on preventive techniques. Nat Clin Pract Gastroenterol
Hepatol 2008;5:552–558.
143. Waldhausen JH, Shaffrey ME, Skenderis BS, et al. Gastrointestinal myoelectric and clinical patterns
of recovery after laparotomy. Ann Surg 1990;211(6):777–784; discussion 785.
144. Condon RE, Cowles VE, Ferraz AA, et al. Human colonic smooth muscle electrical activity during
and after recovery from postoperative ileus. Am J Physiol 1995;269(3 Pt 1):G408–G417.
145. Nadrowski L. Paralytic ileus: recent advances in pathophysiology and treatment. Curr Surg
1983;40(4):260–273.
146. Condon RE, Frantzides CT, Cowles VE, et al. Resolution of postoperative ileus in humans. Ann Surg
1986;203:574–581.
147. Espat NJ, Cheng G, Kelley MC, et al. Vasoactive intestinal peptide and substance P receptor
antagonists improve postoperative ileus. J Surg Res 1995;58(6):719–723.
148. De Winter BY, Robberecht P, Boeckxstaens GE, et al. Role of VIP1/PACAP receptors in
postoperative ileus in rats. Br J Pharmacol 1998;124:1181–1186.
149. Zittel TT, Lloyd KC, Rothenhöfer I, et al. Calcitonin gene-related peptide and spinal afferents partly
mediate postoperative colonic ileus in the rat. Surgery 1998;123(5):518–527.
150. Zittel TT, Reddy SN, Plourde V, et al. Role of spinal afferents and calcitonin gene-related peptide in
the postoperative gastric ileus in anesthetized rats. Ann Surg 1994;219(1):79–87.
151. Frantzides CT, Cowles V, Salaymeh B, et al. Morphine effects on human colonic myoelectric
activity in the postoperative period. Am J Surg 1992;163(1):144–148; discussion 144–148.
152. Thorn SE, Wattwil M, Lindberg G, et al. Systemic and central effects of morphine on
gastroduodenal motility. Acta Anaesthesiol Scand 1996; 40(2):177–186.
153. Ferraz AA, Cowles VE, Condon RE, et al. Opioid and nonopioid analgesic drug effects on colon
contractions in monkeys. Dig Dis Sci 1995; 40(7):1417–1419.
154. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new
therapies. Drugs 2003;63:649–671.
155. Riviere PJ, Pascaud X, Chevalier E, et al. Fedotozine reverses ileus induced by surgery or
peritonitis: action at peripheral kappa-opioid receptors. Gastroenterology 1993;104(3):724–731.
156. Schwarz NT, Kalff JC, Türler A, et al. Prostanoid production via COX-2 as a causative mechanism of
rodent postoperative ileus. Gastroenterology 2001;121:1354–1371.
157. Schwarz NT, Kalff JC, Türler A, et al. Selective jejunal manipulation causes postoperative pan-
enteric inflammation and dysmotility. Gastroenterology 2004;126:159–169.
158. Kalff JC, Türler A, Schwarz NT, et al. Intra-abdominal activation of a local inflammatory response
within the human muscularis externa during laparotomy. Ann Surg 2003;237(3):301–315.
159. de Jonge WJ, The FO, van der Coelen D, et al. Mast cell degranulation during abdominal surgery
initiates postoperative ileus in mice. Gastroenterology 2004;127:535–545.
160. The FO, Bennink RJ, Ankum WM, et al. Intestinal handling-induced mast cell activation and
inflammation in human postoperative ileus. Gut 2008;57:33–40.
161. Holte K, Kehlet H. Postoperative ileus: a preventable event. Br J Surg 2000;87(11):1480–1493.
162. Barquist E, Bonaz B, Martinez V, et al. Neuronal pathways involved in abdominal surgery-induced
gastric ileus in rats. Am J Physiol 1996; 270:R888–R894.
163. Petros JG, Realica R, Ahmad S, et al. Patient-controlled analgesia and prolonged ileus after
uncomplicated colectomy. Am J Surg 1995;170(4):371–374.
164. Stanley BK, Noble MJ, Gilliland C, et al. Comparison of patient-controlled analgesia versus
intramuscular narcotics in resolution of postoperative ileus after radical retropubic prostatectomy. J
Urol 1993;150(5 Pt 1):1434–1436.
165. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: a meta-
analysis. J Am Med Assoc 2003;290:2455–2463.
166. Moraca RJ, Sheldon DG, Thirlby R. The role of epidural anesthesia and analgesia in surgical
practice. Ann Surg 2003;238:663–673.
167. Marret E, Remy C, Bonnet F; Postoperative Pain Forum Group. Meta-analysis of epidural analgesia
1283
booksmedicos.org
versus parenteral opioid analgesia after colorectal surgery. Br J Surg 2007;94:665–673.
168. Napolitano LM. Carbon monoxide and ileus: inhaled gas to prevent retained gas? Crit Care Med
2005;33(6):1445–1446.
169. Moore BA, Overhaus M, Whitcomb J, et al. Brief inhalation of low-dose carbon monoxide protects
rodents and swine from postoperative ileus. Crit Care Med 2005;33(6):1317–1326.
170. Korolkiewicz RP, Sein-Anand J, Ruczyn ski J, et al. The role and interactions of nitric oxide (NO),
carbon monoxide (CO), and prostanoids in the pathogenesis of postoperative ileus in rats. J
Gastrointest Surg 2004;8(3):346–357.
171. Taché Y, Bonaz Y. Corticotropin-releasing factor receptors and stress-related alterations of gut
motor function. J Clin Invest 2007;117:33–40.
172. The FO, Boeckxstaens GE, Snoek SA, et al. Activation of the cholinergic anti-inflammatory pathway
ameliorates postoperative ileus in mice. Gastroenterology 2007;133:1219–1228.
173. de Jonge WJ, van der Zanden EP, The FO, et al. Stimulation of the vagus nerve attenuates
macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005;6:844–
851.
174. Frager DH, Baer JW, Rothpearl A, et al. Distinction between postoperative ileus and mechanical
small-bowel obstruction: value of CT compared with clinical and other radiographic findings. AJR
Am J Roentgenol 1995; 164:891–894.
175. Sagar PM, Kruegener G, MacFie J. Nasogastric intubation and elective abdominal surgery. Br J Surg
1992;79(11):1127–1131.
176. Cheatham ML, Chapman WC, Key SP, et al. A meta-analysis of selective versus routine nasogastric
decompression after elective laparotomy. Ann Surg 1995;221(5):469–476; discussion 476–478.
177. Waldhausen JH, Schirmer BD. The effect of ambulation on recovery from postoperative ileus. Ann
Surg 1990;212(6):671–677.
178. Rao SS, Beaty J, Chamberlain M, et al. Effects of acute graded exercise on human colonic motility.
Am J Physiol 1999;276(5 Pt 1):G1221–G1226.
179. Traut U, Brügger L, Kunz R, et al. Systemic prokinetic pharmacologic treatment for postoperative
adynamic ileus following abdominal surgery in adults. Cochrane Database Syst Rev 2008;
(1):CD004930.
180. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral,
reduces postoperative septic complications. The results of a meta-analysis. Ann Surg
1992;216(2):172–183.
181. Soffer EE, Adrian TE. Effect of meal composition and sham feeding on duodenojejunal motility in
humans. Dig Dis Sci 1992;37(7):1009–1014.
182. Katschinski M, Dahmen G, Reinshagen M, et al. Cephalic stimulation of gastrointestinal secretory
and motor responses in humans. Gastroenterology 1992;103(2):383–391.
183. Asao T, Kuwano H, Nakamura J, et al. Gum chewing enhances early recovery from postoperative
ileus after laparoscopic colectomy. J Am Coll Surg 2002;195(1):30–32.
184. Matros E, Rocha F, Zinner M, et al. Does gum chewing ameliorate postoperative ileus? Results of a
prospective, randomized, placebo-controlled trial. J Am Coll Surg 2006;202:773–778.
185. Purkayastha S, Tilney HS, Darzi AW, et al. Meta-analysis of randomized studies evaluating chewing
gum to enhance postoperative recovery following colectomy. Arch Surg 2008;143:788–793.
186. Zaghiyan K, Felder S, Ovsepyan G, et al. A prospective randomized controlled trial of sugared
chewing gum on gastrointestinal recovery after major colorectal surgery in patients managed with
early enteral feeding. Dis Colon Rectum 2013;56(3):328–335.
187. Craciunas L, Sajid MS, Ahmed AS. Chewing gum in preventing postoperative ileus in women
undergoing caesarean section: a systematic review and meta-analysis of randomised controlled
trials. BJOG 2014;121(7):793–799; discussion 799.
188. Forrester DA, Doyle-Munoz J, McTigue T, et al. The efficacy of gum chewing in reducing
postoperative ileus: a multisite randomized controlled trial. J Wound Ostomy Continence Nurs
2014;41(3):227–232.
189. Mohsenzadeh Ledari F, Barat S, Delavar MA, et al. Chewing sugar-free gum reduces ileus after
cesarean section in nulliparous women: A randomized clinical trial. Iran Red Crescent Med J
2013;15(4):330–334.
1284
booksmedicos.org
190. Li S, Liu Y, Peng Q, et al. Chewing gum reduces postoperative ileus following abdominal surgery: a
meta-analysis of 17 randomized controlled trials. J Gastroenterol Hepatol 2013;28(7):1122–1132.
191. Tandeter H. Hypothesis: hexitols in chewing gum may play a role in reducing postoperative ileus.
Med Hypotheses 2009;72:39–40.
192. Wu Z, Boersema GS, Jeekel J, et al. Nicotine gum chewing: a novel strategy to shorten duration of
postoperative ileus via vagus nerve activation. Med Hypotheses 2014;83(3):352–354.
193. Lobo DN, Bostock KA, Neal KR, et al. Effect of salt and water balance on recovery of
gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet
2002;359(9320):1812–1818.
194. MacKay G, Fearon K, McConnachie A, et al. Randomized clinical trial of the effect of postoperative
intravenous fluid restriction on recovery after elective colorectal surgery. Br J Surg 2006;93:1469–
1474.
195. Holte K, Foss NB, Andersen J, et al. Liberal or restrictive fluid administration in fast-track colonic
surgery: a randomized, double-blind study. Br J Anaesth 2007;99:500–508.
196. Brandstrup B, T⊘nnesen H, Beier-Holgersen R, et al. Effects of intravenous fluid restriction on
postoperative complications: comparison of two perioperative fluid regimens: a randomized
assessor-blinded multicenter trial. Ann Surg 2003;238:641–648.
197. Wakeling HG, McFall MR, Jenkins CS, et al. Intraoperative oesophageal Doppler guided fluid
management shortens postoperative hospital stay after major bowel surgery. Br J Anaesth
2005;95:634–642.
198. Abbas SM, Hill AG. Systematic review of the literature for the use of oesophageal Doppler monitor
for fluid replacement in major abdominal surgery. Anaesthesia 2008;63:44–51.
199. Pillai P, McEleavy I, Gaughan M, et al. A double-blind randomized controlled clinical trial to assess
the effect of Doppler optimized intraoperative fluid management on outcome following radical
cystectomy. J Urol 2011; 186(6):2201–2206.
200. Cullen JJ, Eagon JC, Dozois EJ, et al. Treatment of acute postoperative ileus with octreotide. Am J
Surg 1993;165(1):113–119; discussion 119–120.
201. Garcia-Caballero M, Vara-Thorbeck C. The evolution of postoperative ileus after laparoscopic
cholecystectomy. A comparative study with conventional cholecystectomy and sympathetic
blockade treatment. Surg Endosc 1993;7(5):416–419.
202. Kelley SR, Wolff BG, Lovely JK, et al. Fast-track pathway for minimally invasive colorectal surgery
with and without alvimopan (Entereg)(TM): Which is more cost-effective? Am Surg
2013;79(6):630–633.
203. Fanning J, Valea FA. Perioperative bowel management for gynecologic surgery. Am J Obstet
Gynecol 2011;205(4):309–314.
204. Lee CT, Chang SS, Kamat AM, et al. Alvimopan accelerates gastrointestinal recovery after radical
cystectomy: a multicenter randomized placebo-controlled trial. Eur Urol 2014;66(2):265–272.
205. Vaughan-Shaw PG, Fecher IC, Harris S, et al. A meta-analysis of the effectiveness of the opioid
receptor antagonist alvimopan in reducing hospital length of stay and time to GI recovery in
patients enrolled in a standardized accelerated recovery program after abdominal surgery. Dis Colon
Rectum 2012;55(5):611–620.
206. Hallerback B, Bergman B, Bong H, et al. Cisapride in the treatment of post-operative ileus. Aliment
Pharmacol Ther 1991;5(5):503–511.
207. Davidson ED, Hersh T, Brinner RA, et al. The effects of metoclopramide on postoperative ileus. A
randomized double-blind study. Ann Surg 1979;190(1):27–30.
208. Tollesson PO, Cassuto J, Rimbäck G, et al. Treatment of postoperative paralytic ileus with
cisapride. Scand J Gastroenterol 1991;26(5):477–482.
209. Smith AJ, Nissan A, Lanouette NM, et al. Prokinetic effect of erythromycin after colorectal surgery:
randomized, placebo-controlled, double-blind study. Dis Colon Rectum 2000;43(3):333–337.
210. Yeo CJ, Barry MK, Sauter PK, et al. Erythromycin accelerates gastric emptying after
pancreaticoduodenectomy. A prospective, randomized, placebo-controlled trial. Ann Surg
1993;218(3):229–237; discussion 237–238.
211. Bonacini M, Quiason S, Reynolds M, et al. Effect of intravenous erythromycin on postoperative
ileus. Am J Gastroenterol 1993;88(2):208–211.
1285
booksmedicos.org
212. Jepsen S, Klaerke A, Nielsen PH, et al. Negative effect of metoclopramide in postoperative
adynamic ileus. A prospective, randomized, double blind study. Br J Surg 1986;73(4):290–291.
213. Lykkegaard-Nielsen M, Madsen PV, Nielsen OV. Ceruletide vs. metoclopramide in postoperative
intestinal paralysis. A double-blind clinical trial. Dis Colon Rectum 1984;27(5):288–289.
214. Cheape JD, Wexner SD, James K, et al. Does metoclopramide reduce the length of ileus after
colorectal surgery? A prospective randomized trial. Dis Colon Rectum 1991;34(6):437–441.
215. Hennessy S, Leonard CE, Newcomb C, et al. Cisapride and ventricular arrhythmia. Br J Clin
Pharmacol 2008;66(3):375–385.
216. Toyomasu Y, Mochiki E, Morita H, et al. Mosapride citrate improves postoperative ileus of patients
with colectomy. J Gastrointest Surg 2011;15(8):1361–1367.
217. Xie Q, Zong X, Ge B, et al. Pilot postoperative ileus study of escin in cancer patients after colorectal
surgery. World J Surg 2009;33(2):348–354.
218. Bennett J, Boddy A, Rhodes M. Choice of approach for appendicectomy: a meta-analysis of open
versus laparoscopic appendicectomy. Surg Laparosc Endosc Percutan Tech 2007;17:245–255.
219. Abraham NS, Byrne CM, Young JM, et al. Meta-analysis of non-randomized comparative studies of
the short-term outcomes of laparoscopic resection for colorectal cancer. ANZ J Surg 2007;77:508–
516.
220. Basse L, Hjort Jakobsen D, Billesb⊘lle P, et al. A clinical pathway to accelerate recovery after
colonic resection. Ann Surg 2000;232(1):51–57.
221. Ludwig K, Enker WE, Delaney CP, et al. Gastrointestinal tract recovery in patients undergoing
bowel resection: results of a randomized trial of alvimopan and placebo with a standardized
accelerated postoperative care pathway. Arch Surg 2008;143:1098–1105.
222. Ogilvie WH. William Heneage Ogilvie 1887–1971. large-intestine colic due to sympathetic
deprivation. A new clinical syndrome. Dis Colon Rectum 1987;30:984–987.
223. De Giorgio R, Knowles CH. Acute colonic pseudo-obstruction. Br J Surg 2009;96:229–239.
224. Vanek VW, Al-Salti M. Acute pseudo-obstruction of the colon (Ogilvie’s syndrome). An analysis of
400 cases. Dis Colon Rectum 1986;29(3):203–210.
225. De Giorgio R, Knowles CH. Acute colonic pseudo-obstruction. Br J Surg 2009;96(3):229–239.
226. Strodel WE, Nostrant TT, Eckhauser FE, et al. Therapeutic and diagnostic colonoscopy in
nonobstructive colonic dilatation. Ann Surg 1983;197(4):416–421.
227. Sloyer AF, Panella VS, Demas BE, et al. Ogilvie’s syndrome. Successful management without
colonoscopy. Dig Dis Sci 1988;33(11):1391–1396.
228. Cowlam S, Watson C, Elltringham M, et al. Percutaneous endoscopic colostomy of the left side of
the colon. Gastrointest Endosc 2007;65:1007–1014.
229. Armstrong DN, Ballantyne GH, Modlin IM. Erythromycin for reflex ileus in Ogilvie’s syndrome.
Lancet 1991;337:378.
230. Jiang DP, Li ZZ, Guan SY, et al. Treatment of pediatric Ogilvie’s syndrome with low-dose
erythromycin: a case report. World J Gastroenterol 2007; 13:2002–2003.
231. Lee JT, Taylor BM, Singleton BC. Epidural anesthesia for acute pseudo-obstruction of the colon
(Ogilvie’s syndrome). Dis Colon Rectum 1988; 31:686–691.
232. Sgouros SN, Vlachogiannakos J, Vassiliadis K, et al. Effect of polyethylene glycol electrolyte
balanced solution on patients with acute colonic pseudo obstruction after resolution of colonic
dilation: a prospective, randomized, placebo controlled trial. Gut 2006;55:638–642.
233. Korsten MA, Rosman AS, Ng A, et al. Infusion of neostigmine-glycopyrrolate for bowel evacuation
in persons with spinal cord injury. Am J Gastroenterol 2005;100:1560–1565.
234. Child CS. Prevention of neostigmine-induced colonic activity. A comparison of atropine and
glycopyrronium. Anaesthesia 1984;39(11):1083–1085.
235. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for the treatment of acute colonic pseudo-
obstruction. N Engl J Med 1999;341(3):137–141.
236. Lynch CR, Jones RG, Hilden K, et al. Percutaneous endoscopic cecostomy in adults: a case series.
Gastrointest Endosc 2006;64:279–282.
1286
booksmedicos.org
Chapter 50
Crohn Disease
Scott R. Steele and Eric K. Johnson
Key Points
1 Crohn’s occurs anywhere along the gastrointestinal (GI) tract from mouth to anus and may present
with one or more disease patterns – fistulizing, inflammatory, and fibrostenotic.
2 The indications for operating on Crohn disease involve managing complications of the disease, not
cure.
3 Consider the patient’s disease state and medical therapy for Crohn disease in the decision-making for
surgery – this may require concomitant diversion in this patient population.
4 Whenever possible, preserve length of the small intestine and avoid extensive resections when not
required.
5 Similar to ulcerative colitis, Crohn disease is associated with an increased long-term risk of
developing colorectal cancer compared to the general population.
6 Asymptomatic Crohn disease (e.g., perianal fistula) does not necessarily require treatment.
7 Crohn disease is associated with a propensity for loose bowel movements and nonhealing wounds.
Think of function first when treating perianal disease, and avoid overaggressive procedures on the
sphincter that may alter continence.
INTRODUCTION
1 While many have heard the renowned account that Crohn disease derives its eponymous name more
from the alphabetized listing of its authors (Crohn, Ginzburg, and Oppenheimer) in the 1932 JAMA
publication “Regional ileitis: a pathological and clinical entity,”1 some may not realize that it was a
surgeon, Dr. A.A. Berg, who’s patients and idea it was to evaluate the original 52 specimens.2
Furthermore, the initial description of the condition was actually first made in 1769 by an Italian
physician Giovanni Battista Morgagni – he of the anal columns, aortic sinus, and congenital
diaphragmatic hernia fame.3 Much has changed since then, and continues to evolve in the understanding
and treatment of this idiopathic, ulcerogenic, inflammatory condition of the gastrointestinal (GI) tract.
Therefore, where many students and physicians alike are quick to cite Crohn facts such as its ability to
occur anywhere along the alimentary tract, has no “curative” operation, and is hallmarked by periods of
flares and quiescent disease, what is often forgotten is that three-quarters or more of all patients will
require at least one operation during their lifetime.4 Therefore, not only must the problem at hand be
addressed, but also the patient’s future function should be carefully weighed when considering the
proper therapeutic endeavor. Surgeons also need to be exceedingly aware of the indications, surgical
options, and expected outcomes for patients with Crohn disease, as well as have a thorough
understanding of the principles guiding both medical and surgical care to maximize outcomes. This
chapter will review the pertinent information regarding the background, diagnostic evaluation, and
treatment modalities for Crohn disease.
EPIDEMIOLOGY
Traditionally, Crohn disease is said to have a bimodal distribution with regard to age of onset, initially
in the second and third decades, followed by a later, albeit smaller, peak in the sixth decade.5 More
recently, systematic reviews have found an annual incidence of Crohn disease ranging from 20.2 per
100,000 person-years in North America and 12.7 per 100,000 person-years in Europe to 5.0 person-years
in Asia and the Middle East.6 Even within regions, variations exist – the incidence in western Europe is
almost twice that of eastern Europe, whereas the highest incidence of inflammatory bowel disease in
1287
booksmedicos.org
the world is in the Faroe Islands. While data in developing countries remain relatively sparse, both the
incidence and prevalence of Crohn disease are increasing in the United States and around the world.
There is also an association with latitude, with increased incidences in higher latitude areas (i.e.,
Canada, Scandinavia, and Australia) compared to those closer to the equator. Males and females tend to
be affected equally, though whites and certain ethnic groups such as those of Ashkenazi Jewish descent
have higher overall rates.7
Although Crohn disease is not inherited through traditional Mendelian genetics, there does appear to
be a familial predisposition. A positive family history in patients with Crohn disease occurs in 2% to
14%.8 Closer examination reveals an approximate 5% age-adjusted lifetime risk of a first-degree relative
of a Crohn disease proband developing IBD (up to 8% for those of Jewish ancestry).9 On the other hand,
the concordance rate for monozygotic twins ranges from 20% to 50%,10 suggesting that genetics do play
a role and that the disease is not entirely dependent on environmental and/or acquired factors.
Furthermore, there does not appear to be a genetic concordance with regard to phenotypical
manifestations (i.e., fibrostenotic, fistulizing, phelgmonous or extent of disease) among relatives.
ETIOLOGY
Despite tremendous progress in the overall understanding of the disease and advancements in the
comprehension of the various phenotypical manifestations, the exact etiology of Crohn disease remains
unknown. Most hypotheses suggest there involves interplay among the genetic makeup of the individual
along with environmental, bacteriologic, immunologic, and epidemiologic factors that contribute to its
development. Efforts in each of these areas continue in attempt to determine which are causative factors
versus those that are simply associations.
Current theories revolve around the host–microbiome interaction, and the variable response that
occurs along several pathways that may ultimately lead to the chronic inflammatory state seen in
Crohn’s.11 In this model, intestinal microorganisms initiate an inappropriately regulated host immune
response that results in a cascade of events ranging from altered permeability of the intestinal lumen to
autoimmune “attacks” on several host organ systems.12 The fecal and intestine mucosal bacterial make-
up is also known to be altered in Crohn disease patients; however, it is unknown if this occurs as a
result of the inflammatory process, or is itself a contributing factor to disease development.13 Proteomic
and metagenomic evaluation of commensal and altered GI microbiotia in Crohn patients indicates that
there is an inappropriate pattern recognition with the microbiotia serving as the driver of the disease
pathogenesis.14
Beginning in 1996, linkage studies of the human genome have helped with the discovery of several
IBD genes that signify patients who are susceptible to Crohn disease development.15 Most attention has
revolved around the NOD2 (formerly CARD15) gene on chromosome 16, a region felt to be involved
host interactions with bacterial lipopolysaccharide.16 Genetic differences in the pattern-recognition
proteins for which NOD2 codes may lead to an impaired sensing and handling of bacteria by the
immune system, disrupting the tenuous balance of normal tolerance versus initiating an incorrect
immune response. Since then, genome-wide association studies have provided insight that
polymorphisms in genes such as the ATG16L1 and IRGM play a role in autophagy in Crohn patients.
This process involves the regulation of cell development and differentiation, senescence, and ultimately
the inflammatory system response to what the body deems is normal and abnormal.17 In addition, other
genes such as TLR4, HLA, and IRF5 are involved in the innate and adaptive immune system response
seen in Crohn patients. Other causative immune factors have included overexpression and dysregulation
of tumor necrosis factor, an imbalance between proinflammatory and anti-inflammatory cytokines, and
an impaired mucosal susceptibility in sampling gut antigens.18 Combined, these all contribute to
regulatory mechanisms that may be altered and play a role in Crohn disease pathogenesis.
Infectious theories also continue to exist, 19 with specific organisms including Mycobacterium avium
subspecies paratuberculosis (i.e., Johne disease), Campylobacter concisus, adherent-invasive Escherichia coli
(AIEC), and non-H. pylori Helicobacter species among the most common agents cited. Although the
beneficial effects of antibiotics in the treatment of Crohn disease provide indirect evidence for a
bacterial etiology, no distinct organism has been identified to date. Similarly, several viruses have been
postulated to have an association with Crohn disease, the most common being EBV, CMV, and measles.
However, systematic reviews have found little evidence to support this notion.20 Additionally,
environmental factors are felt to play a role, highlighted by the well-established link to smoking with
both an increased susceptibility and worsened clinical course. Finally, while patients with Crohn disease
1288
booksmedicos.org
frequently have concomitant food intolerances, the role of dietary habits remains debatable.21 Rather
than a causative effect, it is felt that the microbiome in the human GI tract is heavily influenced by
dietary intake, leading to a local environment ripe to foster susceptibility to Crohn disease.
DIAGNOSIS
As is well documented, Crohn disease falls under the umbrella of inflammatory bowel disease along
with ulcerative colitis. In both conditions, there is no specific test at present to permit a definitive
diagnosis; rather a combination of history and physical examination, laboratory, radiographic and
endoscopic findings is utilized. This, in part, contributes to ∼5% to 15% of patients with ulcerative
colitis that will eventually be diagnosed with Crohn disease or patients who carry a diagnosis of
indeterminate colitis.22,23 Once diagnosed, Crohn patients are often categorized in several different
manners, the most common of which involves either the site of disease or the patient’s phenotypical
manifestations (i.e., fibrostenotic, fistulizing, inflammatory). By location, the ileum (∼60%) has the
highest rate of disease incidence (Fig. 50-1). Localized inflammation in the ileocecal region occurs in
∼45% of patients, whereas ∼25% to 33% will have colonic involvement, 25% will have more proximal
small bowel disease, and <10% will have upper GI or perianal disease. In general, patients with
concomitant perianal disease tend to have a more severe clinical course,24 and perianal disease in the
setting of Crohn’s may precede abdominal manifestations in up to 45%.25
When stratifying by disease pattern or phenotype, patients may have fibrostenotic (i.e., stricturing),
fistulizing (i.e., penetrating), or inflammatory (i.e., phlegmonous) characteristics. Due to the
heterogeneous nature of the disease, these manifestations may occur independently, concomitantly, or
may even vary along the longitudinal course of the disease. Fibrostenotic patterns may occur in any
location, though most commonly occur in the terminal ileal region, where patients present with
obstructive-type symptoms such as nausea, vomiting, and decreased oral intake. Due to the recurrent
chronic nature that results in progressive thickening of the bowel wall, medical management is typically
unsuccessful and surgical intervention is required. Inflammatory disease may present with a wide range
of symptoms such as abdominal pain, fever, and an abdominal mass and/or weight loss. Bowel
movements may either be diarrhea or follow an obstructive pattern due to luminal narrowing or
extrinsic compression from the phlegmon. Finally, penetrating or fistulizing disease also has a variable
presentation. Patients may be completely asymptomatic, as in the case of many entero-enteral fistulas,
present with anorectal abscesses and/or fistulas, or more commonly complain of symptoms mirroring
involvement of the secondarily involved organ–recurrent urinary tract infections or pneumaturia,
vaginal discharge, diarrhea, cutaneous feculent drainage, and/or hip/back pain from psoas involvement.
While medical management continues to be a major component of each of the latter two patterns,
surgery is often required for resolution of symptoms.
Figure 50-1. Terminal ileum with forceps pointing to intraloop chronic abscess cavity.
Clinical Evaluation
Small Bowel
The distribution of disease will in large part dictate the clinical presentation. The terminal ileum (along
with the cecum) is the most commonly affected site, in addition to isolated more proximal small bowel
disease. Patients with disease in this location will classically present with abdominal pain, fever,
1289
booksmedicos.org
fatigue, nausea, and vomiting. The weight loss seen is a byproduct of both decreased oral intake as well
as the malabsorptive process associated with Crohn’s. When the disease is in the terminal ileum and
ileocecal region, patients may present with a slow onset of right lower quadrant pain following meals,
an abdominal mass, and (when the psoas is involved) pain with hip extension. Obstructive symptoms
may also occur in patients with either fibrostenotic or acute inflammation (Fig. 50-2). Diarrhea tends to
be nonbloody, though heme-positive stools may occur, and rarely gross blood is a manifestation from a
small bowel source.
Colonic
Colonic involvement may occur in isolation in approximately one in four patients, though it is most
often seen concomitantly in those with perianal (left-sided) or terminal ileal (cecal and ascending colon)
disease.26 Within the colon the distribution is somewhat variable, with approximately one-third of
patients having total colonic involvement, 40% showing segmental disease, and left-sided only in up to
30%.27 Regardless of the exact location within the large intestine, patients with colonic involvement
may experience abdominal pain, and in some cases, malnutrition. Diarrhea is often of smaller volume
and may be from several sources – malabsorptive (e.g., salt/water and bile acid malabsorption),
infectious (e.g., CMV super-infection), or as a result from an entero-colonic fistula.28,29 Unlike ulcerative
colitis, rectal bleeding is not routine, and bowel movements are often nonbloody, except in those with
moderate-to-severe Crohn colitis. In addition, similar to disease in the small bowel, patients can
experience hip pain from fistulas, cramping and obstructive symptoms. Patients with chronic disease
may also demonstrate pseudopolyps on endoscopic examination (Fig. 50-3).
Anorectal
Bissel30 was the first to describe the anorectal component of Crohn, almost two years after the original
description of the disease. Despite advances in the understanding of many features of Crohn disease,
perianal complaints have been recognized as one of its most challenging aspects. Isolated perianal
disease is the presenting symptom in ∼5% to 15% of Crohn patients; though over the course of their
lifetime, it is seen in 25% to 80%. The perianal area in Crohn patients has classically been felt to be a
“window” into the abdomen, and perianal involvement is clearly more common in those with
concomitant rectal or colonic disease.31,32 In addition, active disease in the perineum is felt to act as a
harbinger of an overall more virulent course.33 The traditional anorectal complaints witnessed in non-
Crohn patients are similar to those with the disease, including “standard” hemorrhoids, fissures,
abscesses and fistulae. However, Crohn patients may also manifest edematous (elephant ear) skin tags
(Fig. 50-4), blue discoloration of the anus, and abscesses and fistulas that are often recurrent, multiple,
and located well away from the anal verge. While fissures due to hypertonicity may be identified, more
often Crohn fissures present as deep-seated, burrowing fissures – more like ulcers – and may be
multiple, off the midline, extending in the muscle and associated with large skin tags. Finally, patients
with long-standing Crohn’s may develop anal stenosis or an anal stricture at the verge secondary to
repeated bouts of chronic inflammation.
Figure 50-2. Endoscopic view of a terminal ileum stricture and active Crohn disease.
1290
booksmedicos.org
Figure 50-3. Endoscopic view of colonic pseudopolyps.
Figure 50-4. Anorectal Crohn disease. Large “elephant ear” skin tag.
Clinical evidence of perianal Crohn, as manifested by many of these features, is often deemed a
hallmark of disease diagnosis, although occasionally a biopsy may be necessary. Due to local sepsis and
perianal tenderness, patients may need to undergo an examination under anesthesia to fully identify the
extent of the disease. Patients presenting with perianal findings consistent with Crohn disease should
undergo a full alimentary tract evaluation, as previously stated, with endoscopic and radiologic
evaluation. In addition, a thorough physical examination to identify any extraintestinal manifestations
should be performed.
Upper Gastrointestinal Disease

Upper GI Crohn encompasses disease from the mouth through the jejunum. The incidence of upper tract
involvement varies widely, with most studies reporting overall rates of <5%. In patients with ileocolic
disease, concomitant upper GI manifestations occur in 0.5% to 13%, yet up to 40% of patients will
demonstrate early subclinical evidence of Crohn disease on radiologic and endoscopic evaluation.34
Importantly, when patients have upper GI Crohn disease, they almost uniformly have concomitant
disease of lower tract and should be evaluated to determine the extent of involvement. Upper tract
disease is hallmarked by both obstructive symptoms and fistulas.35 Patients typically present with
abdominal pain, cramping, nausea, vomiting, or intolerance of oral intake leading to weight loss. While
fistulas may be virtually to any site, the majority involving the proximal tract are gastrocolic or
ileogastric in nature. Patients may be asymptomatic or present with diarrhea from high-output and
colonic involvement. Crohn disease of the esophagus is exceedingly rare, involving <0.5% of patients.
Most patients will have inflammation or ulcers, though strictures and fistula have also been reported. As
with other upper tract Crohn disease, extra-esophageal disease is nearly always present.36
1291
booksmedicos.org
Extra-Intestinal Disease
Similar to ulcerative colitis, patients with Crohn disease may have manifestations from the disease
process that extend outside of the GI tract (Table 50-1). Extra-intestinal disease (EID) has been reported
in ∼6% to 47% of patients with inflammatory bowel disease, and has an increased concordance among
siblings and first-degree relatives – suggesting a genetic component that has been linked to the major
histocompatibility complex (MHC) on chromosome 6.37,38 EID occurs secondary to the systemic
inflammatory process associated with the underlying disease and affect a wide range of organ systems.
While the GI tract may be the primary source, the dysfunction in immune regulation incites a pathologic
response that may occur in nearly every location in the body simultaneous with, preceding, or following
GI manifestations.39 Overall, rheumatologic/joint problems (e.g., peripheral or sacroiliac arthritis,
arthralgias) are the most common, occurring in up to one-third of patients. Other more frequent sites of
involvement include the skin (Fig. 50-5), eyes, and hepatobiliary system; while the renal, pulmonary,
nervous, and coagulation systems are typically involved to a lesser extent. It is important to distinguish
between manifestations that parallel bowel disease activity (episcleritis, peripheral arthritis, and
erythema nodosum) from those that do not (ankylosing spondylitis, pyoderma gangrenosum, and
primary sclerosing cholangitis). Surgical intervention directed at the bowel may occasionally be
required for recalcitrant EID that may appropriately go into remission following bowel resection.40
Table 50-1 Classification of Extra-intestinal Manifestations of Crohn Disease
Figure 50-5. Peristomal pyoderma gangrenosum. (Courtesy of W. Brian Sweeney, MD.)
Radiology
Fluoroscopic Imaging
Radiologic work-up for Crohn patients is an invaluable part of the diagnostic evaluation. In addition to
providing information on the acute process (i.e., abscess, phlegmon, fistula, stricture), diagnostic
imaging is used to determine the extent of disease. Historically, contrast studies such as a barium enema
have helped diagnose Crohn disease by identifying longitudinal and transverse linear ulcerations that
create cobblestone and nodular patterns, skip lesions, fistulas, and strictures.41 A small bowel follow-
through has also been a long-standing modality utilized to evaluate for strictures, active disease
(highlighted by ulceration, mucosal granularity, and loss of villous morphology), and fistulas (Fig. 50-
1292
booksmedicos.org
6).
Computed Tomography
In many centers, computed tomography (CT) has now largely replaced the barium enema and small
bowel follow-through, with the added ability to identify the extent of the disease and involvement of
surrounding structures, manifested by segmental bowel thickening (Fig. 50-7), mesenteric fat stranding,
and intra-abdominal fluid.42 Additionally, CT is useful to identify secondarily involved organs or
provide information that may be pertinent to preoperative planning, such as bladder or vaginal air
indicating presence of a fistula, an adjacent psoas abscess in ileocecal disease, or ureteral obstruction
that may require stenting. CT and magnetic resonance (MR) enterography provide improved detail of
the mucosal surface and are especially useful in depicting fistulas and strictures, along with the added
benefit of lower levels of radiation exposure. The latter is especially relevant considering the generally
younger patient population, body habitus, and potential need for life-long repeat imaging associated
with Crohn’s.
Figure 50-6. Small bowel follow-through demonstrating a tight stricture with proximal dilation.
Figure 50-7. Coronal cut of a CT demonstrating a jejunal stricture.
Magnetic Resonance Imaging

MR enterography in particular has been shown to be over 85% accurate in predicting stenosis (Fig. 50-
1293
booksmedicos.org
8), abscess and fistula in preoperative planning, as well as changing the surgical strategy/approach in
up to 10% of Crohn patients.43 Furthermore, its sensitivity (85% to 90%), specificity (100%), and
negative predictive value (77%) have made it ideal for detecting recurrent disease after surgery.44,45
MRI has also particularly been useful in the evaluation of complex perianal fistulas seen in Crohn
patients, identifying secondary “hidden” tracts and occult abscesses that lend to higher failure rates if
not addressed.46 More recently, diffusion-weighted imaging and magnetization transfer imaging
sequences have allowed bowel resolution previously not achievable to help identify disease, depict
disease activity, and target interventions.47
PET Scan
Another modality typically not associated with inflammatory bowel disease, 18F-FDG positron emission
tomography (PET) has been used for Crohn disease largely in academic and research centers to date.48
While cost seems to be somewhat prohibitive, this emerging indication has the potential to (a)
determine disease activity in a noninvasive manner, (b) provide information regarding subclinical
disease, (c) deliver a qualitative measure of response to treatment, and (d) indicate disease activity that
would otherwise be unobtainable by traditional methods.
Video Capsule Endoscopy

Finally, video capsule endoscopy uses wireless technology to capture continuous images of the upper GI
tract mucosa. As up to 30% of patients will have disease limited to the small bowel, capsule endoscopy
plays a unique role to determine disease presence and activity that are outside the reach of endoscopy
and the limitations of traditional small bowel imaging. While the diagnostic yield may not be as high, it
has been shown to be comparable to ileocolonoscopy and better than small bowel follow-through for
the detection of small bowel inflammation.49 Furthermore, negative predictive values range from 96%
to 100%, essentially ruling out the diagnosis of Crohn’s when the results are normal.50 Of note, it is
imperative to exclude the presence of moderate–severe strictures prior to its use, as their presence can
result in bowel obstruction from the capsule becoming lodged at the point of stenosis (Fig. 50-9).
Figure 50-8. MR enterography demonstrating a small bowel stricture.
Figure 50-9. Video capsule endoscopy “pill” lodged in a Crohn stricture causing a bowel obstruction. (Courtesy of Justin A.
1294
booksmedicos.org
Maykel, MD.)
Endoscopy
Whereas direct observation of the perianal area and anoscopy will identify disease such as skin tags,
external fistula openings and fissures, endoscopy is needed to identify the extent and severity of the
disease and perform biopsies to aid in diagnosis.51 In the clinic, flexible or rigid sigmoidoscopy can be
performed as adjuncts to the physical examination to evaluate the mid-to-upper rectum and sigmoid
colon. However, endoscopic evaluation of the entire colon, including the terminal ileum, with
colonoscopy along with appropriate biopsies is required in patients suspected of Crohn disease. Early
changes seen in the mucosa include aphthous ulcerations, erosions, and serpiginous ulcers that occur in a
skip-type pattern. As the full-thickness inflammatory cycle continues, these ulcerated areas become
progressive, enlarge, and coalesce forming the cobblestone-type pattern. The presence of rectal sparing
and terminal ileal disease may help differentiate Crohn disease from ulcerative colitis, although the
latter may demonstrate similar characteristics due to medical therapy and backwash ileitis,
respectively.52 Finally, the presence of strictures or associated masses may indicate the need for surgical
or therapeutic intervention.
Esophagogastroduodenoscopy (EGD) also plays a role for patients with suspected or known proximal
disease and can identify ulcers, fistulas, and strictures that may be responsible for various upper GI
symptoms (Fig. 50-10). In addition, EGD allows for therapeutic intervention such as dilation for those
with gastric outlet obstruction.53 Overall, both upper and lower endoscopies are relatively safe
procedures with complications in IBD patients occurring in <5%,54 and generally consist of bleeding –
though perforation remains a very small risk of every endoscopic procedure. Additionally, endoscopic
evaluation provides an ability to track and quantify disease activity by use of the scoring systems such
as the Crohn disease endoscopic index of severity (CDEIS) or Simple Endoscopic Score for Crohn disease
(SES-CD).55
Figure 50-10. Endoscopic view of pyloric stenosis in a Crohn patient; this high-grade stenosis requires balloon dilation to pass the
scope. (Courtesy of Mark Cumings, MD.)
Pathology
Classically, the presence of noncaseating granulomas on pathologic examination is pathognomonic of
Crohn disease. However, in reality they are only found in 25% to 42% of patients, and may simply be a
marker of more virulent disease.56 In addition, long-standing ulcerative colitis patients may occasionally
show granulomas on biopsy.57 Furthermore, granulomas may be present but are not typically
demonstrated on the specimens that are taken with routine depth endoscopic biopsies, rather only
visible on resected full-thickness specimens. Other histologic evidence of Crohn disease includes
architectural distortion of the crypts (size, shape, and symmetry) (Fig. 50-11), ulcerations, pseudopolyps
(Fig. 50-12), and skip areas – some of which may also be found in ulcerative colitis. Other
discriminating features of Crohn’s include the potential for full-thickness involvement of the bowel wall,
and the presence of “creeping fat,” where the mesenteric fat extends over the serosal surface of the
bowel wall – “creeping” over the normally distinct mesenteric/bowel wall interface. Furthermore, gross
pathologic examination of Crohn specimens may range from acutely inflamed, edematous, hyperemic
bowel to thickened, fibrotic, and “woody.” Finally, the mesentery is classically thickened, with marked
edema, friability and hypervascular in nature.
1295
booksmedicos.org
Figure 50-11. Active colitis with crypt abscess formation and atypical regenerative features consistent with chronic crypt-
destructive colitis. (Courtesy of George Leonard, MD.)
Figure 50-12. Full-thickness involvement of chronic inflammatory infiltrate from mucosa to serosa and pseudopolyp formation.
(Courtesy of George Leonard, MD.)
Laboratory Analysis
No single laboratory examination will provide a definitive diagnosis of Crohn disease; yet, there are
tests available to help discriminate between Crohn’s and other processes. Routine serum profiles such as
perinucelar antineutrophil cytoplasmic antibodies (p-ANCA) and anti-Saccharomyces cerevisiae
antibodies (ASCA) have traditionally been used to help differentiate Crohn disease from ulcerative
colitis. The former is a known marker associated with ulcerative colitis, whereas elevated levels of
ASCA are associated with Crohn disease. Unfortunately, only 30% to 50% of Crohn patients will test
positive for ASCA, and up to 10% of healthy individuals will also have elevated serum levels.58
C-reactive protein is a nonspecific marker for inflammation that has been useful in tracking disease
activity and response to treatment. More recently, fecal biomarkers such as fecal calprotectin,59
lactoferrin, and neopterin60 are used to monitor intestinal inflammation, and have been shown to
reliably correlate with disease activity and mucosal healing as measured endoscopically.61 In addition
they may play a role in helping to make a distinction between inflammatory bowel disease and
functional bowel disorders, with reported sensitivities and specificities of ∼80% to 85%.62 While
nonspecific, persistent elevations in fecal biomarkers have been shown also to correlate with higher
levels of recurrence following surgical resection.63
DIFFERENTIAL DIAGNOSIS
The differential diagnosis in Crohn disease is wide and includes both benign and malignant processes
(Table 50-2). While Crohn disease has certain traits that are more suggestive of its presence (e.g.,
noncontiguous multisite disease, fistulas, creeping fat), a variety of abdominal process may mimic
Crohn’s (Fig. 50-13). It is not an uncommon scenario for ileocolic Crohn’s to be ultimately diagnosed
from a clinical picture that may at first resemble acute appendicitis, right-sided diverticulitis, an
infectious process, or a perforated malignancy. Radiologic studies may demonstrate similar patterns of
bowel inflammation, laboratory examination often shows elevated CRP and/or white blood cell counts
1296
booksmedicos.org
in each, and the patient demographics are routinely alike. When this occurs intraoperatively, a decision
must then be made regarding whether or not to proceed with resection versus closure and medical
management alone based on clinical findings. If a resection is performed, questions arise regarding the
extent of resection such as whether or not to perform an ileocectomy versus appendectomy alone and
what margins of resection are required for the situation at hand.
Table 50-2 Differential Diagnosis of Crohn Disease
When confronted with this situation in the operating room and Crohn’s is suspected, traditional
teaching recommends performing an appendectomy if the cecum is normal, or to withhold on resection
and undergo medical treatment only. Yet, there are data to support performing an ileocolic resection at
the time of surgery, with one series reporting almost half of patients required no further surgery as a
result of their Crohn disease, compared to 92% of those undergoing appendectomy only (65% within
the next 3 years).64 Hence early ileocolonic resection may be in the patient’s long-term best interests to
avoid recurrent disease and repeated trips to the operating room.
When disease is isolated to the colon, the major differentiation involves distinguishing Crohn colitis
from ulcerative colitis, though other infectious and inflammatory colitides remain in the differential. As
previously noted, many of the same clinical and histopathologic traits are shared in both diseases, and
contribute to the initial diagnostic dilemma, as well as those patients with indeterminate colitis or those
that undergo a change in diagnosis from ulcerative colitis to Crohn’s. Ultimately it is the entire
evaluation to include information taken from laboratory, pathologic, endoscopic, radiologic, and clinical
examinations as outlined above that will help clarify the picture and aid in diagnosis.
Figure 50-13. “Creeping” fat on an ileal specimen.
TREATMENT
Medical Management
While an in-depth look regarding the medical management of Crohn disease is beyond the scope of this
chapter, a few points are worth noting (Table 50-3). First, despite the spectrum of disease presentations,
Crohn’s remains one hallmarked by inflammation (i.e., abdominal pain) and diarrhea. As such,
supportive care to include antidiarrheals and antimotility agents, along with a bland diet, are good first-
line approaches to provide symptomatic control. It is important to exclude the concomitant presence of
“super-infections” such as cytomegalovirus or Clostridium difficile infection, as antimotility medications
may result in the onset of toxic megacolon and a rapidly progressive clinical deterioration. Yet, simple
over-the-counter, readily available medications such as loperamide, diphenoxylate, and bismuth, along
with prescription medications such as codeine and tincture of opium often provide tremendous relief to
1297
booksmedicos.org
abdominal pain, cramping, and loose stools.
Crohn’s has also been traditionally been called a “wasting disease,” though increasing numbers of
obese patients with Crohn’s are observed. Despite this seeming paradox, nutritional support in both
groups remains paramount. Ideally, preservation of oral feeding in any form is crucial for maintenance
of the absorptive and protective mechanisms provided by the GI mucosal lumen villi and microvilli.
However, when this is not possible, parenteral nutrition has become invaluable in preserving nutritional
stores, aiding in maintenance of positive nitrogen balance, preventing weight loss and improving
perioperative outcomes.65 This must be weighed against the potential complications involved with
intravenous routes to include infectious complications and thromboembolic events.
A tiered strategy for medical therapy is often utilized, taking into account the disease activity (flare
vs. chronic), pattern (inflammatory vs. fistulizing vs. fibrotic) and location. Antibiotics and
aminosalicylates are typically used in the induction and maintenance of remission, respectively,
especially for those with mild-to-moderate disease. Antibiotics are also utilized for the treatment of an
acute infection for both the abdominal and perianal locations, with metronidazole and fluoroquinolones
among the most commonly used. In select cases, antibiotics can be given to patients with perianal
disease including fistulas for maintenance of remission as well as decreasing pain. While the exact
mechanism of action of antibiotics in Crohn disease is debated, by decreasing bacterial load and altering
the bacterial milieu of the GI tract, disease activity is lessened.
Aminosalicylates (5-ASA) are traditionally used as first-line maintenance agents, and are generally
well tolerated by patients. Depending on the predominant location of the disease, different moieties can
be formulated to allow maximal drug concentration to be targeted at the appropriate site. 5-ASA
compounds are not aspirin or nonsteroidal derivatives, though they do work to decrease
proinflammatory mediators and function at the mucosal level with reduced systemic absorption. Similar
to antibiotics, the mechanism of action in inflammatory bowel disease remains unclear, though levels of
NF-KB, TNF, and interleukin-1 have all been shown to decrease, as well as inhibiting both B- and T-cell
function.66 Additionally, they can be used in the perioperative period without increasing the risk of
postoperative complications. Overall, this class of medications has been shown to prevent disease flares
and minimize Crohn disease activity index for patients with mild disease, though the results have been
inconsistent with questionable clinical benefit.67 However, at most they have little downside and there
is some data to suggest a decrease in disease recurrence following resection.
Steroids remain a mainstay in the treatment of Crohn disease for both the induction and maintenance
of remission. They are especially useful in the setting of disease flares, where a “burst” followed by a
weaning strategy may allow some of the more well-tolerated medications to be initiated as a
maintenance regimen. Purported advantages to steroids include their low cost, ability to give via the
intravenous, oral and rectal routes, and the relative speed and efficacy that they are able to help achieve
quiescent disease. On the downside, ∼14% to 45% of patients will ultimately have steroid recalcitrant
disease, requiring either an escalation of medical therapy or surgical resection. Additionally, the wide
range of potential complications of steroids ranging from adrenal suppression, insulin resistance, ocular
disease, and osteopenia to psychosis, acne and weight gain, limits durable sustained use considerably.
Budesonide is a synthetic corticosteroid that is taken orally or rectally, and the steroid effect is
predominantly local due to a significant first-pass metabolism in the liver. While pooled analysis
demonstrated inferior effects compared to systemic steroids, it has been shown to maintain rates of
remission higher than placebo and comparable to prednisolone for those with mild disease.68
Table 50-3 Medical Treatment for Crohn Disease
1298
booksmedicos.org
The immunomodulator class of medications includes 6-mercaptopurine, azathioprine, methotrexate,
tacrolimus, and cyclosporine. They work via different mechanisms of action, yet all serve a common
purpose to alter the immune system in some capacity to blunt the patient’s intrinsic response to what is
considered “foreign” and to decrease inflammation. The first two (thiopurines) act via inhibition of
purine synthesis, and must be monitored, as metabolites can lead to bone marrow suppression and
hepatotoxicity. These drugs are useful for both the induction and maintenance of remission and
particularly helpful in dose reduction and weaning patients off prednisone.69 They also have a longer
onset of action, and may take months until the full effect of the medication is witnessed. Methotrexate
inhibits dihydrofolate reductase, also inhibiting purine and pyrimidine synthesis, and ultimately
cytokine production. Its effects are better demonstrated with intramuscular or subcutaneous injection
compared to oral, where both induction and remission rates are significantly worse.70 Side effects range
from blood dyscrasias and secondary malignancies to pneumonitis and hepatic fibrosis, and serial
monitoring of liver function tests is recommended.
The comparatively new group of medications are the biologic agents such as infliximab, adalimumab,
and certolizumab, which are monoclonal antibodies targeting tumor necrosis factor-α. They are also
administered via subcutaneous or intravenous injection, with dosing intervals dependent on the patient
response. Adalimumab is a fully human monoclonal antibody, and while still possible, provides the
advantage of being less likely to develop drug antibodies than infliximab.71 Together they are extremely
useful in the induction of remission, and more and more are utilized as first-line therapy for moderate-
to-severe disease (especially those with fistulizing disease), as well as in the maintenance of remission
for medically refractory patients. Several large-scale multicenter randomized trials including CLASSIC I
and II, CHARM, PRECiSE-1, and WELCOME have all demonstrated not only their collective efficacy, but
also the ability to induce and maintain remission in patients who had previously lost response to one of
the others.72 They are not without reported significant side effects, however, including anaphylaxis,
secondary malignancies, and opportunistic infections. Patients should be tested for latent tuberculosis
prior to their administration to avoid resurgence. Additionally there is considerable debate in the
literature as to their impact on perioperative complications and anastomotic leaks, with large center
studies reporting contradictory results, and pooled analysis demonstrating a nonsignificant trend toward
increased total complications (OR 1.72; 95% CI 0.93 to 3.19).73 Despite this controversy, discretion may
warrant consideration for diversion when these medications are used in the setting of higher-risk
anastomoses.
Operative Management
Indications for Surgery
2 One of the basic tenets in the management of Crohn disease is that surgery is typically reserved either
for failure of medical therapy (i.e., intractable disease or steroid dependency) or complications from the
disease. Failure of medical management is still the most common reason for surgery in patients with
Crohn disease, especially in colonic disease. Complications resulting in a potential need for operative
intervention include fistula, abscess, obstruction (stricture), growth retardation, perforation, EID,
bleeding, and malignancy. Of note, hemorrhage in Crohn disease tends to be a more rare event, and is
1299
booksmedicos.org
more commonly seen in ulcerative colitis or diverticular disease. Each of these will be outlined in the
following sections. Despite improvements in medical therapy, over 70% of all Crohn patients will
require surgery at some point in their lives, with almost half of those undergoing one operation
requiring additional procedures. Therefore, having a firm understanding of the general principles and
technical specifics is important to surgeons who care for these patients.
General Principles
3 While Crohn disease can affect the entire GI tract from mouth to anus, certain overriding principles
can help guide the planning and operative management. First, Crohn disease is a process marked by
lifelong potential for recurrence; therefore, preservation of bowel when possible and consideration of
future function are paramount concerns during the planning phase.74 Next, the extent of resection
required is dependent on multiple factors, including location and duration of disease, ability to exclude
malignancy, and prior resections that may have resulted in shortened small bowel. In addition, as the
stools tend to be loose, consideration must be given to rectal compliance and sphincter function during
surgical planning to avoid a “perineal colostomy,” whereby in-continuity management is preserved but
the patient has no control. Furthermore, unlike ulcerative colitis, segmental resection for both small and
large bowel is common with ileocolonic, colo-colonic, and rectal anastomoses all playing a role in
avoiding a permanent stoma while maximizing functional bowel.75 Crohn patients with pancolitis may
undergo a total abdominal colectomy with ileorectal anastomosis (for those with rectal-sparing) or total
proctocolectomy with end ileostomy.76 Total proctocolectomy with ileal pouch-anal anastomosis is
typically discouraged, and is normally the result of an initial misdiagnosis of ulcerative colitis.
4 Technical tips also come into play when planning for Crohn resections. For example, when
performing a proctectomy, it is important to consider the potential for a delayed or nonhealed perineal
wound. An intersphincteric dissection, which maximizes the amount of healthy muscle/tissue remaining,
facilitates closure in attempt to avoid this complication. Some patients will require more extensive
procedures such as flaps that utilize adjacent tissues (i.e., gracilis, bulbocavernosus), and may require
plastic surgeon involvement.77 In addition, as in the small bowel, length of resection margins does not
influence the risk of relapse with segmental resections, and only grossly normal bowel is all that is
required.78 Finally, diversion may be more commonly used due to both the presence of active disease as
well as the potential negative healing effects of the Crohn medications.
ABDOMINAL FISTULAS
Intra-abdominal fistulas may arise from either the small or large bowel and affect nearly every adjacent
structure. Similar to any fistula, it is important to determine the site of origin of the fistula, as this
section of bowel will typically require a formal resection when symptomatic (Fig. 50-14). On the other
hand, a section of bowel may simply be involved in the process secondarily as a “bystander,” and the
preferred treatment is to take the fistula down and primarily repair the site. It is important to ensure
there is no significant active disease at the closure site, as this may predispose to healing problems and
a subsequent leak. In this case, the preferred strategy would be to perform a segmental resection.79
Transmural bowel inflammation and communication can also occur more commonly with the skin,
bladder, or vagina. Once again, the bowel is the offending organ and should be resected, while ligation
of the fistula and closure of the secondarily involved organ is adequate treatment. In certain cases, the
inflammatory process is so intense, or there is a concern for concomitant malignancy, that the entire
process should be resected en bloc. When an abscess is present, it is often preferable to percutaneously
drain the abscess and ensure adequate medical therapy (that often includes biologics), prior to
embarking on abdominal exploration.80 Finally, asymptomatic entero-enteric or entero-colonic fistulas
are often best left alone and treated medically, especially with the relative success of anti-TNF agents.81
1300
booksmedicos.org
Figure 50-14. Entero-enteric-colonic fistula.
OBSTRUCTION AND STRICTURE

Strictures in Crohn disease most commonly occur in the terminal ileum, but may arise anywhere along
the GI tract (Fig. 50-15). Due to the transmural inflammation, it is not uncommon to have luminal
narrowing within the bowel especially with repeated flares. However, the underlying pathophysiology
may be from a phlegmonous/inflammatory process or secondary to the fibrostenotic pattern of disease.
In the former, medical management may be successful, decreasing the inflammation and resolving the
intrinsic or extrinsic “compression” on the bowel wall. On the other hand, patients with fibrotic
strictures typically have little to no response to medical management (including anti-TNF agents) and
most often require surgery.82–84 Emerging evidence suggests early treatment of strictures with
aggressive biologic therapy may aid in preventing the onset of fibrosis, especially in patients under 40,
prior to the onset of the irreversible cascade of fibrosis where surgery becomes inevitable.85
Figure 50-15. Endoscopic balloon passing through the ileocecal valve to dilate a stricture.
Strictures also differ somewhat based on their location. The rate of colonic strictures has been
reported to be as high as 7% to 17%.86 In general, these benign strictures are responsive to medical
management as well as endoscopic dilation for moderate-to-high–grade stenosis. Complicating the
situation, malignancy has been shown to be present in ∼7% of all colonic strictures,87 and Crohn
disease carries an increased risk of colorectal cancer above the general population. Furthermore, it is
very difficult to differentiate malignant from benign strictures on strictly clinical basis. Therefore all
colonic strictures should undergo endoscopic evaluation and biopsy. If malignancy is detected (or the
lesion appears worrisome and remains indeterminate on work-up), a standard oncologic resection
should normally be performed. For those that are clearly benign and nonresponsive to medical
management, endoscopic dilation has been shown to provide symptomatic relief. Technical success
occurs in ∼70% to 90%, and provides initial symptomatic resolution in over 80% of patients.88
Unfortunately, most patients with colonic strictures require repeated dilations. The procedure is
generally safe, with hemorrhage and perforation occurring in <5%, and most often occur when balloon
sizes over 25 mm are used. Although concomitant direct injection of the stricture with steroids or
treatment with systemic steroids immediately after dilation have both demonstrated some success in
1301
booksmedicos.org
case series, the true effect of this remains uncertain.
Strictures of the small bowel have been reported in 20% to 40% of Crohn patients.89 Treatment
typically consists of medical management, though depending on the severity, many patients will require
intervention. Small bowel strictures are often amenable to dilation via double-balloon enteroscopy,
especially in the 10- to 20-mm range, though perforation is a known risk.90,91 Symptomatic relief occurs
in ∼75% to 90% following the first dilation, while approximately 30% to 40% will require repeated
intervention over the next 3 years. For those with initial success, the cumulative dilation-free rate at 3
years is ∼40% to 50%.92 Overall complications occur in ∼10% to 15% (<5% major complications),
and include pain, fistula, fevers, bleeding, and perforation.93 Despite this success, many will require
operative intervention when symptoms fail to resolve, repeated bouts occur, or when a stricture is
associated with a nonresolving inflammatory process, malnutrition, immunosuppression or fistula.
Options then include strictureplasty (see below) or resection.
Strictureplasty preserves bowel length by avoiding resection altogether. The Heineke–Mikulicz
method involves a longitudinal incision along the antimesenteric border of the bowel with a transverse
closure, and is useful for shorter segments of bowel. Additional techniques include the Finney
strictureplasty, classically used for longer strictures of 7 to 15 cm in length, where the diseased segment
is opened longitudinally, the bowel is folded upon itself, and a full-thickness anastomosis is formed. In
another method, an isoperistaltic strictureplasty is constructed such that the narrowed diseased portion
of the bowel is anastomosed to the dilated segment of an adjacent loop in a side-to-side manner.
Complications have been reported in 4% to 15% in large series, and include obstruction, bleeding,
sepsis, perforation, and death.94,95 Overall, 5-year recurrence rates for strictureplasty in jejunoileal and
ileocolonic locations have been reported between 25% and 30%, including an ∼3% site-specific
recurrence. Similar to endoscopic dilation, malnutrition, presence of a phlegmon/perforation/fistula at
the site, multiple strictures within a small segment, and suspicion of a malignancy are all
contraindications to strictureplasty.96
Strictures at prior anastomotic sites may occur from recurrent disease or secondary to technical
problems. They are often amenable to dilation,97 yet they are often fibrotic in nature and
nonresponsive, thus requiring resection for symptomatic strictures. To prevent this, evidence from
systematic reviews and meta-analyses suggests that side-to-side stapled anastomoses in Crohn patients
undergoing an ileocolonic resection have a decreased rate of postoperative complications (OR = 0.54),
leak (OR = 0.45), recurrent (OR = 0.2), and reoperation (OR = 0.18) when compared to hand-sewn
end-to-end anastomoses.98,99
MALIGNANCY
5 Historically, the risk of malignancy with Crohn disease was felt to be only slightly higher than the
general population and significantly lower than the risk of patients with ulcerative colitis.100 More
recently, population-based data suggest that the cancer risk with long-standing Crohn’s is ∼4- to 20-fold
above that of the average population, and equivalent to patients with ulcerative colitis. Known risk
factors for malignancy include pancolitis (at least one-third) and a disease duration of >8 years.101–103
Endoscopic surveillance strategies to detect malignancy have had to date mixed results.104 Data from a
large meta-analysis found that surveillance colonoscopy has not shown to effect survival in these
patients, though lesions are typically detected earlier.105,106
The optimal surveillance strategy for patients with Crohn disease has not been determined. As such,
most recommendations favor mimicking surveillance for ulcerative colitis in patients with Crohn colitis.
In this algorithm, surveillance colonoscopy begins 8 years after disease onset for pancolitis and 15 years
for patients with left-sided disease, and is repeated every 1 to 2 years. In addition, the American Society
for GI Endoscopy, American College of Gastroenterology, and American Gastroenterological Association
were unable to draw conclusions regarding the benefit or need to perform random surveillance
biopsies.107–109 Treatment for malignancy in the Crohn patient is similar to that of the general
population, with resection following standard oncologic principles. As synchronous and metachronous
lesions have been reported in up to 10%, consideration should be given to a subtotal colectomy with
ileorectal anastomosis in the absence of rectal lesions.
While most evidence is from patients with ulcerative colitis, a polyp in a setting of colitis
(nonadenoma dysplasia–associated lesion or mass-DALM) has traditionally felt to carry a significant risk
of malignancy and is a strong indication for a formal resection.101,110–113 While these nonadenoma-like
1302
booksmedicos.org
DALMs should typically undergo a colectomy, more recent evidence suggests that complete endoscopic
excision of an adenoma-like DALM (i.e., a sporadic adenoma occurring in a patient with colitis with or
without active disease) may be safely undergo a surveillance protocol.114 Low-grade dysplasia outside
the setting of a nonadenoma-like DALM, and even in areas flat mucosa, warrants close follow-up,
although the need for follow-up resection remains unproven.101,113
HEMORRHAGE
Patients with Crohn may complain of bloody stools, however, frank hemorrhage in Crohndisease is
fairly uncommon. Possible sources include deep ulcerations, toxic colitis, an underlying mass, or
concomitant diverticular bleed. Significant upper GI bleeding is also rare, and likely from a secondary
source other than Crohn’s (e.g., ulcer, varices, esophageal tear, malignancy). Similar to any other
patient with a significant GI hemorrhage, patients require continued resuscitation, correction of any
coagulopathy, and transfusion as indicated. Adjunctive measures such as intravascular vasopressin and
infliximab have also been described,115,116 though should not be considered first-line agents. Endoscopy
is the most useful diagnostic and therapeutic maneuver for bleeding from either an upper or lower
source. When endoscopy or medical therapy is unsuccessful or bleeding recurs, segmental resection is
preferred when the source is localized in the large or small bowel. In the setting of unlocalized disease,
every effort should be made to identify the source of bleeding, including upper and lower endoscopies,
nuclear medicine scans, angiography, and small bowel evaluation (push endoscopy, video capsule
endoscopy, or small bowel follow-through). However in the unstable or nonlocalizable lower source, a
subtotal colectomy with end ileostomy may be required.117 In the case of upper GI bleeding, the source
may be localized and controlled with endoscopy or may require a resection or ligation as in patients
without Crohn disease depending on the underlying pathology.
SPECIFIC CONSIDERATIONS
Gastroduodenal Disease
As stated, gastroduodenal disease occurs in 0.5% to 4% of all Crohn patients. The most common
indications likely to require advanced or surgical intervention involve stricture/obstruction, fistula or
bleeding. Isolated gastric disease is even more rare,118 as the stomach will hardly ever be the sole
source for the patient’s complaints. It is important to exclude H. pylori infection, gastritis (NSAIDs),
ulcers, and malignancy in the absence of disease elsewhere in the GI tract. Most patients will respond to
medical management, especially with the anti–TNF-α therapy.119 Gastric outlet obstruction at the level
of the pylorus and first portion of the duodenum is often amenable to endoscopic balloon dilation, with
avoidance of surgery in approximately half of patients.120
Duodenal strictures are more frequent with disease in this location, and case series have demonstrated
successful amelioration of symptoms with endoscopic dilation.121 More often, symptomatic duodenal
strictures nonresponsive to medical therapy will be managed by strictureplasty, resection, or to a lesser
extent, bypass (i.e., gastrojejujostomy). As previously noted, the type of strictureplasty will depend on
the location, status of the surrounding tissues (i.e., ability to mobilize), and length of the stricture.122
Fistulas typically arise from disease located more distally in the small bowel, and therefore require
resection of the primary site with closure of the stomach or duodenum. Occasionally the upper tract is
the original of the fistula and resection or bypass is required. With appropriate expertise, a laparoscopic
approach has been associated with fewer complications and improved recovery. If bypass is performed,
vagotomy is not needed; however, every effort should be made to avoid bypass if possible, as this is
associated with worsening diarrhea and nutritional abnormalities.123 For those cases where resection or
closure of the duodenum is required, a jejunal serosal patch or Roux-en-Y duodenojejunostomy may help
minimizing wound breakdown and recurrent fistulas.124
Small Bowel Disease

Most small bowel disease is amenable to surgical resection and primary anastomosis. As stated,
strictureplasty is another option for those patients with short bowel, multiple sites of noncontiguous
disease, and early recurrence – especially for those with noninflammatory patterns. Following resection,
consideration should be given to the nutritional status of the patient, medications, and overall
1303
booksmedicos.org
physiologic state, as diverting stoma may be required to minimize the incidence and consequences of an
anastomotic leak. A minimally invasive approach, similar to other disease states, has been associated
with improved short-term outcomes in Crohn patients including decreased morbidity, shorter length of
stay, and reduced hospital charges for both primary and recurrent diseases.125 In addition, despite some
contradictory evidence, laparoscopy and open approaches appear to have similar long-term rates of
disease recurrence.126
Bypass is rarely performed for small bowel disease. The rare case of a septic, obstructed patient with
a large terminal ileum/ascending colon phlegmon involving the retroperitoneum that does not allow for
safe mobilization or identification of the ureter and vascular anatomy may be one indication where
bypass could still prove useful. These procedures have largely been abandoned as the underlying
inflammatory process remains and has not been adequately addressed. Therefore, resection and
strictureplasty continue to be the primary modalities to approach small bowel disease.
The mesentery in active Crohn disease always presents a particular challenge for surgeons. Due to its
thick, edematous nature with increased neovascularization, adequate hemostasis is always a point of
concern. Safe division in the era of open surgery involved techniques such as overlapping clamps with
both mass and individual vessel suture ligation, where appropriate. Laparoscopic approaches typically
rely on advanced vessel sealing devices for hemostasis, though they may be inadequate in the Crohn
patient. Surgeons must then rely on other means such as placing an ENDOLOOP (Ethicon, Cincinnati,
OH) on the major vessels or intracorporeal suturing. Crucial to whatever method is used is the notion to
avoid mesenteric hematomas, as these may result in continued bleeding as well compromise the blood
supply to the healthy remaining bowel.
Colorectal Conditions
Toxic Colitis
Toxic colitis may occur in Crohn patients similar to those with ulcerative colitis.127 Following
resuscitation and intravenous steroids or immunosuppressants, emergent surgical intervention is often
required for those with recalcitrant disease, perforation, or a deteriorating clinical state. The operative
procedure of choice is a subtotal colectomy with end-ileostomy. Debate exists as to the handling of the
rectal stump, though options include a distal mucus fistula with remnant sigmoid, implantation into the
subcutaneous space, or local reinforcement of the stump. Proctocolectomy should be avoided in this
situation due to the prolonged operative time and increased risk of morbidity and mortality.
Table 50-4 Perioperative Complications of Bowel Resection in Crohn Patientsa
Ileo-Anal Pouch
Ileo-anal pouch in the patient with Crohn disease most commonly occurs in the setting of an initial
“mis”diagnosis of ulcerative colitis. More often to the point, the pouch is performed, and the patient
will manifest Crohn disease at a later stage. While certain expert centers may advocate total
proctocolectomy and ileal pouch construction for highly select patients with Crohn disease128, in
general, this is to be discouraged. Retrospective studies have reported 35% to 93% of patients will have
Crohn’s-related complications such as pouchitis, abscesses, and pouch-anal fistulas, with another 10%
requiring pouch excision or permanent diversion. Furthermore, roughly half of patients will experience
urgency or continence issues. Of those patients with a functioning pouch, over half will continue to
require medication to treat active Crohn disease86,129,130 (Table 50-4).
Treatment of Anorectal Conditions
1304
booksmedicos.org
6 A distinguishing characteristic of the surgical treatment for anorectal Crohn disease is to first consider
whether or not they are symptomatic (see Algorithm 50-1). As a follow-on principle, aggressive
intervention in the asymptomatic patient is unwarranted and potentially dangerous.
Algorithm 50-1. Crohn disease with anal complaints.
Algorithm 50-2. Anal skin tags in Crohn disease.
Specific Clinical Disease Processes

Anal Skin Tags and Hemorrhoids
7 Crohn patients often suffer from skin tags that appear as large, edematous, and blue colored (see
Algorithms 50-2 and 50-3). Similarly, they may also suffer from internal and external hemorrhoids that
may bleed, prolapsed, and cause difficulty with hygiene and irritation. It is important to keep in mind
that Crohn patients have the propensity for poor healing, especially in the face of diarrhea. Patients
should be counseled as to the risk of nonhealing wounds, continence problems, and mucus drainage.131
Therefore, at least an initial attempt at conservative treatment with warm sitz baths and control of
diarrhea is warranted. During this time, medical therapy toward Crohn should be also optimized, as
active inflammation/proctitis will lead to increased morbidity. Should a conservative route fail,
standard hemorrhoidectomy may be performed (in the absence of active proctitis). Topical
metronidazole has been shown to improve posthemorrhoidectomy pain as well as improve healing, with
very little downside.132 Finally, although internal hemorrhoids may occur as in any other patient, they
tend to be less symptomatic and often respond to conservative measures.
Anorectal Abscess/Fistula
Treatment of anorectal abscesses in the setting of Crohn is essentially no different than those of
1305
booksmedicos.org
cryptoglandular origin – incision and drainage (see Algorithm 50-4). Crohn patients may have more
extensive disease, and adjunct radiology testing may be useful, especially when the examination does
not match the patient’s symptoms. From a technical standpoint, it is important to place the incision as
close to the anal verge as possible while still achieving adequate drainage, considering the possibility of
fistula development.133 Alternatively, a small pessar mushroom tipped catheter may be placed in the
cavity, thus evacuating the abscess and allowing the cavity to close around the catheter, while allowing
continued drainage.
Algorithm 50-3. Hemorrhoids in Crohn disease.
Algorithm 50-4. Anal abscess/fistula in Crohn disease.
Perianal fistulas are often deep, eroding through sphincter and occur in the setting of extensive
scarring around the sphincter. Moreover, they can have high blind tracts, originate at levels well above
the dentate line and are often found in conjunction with active proctitis. Determining the anatomy of
the tract is required, but attention should also be given to the presence or absence of proctitis, status of
the sphincter, prior anal operations, and potential for chronic diarrhea (i.e., medically controlled or
not). Aggressive fistulotomies must be avoided. Yet, low-lying fistulas in the absence of overt proctitis
can often be treated safely with fistulotomy.134 When the fistula is higher or more complex, endoanal
advancement flaps, fistula plugs, or the LIFT procedure (ligation of the intersphincteric fistula tract)
1306
booksmedicos.org
may all be performed with varying rates of success. Many patients with fistulous disease require chronic
indwelling setons such as silastic vessel loops. Patients should be periodically reexamined both to ensure
that there is adequate drainage, as well as to look for a potential malignant growth, with case reports of
squamous cell and adenocarcinoma arising in a fistulous tract (Fig. 50-16). Unfortunately, fistulas and
fistula procedures all vary in their outcomes, with healing rates ranging from 15% to 97% and
morbidity rates 3% to 78%, making it difficult to accurately compare results. As such, consideration
should be given for a diverting stoma for recurrent or complex fistulas. Finally, a small percentage of
patients may require permanent diversion or even proctectomy.135
Rectovaginal/Anovaginal Fistula
Rectovaginal fistulas are particularly problematic in Crohn patients (Fig. 50-17). Because many of these
fistulas are associated with a deeply erosive process and intense inflammation, extensive tracts and
hidden associated abscesses may also be present. In addition, a rectovaginal fistula may originate from
small bowel, thus limiting potential diagnostic methods such as the methylene blue enema. Many
patients require diversion in this setting prior to any definitive repair to aid with control of proctitis and
to optimize the conditions needed for successful healing. First-line options include use of the fistula
plug, endorectal advancement flap, and LIFT procedure.136 Due to the complexity of the wounds and
need for healthy tissue interposition, muscle flaps (e.g., gracilis, bulbocavernosus) are especially useful,
and may require a multidisciplinary team.
Figure 50-16. Adenocarcinoma arising out of a chronic fistula tract in a Crohn patient. (Courtesy of Howard Ross, MD.)
Figure 50-17. Rectovaginal fistula in a Crohn patient.
Anal Fissure
Patients with Crohn disease and anal fissures present a particular challenge. Decreasing the continence
in any way may worsen an already difficult clinical situation, and limit the number of patients that may
successfully undergo surgery (see Algorithm 50-5). Despite an appearance that is hallmarked by deep,
burrowing, off the midline and sometimes multiple wounds (Fig. 50-18), many anal fissures are
fortunately painless and require no intervention. Excessive pain should raise the suspicion for an
underlying abscess and prompt an examination under anesthesia. Initial attempts at conservative
therapy with topical metronidazole, smooth muscle relaxants and local anesthetics may be attempted to
palliate symptoms and help with healing.137 For particularly symptomatic fissures, botulinum toxin has
1307
booksmedicos.org
also been used. In contrast, other authors have advocated a more aggressive surgical approach in Crohn
patients, with one report citing 67% of patients who were treated surgically ultimately healed.138 Yet,
given the continence risks associated with surgery, medical management is the preferred initial therapy
in patients with Crohn-related fissures. Surgical intervention should be reserved for those patients with
minimal active anorectal inflammation who fail all reasonable conservative therapy, and still sphincter
muscle division should be kept to a minimum.
Figure 50-18. Crohn fissure – notice the deep burrowing nature off the midline with signs of old fistula tracts.
Algorithm 50-5. Anal fissure in Crohn disease.
1308
booksmedicos.org
Algorithm 50-6. Anal stenosis/stricture and Crohn disease.
Anal Stenosis and Ulcer

Anal ulcers, stenosis, and strictures secondary to Crohn, while uncommon, can be extremely debilitating
(see Algorithm 50-6). Single institutional series have demonstrated success rates of biologic agents in
18% to 60%.139,140 Up to one-third of patients will have concomitant abscess or fistulas, and these
should be appropriately drained. Due to the association of chronic inflammation with the development
of malignancy, biopsy of any suspicious lesions should also be performed. For low-grade strictures, anal
dilation has proven successful, though repeated session is the norm. Other options include steroid
injection or biologics, balloon dilation, strictureplasty, flaps, and even proctectomy – depending on the
severity and response to therapy.141
Anorectal Malignancy
Anorectal cancer may occur in any setting, including Crohn disease. Risk factors in patients with Crohn
disease include the presence of chronic inflammation, long-standing open wounds, and use of
immunosuppressant medication. Both squamous cell carcinoma (Marjolin ulcer), adenocarcinoma, and
their variants may occur.142 Patients (especially those with long-term indwelling setons) should be
periodically examined to exclude the presence of malignancy. All suspicious lesions should undergo
biopsy and any malignancy identified should undergo proper staging and treatment.
SUMMARY
Crohn disease remains a complex disease process with many different manifestations in the GI tract.
Although advances in medical therapy continue to evolve and significantly alter the way patients are
managed, surgeons still play a large role in both the medical and surgical therapies of the disease. Due
to its recurring nature, surgeons must adhere to the principles of preventing and managing disease
complications versus aiming for cure. By focusing on the maximization of functional outcomes, surgeons
can optimize outcomes through a multimodality approach and minimize additional complications.
Financial Disclosure: No outside financial support or provision of supplies was solicited or received
in connection with this work.
Disclosure and Proprietary Statement: This is an original work by the above authors. The opinions
expressed are the authors’ alone. They do not necessarily reflect the opinion of the United States
Government, the US Department of Defense, or Madigan Army Medical Center.
References
1. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis: a pathologic and clinical entity. JAMA
1932;99(6):1323–1329.
2. Crohn BB, Ginzburg L, Oppenheimer GD. Landmark article Oct 15, 1932. Regional ileitis. A
1309
booksmedicos.org
pathological and clinical entity. By Burril B. Crohn, Leon Ginzburg, and Gordon D. Oppenheimer.
JAMA 1984; 251(1):73–79.
3. Zani A, Cozzi DA. Giovanni Battista Morgagni and his contribution to pediatric surgery. J Pediatr
Surg 2008;43(4):729–733.
4. Whelan G, Farmer RG, Fazio VW, et al. Recurrence after surgery in Crohn’s disease. Relationship to
location of disease (clinical pattern) and surgical indication. Gastroenterology 1985;88(6):1826–
1833.
5. Polito MJ, Childs B, Mellits ED, et al. Crohn’s disease: influence of age at diagnosis on site and
clinical type of disease. Gastroenterology 1996;111(3): 580–586.
6. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory
bowel diseases with time, based on systematic review. Gastroenterology 2012;142(1):46–54.
7. Loftus EV Jr, Silverstein MD, Sandborn WJ, et al. Crohn’s disease in Olmsted County, Minnesota,
1940–1993: Incidence, prevalence, and survival. Gastroenterology 1998;114:1161–1168.
8. Halme L, Paavola-Sakki P, Turunen U, et al. Family and twin studies in inflammatory bowel
disease. World J Gastroenterol 2006;12(23):3668–3672.
9. Yang H, McElree C, Roth MP, et al. Familial empirical risks for inflammatory bowel disease:
differences between Jews and non-Jews. Gut 1993;34(4):517–524.
10. Halfvarson J, Bodin L, Tysk C, et al. Inflammatory bowel disease in a Swedish twin cohort: a long-
term follow-up of concordance and clinical characteristics. Gastroenterology 2003;124(7):1767–1773.
11. Huttenhower C, Kostic AD, Xavier RJ. Inflammatory bowel disease as a model for translating the
microbiome. Immunity 2014;40(6):843–854.
12. Reiff C, Kelly D. Inflammatory bowel disease, gut bacteria and probiotic therapy. Int J Med
Microbiol 2010;300(1):25–33.
13. Macfarlane GT, Blackett KL, Nakayama T, et al. The gut microbiota in inflammatory bowel disease.
Curr Pharm Des 2009;15(13):1528–1536.
14. Haag LM, Siegmund B. Exploring & exploiting our ‘other self’ - does the microbiota hold the key to
the future therapy in Crohn’s? Best Pract Res Clin Gastroenterol 2014;28(3):399–409.
15. Hugot JP, Laurent-Puig P, Gower-Rousseau C, et al. Mapping of a susceptibility locus for Crohn’s
disease on chromosome 16. Nature 1996;379:821–823.
16. Cho JH. The Nod2 gene in Crohn’s disease: implications for future research into the genetics and
immunology of Crohn’s disease. Inflamm Bowel Dis 2001;7(3):271–275.
17. Műzes G, Tulassay Z, Sipos F. Interplay of autophagy and innate immunity in Crohn’s disease: a key
immunobiologic feature. World J Gastroenterol 2013;19(28):4447–4454.
18. Wallace KL, Zheng LB, Kanazawa Y, et al. Immunopathology of inflammatory bowel disease. World
J Gastroenterol 2014;20(1):6–21.
19. Gilardoni LR, Paolicchi FA, Mundo SL. Bovine paratuberculosis: a review of the advantages and
disadvantages of different diagnostic tests. Rev Argent Microbiol 2012;44(3):201–215.
20. Wagner J, Sim WH, Lee KJ, et al. Current knowledge and systematic review of viruses associated
with Crohn’s disease. Rev Med Virol 2013;23(3):145–171.
21. Cabré E, Domènech E. Impact of environmental and dietary factors on the course of inflammatory
bowel disease. World J Gastroenterol 2012;18(29):3814–3822.
22. Yantiss RK, Odze RD. Diagnostic difficulties in inflammatory bowel disease pathology.
Histopathology 2006;48(2):116–132.
23. Matsui T, Yao T, Sakurai T, et al. Clinical features and pattern of indeterminate colitis: Crohn’s
disease with ulcerative colitis-like clinical presentation. J Gastroenterol 2003;38(7):647–655.
24. Dias CC, Rodrigues PP, da Costa-Pereira A, et al. Clinical prognostic factors for disabling Crohn’s
disease: a systematic review and meta-analysis. World J Gastroenterol 2013;19(24):3866–3871.
25. Schwartz DA, Loftus EV Jr, Tremaine WJ, et al. The natural history of fistulizing Crohn’s disease in
Olmsted County, Minnesota. Gastroenterology 2002;122(4):875–880.
26. Farmer RG, Hawk WA, Turnbull RB Jr. Clinical patterns in Crohn’s disease: a statistical study of
615 cases. Gastroenterology 1975;68(4 Pt 1):627–635.
27. Lapidus A, Bernell O, Hellers G, et al. Clinical course of colorectal Crohn’s disease: a 35-year
follow-up study of 507 patients. Gastroenterology 1998; 114(6):1151–1160.
1310
booksmedicos.org
28. Binder HJ. Mechanisms of diarrhea in inflammatory bowel diseases. Ann N Y Acad Sci
2009;1165:285–293.
29. Wenzl HH. Diarrhea in chronic inflammatory bowel diseases. Gastroenterol Clin North Am
2012;41(3):651–675.
30. Bissel AD. Localized chronic ulcerative ileitis. Ann Surg 1934;99:957–966.
31. McKee RF, Keenan RA. Perianal Crohn’s disease–is it all bad news? Dis Colon Rectum
1996;39(2):136–142.
32. Homan WP, Tang C, Thorgjarnarson B. Anal lesions complicating Crohn disease. Arch Surg
1976;111(12):1333–1335.
33. Solomon MJ. Fistulae and abscesses in symptomatic perianal Crohn’s disease. Int J Colorectal Dis
1996;11(5):222–226.
34. Isaacs KL. Upper gastrointestinal tract endoscopy in inflammatory bowel disease. Gastrointest Endosc
Clin N Am 2002;12(3):451–462, vii.
35. Wagtmans MJ, van Hogezand RA, Griffioen G, et al. Crohn’s disease of the upper gastrointestinal
tract. Neth J Med 1997;50(2):S2–S7.
36. Decker GA, Loftus EV Jr, Pasha TM, et al. Crohn’s disease of the esophagus: clinical features and
outcomes. Inflamm Bowel Dis 2001;7(2):113–119.
37. Satsangi J, Grootscholten C, Holt H, et al. Clinical patterns of familial inflammatory bowel disease.
Gut 1996;38(5):738–741.
38. Orchard TR, Thiyagaraja S, Welsh KI, et al. Clinical phenotype is related to HLA genotype in the
peripheral arthropathies of inflammatory bowel disease. Gastroenterology 2000;118(2):274–278.
39. Rothfuss KS, Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in
inflammatory bowel diseases. World J Gastroenterol 2006; 12(30):4819–4831.
40. Rispo A, Musto D, Tramontano ML, et al. Surgery-induced remission of extraintestinal
manifestations in inflammatory bowel diseases. J Crohns Colitis 2013;7(10):e504–e505.
41. Kelvin FM, Oddson TA, Rice RP, et al. Double contrast barium enema in Crohn’s disease and
ulcerative colitis. AJR Am J Roentgenol 1978;131(2):207–213.
42. Dambha F, Tanner J, Carroll N. Diagnostic imaging in Crohn’s disease: what is the new gold
standard? Best Pract Res Clin Gastroenterol 2014;28(3):421–436.
43. Spinelli A, Fiorino G, Bazzi P, et al. Preoperative magnetic resonance enterography in predicting
findings and optimizing surgical approach in Crohn’s disease. J Gastrointest Surg 2014;18(1):83–90.
44. Siddiki HA1, Fidler JL, Fletcher JG, et al. Prospective comparison of state-of-the-art MR
enterography and CT enterography in small-bowel Crohn’s disease. AJR Am J Roentgenol
2009;193(1):113–21.
45. Gallego Ojea JC, Echarri Piudo AI, Porta Vila A. [Crohn’s disease: the usefulness of MR
enterography in the detection of recurrence after surgery]. Radiologia 2011;53(6):552–559.
46. Vanbeckevoort D, Bielen D, Vanslembrouck R, et al. Magnetic resonance imaging of perianal
fistulas. Magn Reson Imaging Clin N Am 2014;22(1):113–123.
47. Al-Hawary M, Zimmermann EM. A new look at Crohn’s disease: novel imaging techniques. Curr
Opin Gastroenterol 2012;28(4):334–340.
48. Shyn PB. 18F-FDG positron emission tomography: potential utility in the assessment of Crohn’s
disease. Abdom Imaging 2012;37(3):377–386.
49. Leighton JA, Gralnek IM, Cohen SA, et al. Capsule endoscopy is superior to small-bowel follow-
through and equivalent to ileocolonoscopy in suspected Crohn’s disease. Clin Gastroenterol Hepatol
2014;12(4):609–615.
50. Hall B, Holleran G, Costigan D, et al. Capsule endoscopy: High negative predictive value in the
long term despite a low diagnostic yield in patients with suspected Crohn’s disease. United European
Gastroenterol J 2013; 1(6):461–466.
51. Carter D, Eliakim R. Current role of endoscopy in inflammatory bowel disease diagnosis and
management. Curr Opin Gastroenterol 2014;30(4):370–377.
52. Joo M, Odze RD. Rectal sparing and skip lesions in ulcerative colitis: a comparative study of
endoscopic and histologic findings in patients who underwent proctocolectomy. Am J Surg Pathol
2010;34(5):689–696
1311
booksmedicos.org
53. Kochhar R, Kochhar S. Endoscopic balloon dilation for benign gastric outlet obstruction in adults.
World J Gastrointest Endosc 2010;2(1):29–35.
54. Ferreira J, Akbari M, Gashin L, et al. Prevalence and lifetime risk of endoscopy-related
complications among patients with inflammatory bowel disease. Clin Gastroenterol Hepatol
2013;11(10):1288–1293.
55. Vucelic B. Inflammatory bowel diseases: controversies in the use of diagnostic procedures. Dig Dis
2009;27(3):269–277.
56. Morpurgo E, Petras R, Kimberling J, et al. Characterization and clinical behavior of Crohn’s disease
initially presenting predominantly as colitis. Dis Colon Rectum 2003;46(7):918–924.
57. Mahadeva U, Martin JP, Patel NK, et al. Granulomatous ulcerative colitis: a re-appraisal of the
mucosal granuloma in the distinction of Crohn’s disease from ulcerative colitis. Histopathology
2002;41(1):50–55.
58. Kim BG, Kim YS, Kim JS, et al. Diagnostic role of anti-Saccharomyces cerevisiae mannan antibodies
combined with antineutrophil cytoplasmic antibodies in patients with inflammatory bowel disease.
Dis Colon Rectum 2002;45(8):1062–1069.
59. Inoue K, Aomatsu T, Yoden A, et al. Usefulness of a novel and rapid assay system for fecal
calprotectin in pediatric patients with inflammatory bowel diseases. J Gastroenterol Hepatol
2014;29(7):1406–1412.
60. Nancey S, Boschetti G, Moussata D, et al. Neopterin is a novel reliable fecal marker as accurate as
calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel
diseases. Inflamm Bowel Dis 2013;19(5):1043–1052.
61. D’Haens G, Ferrante M, Vermeire S, et al. Fecal calprotectin is a surrogate marker for endoscopic
lesions in inflammatory bowel disease. Inflamm Bowel Dis 2012;18(12):2218–2224.
62. Gisbert JP, McNicholl AG, Gomollon F. Questions and answers on the role of fecal lactoferrin as a
biological marker in inflammatory bowel disease. Inflamm Bowel Dis 2009;15(11):1746–1754.
63. Abraham BP, Kane S. Fecal markers: calprotectin and lactoferrin. Gastroenterol Clin North Am
2012;41(2):483–495.
64. Weston LA, Roberts PL, Schoetz DJ, Jr., et al. Ileocolic resection for acute presentation of Crohn’s
disease of the ileum. Dis Colon Rectum 1996; 39(8):841–846.
65. Li G, Ren J, Wang G, et al. Preoperative exclusive enteral nutrition reduces the postoperative septic
complications of fistulizing Crohn’s disease. Eur J Clin Nutr 2014;68(4):441–446.
66. Caprilli R, Cesarini M, Angelucci E, et al. The long journey of salicylates in ulcerative colitis: The
past and the future. J Crohns Colitis 2009;3(3):149–156.
67. Lim WC, Hanauer S. Aminosalicylates for induction of remission or response in Crohn’s disease.
68. Seow CH, Benchimol EI, Griffiths AM, et al. Budesonide for induction of remission in Crohn’s
disease. Cochrane Database Syst Rev 2008;(3):CD000296.
69. Prefontaine E, Macdonald JK, Sutherland LR. Azathioprine or 6-mercaptopurine for induction of
remission in Crohn’s disease. Cochrane Database Syst Rev 2010;(6):CD000545.
70. Alfadhli AA, McDonald JW, Feagan BG. Methotrexate for induction of remission in refractory
Crohn’s disease. Cochrane Database Syst Rev 2005;(1):CD003459.
71. Lapadula G, Marchesoni A, Armuzzi A, et al. Adalimumab in the treatment of immune-mediated
diseases. Int J Immunopathol Pharmacol 2014; 27(1 suppl):33–48.
72. Scott FI, Osterman MT. Medical management of crohn disease. Clin Colon Rectal Surg
2013;26(2):67–74.
73. Kopylov U, Ben-Horin S, Zmora O, et al. Anti-tumor necrosis factor and postoperative complications
in Crohn’s disease: systematic review and meta-analysis. Inflamm Bowel Dis 2012;18(12):2404–2413.
74. Wolff BG. Resection margins in Crohn’s disease. Br J Surg 2001;88(6):771–772.
75. Bernell O, Lapidus A, Hellers G. Recurrence after colectomy in Crohn’s colitis. Dis Colon Rectum
2001;44(5):647–654.
76. Tekkis PP, Purkayastha S, Lanitis S, et al. A comparison of segmental vs subtotal/total colectomy
for colonic Crohn’s disease: a meta-analysis. Colorectal Dis 2006;8(2):82–90.
77. Scammell BE, Keighley MR. Delayed perineal wound healing after proctectomy for Crohn’s colitis.
1312
booksmedicos.org
Br J Surg 1986;73(2):150–152.
78. Raab Y, Bergstrom R, Ejerblad S, et al. Factors influencing recurrence in Crohn’s disease. An
analysis of a consecutive series of 353 patients treated with primary surgery. Dis Colon Rectum
1996;39(8):918–925.
79. Cellini C, Safar B, Fleshman J. Surgical management of pyogenic complications of Crohn’s disease.
Inflamm Bowel Dis 2010;16(3):512–517.
80. Sampietro GM, Casiraghi S, Foschi D. Perforating Crohn’s disease: conservative and surgical
treatment. Dig Dis 2013;31(2):218–221.
81. Poritz LS, Rowe WA, Koltun WA. Remicade does not abolish the need for surgery in fistulizing
Crohn’s disease. Dis Colon Rectum 2002;45(6):771–775.
82. Kawalec P, Mikrut A, Wiśniewska N, et al. Tumor necrosis factor-α antibodies (infliximab,
adalimumab and certolizumab) in Crohn’s disease: systematic review and meta-analysis. Arch Med
Sci 2013;9(5):765–779.
83. Van Assche G, Geboes K, Rutgeerts P. Medical therapy for Crohn’s disease strictures. Inflamm Bowel
Dis 2004;10(1):55–60.
84. Bettenworth D, Rieder F. Medical therapy of stricturing Crohn’s disease: what the gut can learn
from other organs - a systematic review. Fibrogenesis Tissue Repair 2014;7(1):5.
85. Govani SM, Stidham RW, Higgins PD. How early to take arms against a sea of troubles? The case
for aggressive early therapy in Crohn’s disease to prevent fibrotic intestinal strictures. J Crohns
Colitis 2013;7(11):923–927.
86. Brown CJ, Maclean AR, Cohen Z, et al. Crohn’s disease and indeterminate colitis and the ileal
pouch-anal anastomosis: outcomes and patterns of failure. Dis Colon Rectum.2005;48(8):1542–1549.
87. Yamazaki Y, Ribeiro MB, Sachar DB, et al. Malignant colorectal strictures in Crohn’s disease. Am J
Gastroenterol 1991;86(7):882–885.
88. Stienecker K, Gleichmann D, Neumayer U, et al. Long-term results of endoscopic balloon dilatation
of lower gastrointestinal tract strictures in Crohn’s disease: A prospective study. World J
Gastroenterol 2009;15(21):2623–2627.
89. Swaminath A, Lichtiger S. Dilation of colonic strictures by intralesional injection of infliximab in
patients with Crohn’s colitis. Inflamm Bowel Dis 2008;14(2):213–216.
90. Despott EJ, Gupta A, Burling D, et al. Effective dilation of small-bowel strictures by double-balloon
enteroscopy in patients with symptomatic Crohn’s disease (with video). Gastrointest Endosc
2009;70(5):1030–1036.
91. Gill RS, Kaffes AJ. Small bowel stricture characterization and outcomes of dilatation by double-
balloon enteroscopy: a single-centre experience. Therap Adv Gastroenterol 2014;7(3):108–114.
92. Hirai F, Beppu T, Takatsu N, et al. Long-term outcome of endoscopic balloon dilation for small
bowel strictures in patients with Crohn’s disease. Dig Endosc 2014;26(4):545–551.
93. Endo K, Takahashi S, Shiga H, et al. World J Short and long-term outcomes of endoscopic balloon
dilatation for Crohn’s disease strictures. World J Gastroenterol 2013;19(1):86–91.
94. Yamamoto T, Fazio VW, Tekkis PP. Safety and efficacy of strictureplasty for Crohn’s disease: a
systematic review and meta-analysis. Dis Colon Rectum 2007;50(11):1968–1986.
95. Campbell L, Ambe R, Weaver J, et al. Comparison of conventional and nonconventional
strictureplasties in Crohn’s disease: a systematic review and meta-analysis. Dis Colon Rectum
2012;55(6):714–726.
96. Hesham W, Kann BR. Strictureplasty. Clin Colon Rectal Surg 2013;26(2):80–83.
97. Chen M, Shen B. Comparable Short- and Long-term Outcomes of Colonoscopic Balloon Dilation of
Crohn’s Disease and Benign Non-Crohn’s Disease Strictures. Inflamm Bowel Dis 2014;20(10):1739–
1746.
98. He X, Chen Z, Huang J, et al. Stapled side-to-side anastomosis might be better than handsewn end-
to-end anastomosis in ileocolic resection for Crohn’s disease: a meta-analysis. Dig Dis Sci
2014;59(7):1544–1551.
99. Simillis C, Purkayastha S, Yamamoto T, et al. A meta-analysis comparing conventional end-to-end
anastomosis vs. other anastomotic configurations after resection in Crohn’s disease. Dis Colon
Rectum 2007;50(10):1674–1687.
100. Greenstein AJ, Sachar DB, Smith H, et al. Patterns of neoplasia in Crohn’s disease and ulcerative
1313
booksmedicos.org
colitis. Cancer 1980;46(2):403–407.
101. Jess T, Loftus EV Jr, Velayos FS, et al. Risk of intestinal cancer in inflammatory bowel disease: a
population-based study from Olmsted county, Minnesota. Gastroenterology 2006;130(4):1039–1046.
102. Maykel JA, Hagerman G, Mellgren AF, et al. Crohn’s colitis: the incidence of dysplasia and
adenocarcinoma in surgical patients. Dis Colon Rectum 2006;49(7):950–957.
103. Friedman S, Rubin PH, Bodian C, et al. Screening and surveillance colonoscopy in chronic Crohn’s
colitis. Gastroenterology 2001;120(4):820–826.
104. Siegel CA, Sands BE. Risk factors for colorectal cancer in Crohn’s colitis: a case-control study.
Inflamm Bowel Dis 2006;12(6):491–496.
105. Shanahan F. Review article: colitis-associated cancer – time for new strategies. Aliment Pharmacol
Ther 2003;18 suppl 2:6–9.
106. Collins PD, Mpofu C, Watson AJ, et al. Strategies for detecting colon cancer and/or dysplasia in
patients with inflammatory bowel disease. Cochrane Database Syst Rev 2006;(2):CD000279.
107. Hanauer SB, Meyers S. Management of Crohn’s disease in adults. Am J Gastroenterol
1997;92(4):559–566.
108. Farraye FA, Odze RD, Eaden J, et al; AGA Institute Medical Position Panel on Diagnosis and
Management of Colorectal Neoplasia in Inflammatory Bowel Disease. AGA medical position
statement on the diagnosis and management of colorectal neoplasia in inflammatory bowel disease.
109. Leighton JA, Shen B, Baron TH, et al; Standards of Practice Committee, American Society for
Gastrointestinal Endoscopy. ASGE guideline: endoscopy in the diagnosis and treatment of
inflammatory bowel disease. Gastrointest Endosc 2006;63(4):558–565.
110. Cooper DJ, Weinstein MA, Korelitz BI. Complications of Crohn’s disease predisposing to dysplasia
and cancer of the intestinal tract: considerations of a surveillance program. J Clin Gastroenterol
1984;6(3):217–224.
111. Itzkowitz SH, Harpaz N. Diagnosis and management of dysplasia in patients with inflammatory
bowel diseases. Gastroenterology 2004;126(6):1634–1648.
112. Greenson JK. Dysplasia in inflammatory bowel disease. Semin Diagn Pathol 2002;19(1):31–37.
113. Befrits R, Ljung T, Jaramillo E, et al. Low-grade dysplasia in extensive, long-standing inflammatory
bowel disease: a follow-up study. Dis Colon Rectum 2002;45(5):615–620.
114. Wanders LK, Dekker E, Pullens B, et al. Cancer risk after resection of polypoid dysplasia in patients
with longstanding ulcerative colitis: a meta-analysis. Clin Gastroenterol Hepatol 2014;12(5):756–764.
115. Alla VM, Ojili V, Gorthi J, et al. Revisiting the past: intra-arterial vasopressin for severe
gastrointestinal bleeding in Crohn’s disease. J Crohns Colitis 2010;4(4):479–482.
116. Ando Y, Matsushita M, Kawamata S, et al. Infliximab for severe gastrointestinal bleeding in Crohn’s
disease. Inflamm Bowel Dis 2009;15(3):483–484.
117. Veroux M, Angriman I, Ruffolo C, et al. Severe gastrointestinal bleeding in Crohn’s disease. Ann Ital
Chir 2003;74(2):213–215; discussion 216.
118. Firth MG, Prather CM. Unusual gastric Crohn’s disease treated with infliximab - a case report. Am J
Gastroenterol 2002;97:S190.
119. Banerjee S, Peppercorn MA. Inflammatory bowel disease. Medical therapy of specific clinical
presentations. Gastroenterol Clin North Am 2002;31:185–202
120. Rana SS, Bhasin DK, Chandail VS, et al. Endoscopic balloon dilatation without fluoroscopy for
treating gastric outlet obstruction because of benign etiologies. Surg Endosc 2011;25(5):1579–1584.
121. Singh VV, Draganov P, Valentine J. Efficacy and safety of endoscopic balloon dilation of
symptomatic upper and lower gastrointestinal Crohn’s disease strictures. J Clin Gastroenterol
2005;39(4):284–290.
122. Tonelli F, Alemanno G, Bellucci F, et al. Symptomatic duodenal Crohn’s disease: is strictureplasty
the right choice? J Crohns Colitis 2013;7(10):791–796.
123. Shapiro M, Greenstein AJ, Byrn J, et al. Surgical management and outcomes of patients with
duodenal Crohn’s disease. J Am Coll Surg 2008;207(1):36–42.
124. Pettit S, Irving M. The operative management of fistulating Crohn’s disease—experience with 100
consecutive cases. Surg Gynecol Obstet 1988;167:223–228.
1314
booksmedicos.org
125. Lesperance K, Martin M J, Lehmann R, et al. National trends and outcomes for the surgical therapy
of ileocolonic Crohn’s disease: a population-based analysis of laparoscopic vs. open approaches. J
Gastrointest Surg 2009;13(7):1251–1259
126. Aarons CB. Laparoscopic surgery for Crohn disease: a brief review of the literature. Clin Colon
Rectal Surg 2013;26(2):122–127.
127. Stewart D, Chao A, Kodner I, et al. Subtotal colectomy for toxic and fulminant colitis in the era of
immunosuppressive therapy. Colorectal Dis 2009;11(2):184–190.
128. Joyce MR, Fazio VW. Can ileal pouch anal anastomosis be used in Crohn’s disease? Adv Surg
2009;43:111–137.
129. Hartley JE, Fazio VW, Remzi FH, et al. Analysis of the outcome of ileal pouch-anal anastomosis in
patients with Crohn’s disease. Dis Colon Rectum 2004;47(11):1808–1815.
130. Braveman JM, Schoetz DJ Jr, Marcello PW, et al. The fate of the ileal pouch in patients developing
Crohn’s disease. Dis Colon Rectum 2004;47(10):1613–1619.
131. Cracco N, Zinicola R. Is haemorrhoidectomy in inflammatory bowel disease harmful? An old dogma
re-examined. Colorectal Dis 2014;16(7):516–519.
132. Nicholson TJ, Armstrong D. Topical metronidazole (10 percent) decreases posthemorrhoidectomy
pain and improves healing. Dis Colon Rectum 2004;47(5):711–716.
133. Lewis RT, Bleier JI. Surgical treatment of anorectal Crohn disease. Clin Colon Rectal Surg
2013;26(2):90–99.
134. Sneider EB, Maykel JA. Anal abscess and fistula. Gastroenterol Clin North Am 2013;42(4):773–784.
135. Causey MW, Nelson D, Johnson EK, et al. An NSQIP evaluation of practice patterns and outcomes
following surgery for anorectal abscess and fistula in patients with and without Crohn’s disease.
Gastroenterol Rep (Oxf) 2013;1(1):58–63.
136. Tozer PJ, Balmforth D, Kayani B, et al. Surgical management of rectovaginal fistula in a tertiary
referral centre: many techniques are needed. Colorectal Dis 2013;15(7):871–877.
137. D’Ugo S, Franceschilli L, Cadeddu F, et al. Medical and surgical treatment of haemorrhoids and anal
fissure in Crohn’s disease: a critical appraisal. BMC Gastroenterol 2013;13:47.
138. Fleshner PR, Schoetz DJ Jr, Roberts PL, et al. Anal fissure in Crohn’s disease: a plea for aggressive
management. Dis Colon Rectum 1995;38(11):1137–1143.
139. Brochard C, Siproudhis L, Wallenhorst T, et al. Anorectal stricture in 102 patients with Crohn’s
disease: natural history in the era of biologics. Aliment Pharmacol Ther 2014;40(7):796–803.
140. Bouguen G, Trouilloud I, Siproudhis L, et al. Long-term outcome of non-fistulizing (ulcers,
stricture) perianal Crohn’s disease in patients treated with infliximab. Aliment Pharmacol Ther
2009;30(7):749–756.
141. Lawal TA, Frischer JS, Falcone RA, et al. The transanal approach with laparoscopy or laparotomy
for the treatment of rectal strictures in Crohn’s disease. Laparoendosc Adv Surg Tech A
2010;20(9):791–795.
142. Scharl M, Frei P, Frei SM, et al. Epithelial-to-mesenchymal transition in a fistula-associated anal
adenocarcinoma in a patient with long-standing Crohn’s disease. Eur J Gastroenterol Hepatol
2014;26(1):114–118.
1315
booksmedicos.org
Chapter 51
Small Bowel Tumors

Steven G. Leeds and James W. Fleshman
Key Points
1 The main types of primary small bowel tumors include adenoma, adenocarcinoma, neuroendocrine
(carcinoid), lymphoma, and sarcoma (GIST). Surgical resection remains the treatment of choice for
all except lymphoma (only needed for symptomatic lesions causing obstruction or bleeding).
2 There is a rising incidence of small bowel tumors, directly caused by a relative increase in the
incidence of carcinoid tumors over adenocarcinoma of the small bowel. This trend is occurring
globally.
3 Research is now focused on the molecular cause of the discrepancy between the number of small
bowel and colorectal adenocarcinomas.
4 Size and location influence the symptoms caused by tumors within the small bowel. The majority of
tumors found incidentally are asymptomatic.
5 Capsule endoscopy (CE) is helpful for diagnosis but lack of spatial orientation, inability to biopsy,
and capsule retention causing obstruction limit its usefulness. Small bowel enteroscopy, device-
assisted enteroscopy (DAE), or deep enteroscopy (DE), are excellent alternative modalities.
6 Even though small neuroendocrine tumors (NETs) can metastasize, the risk of metastasis correlates
with the size of the primary tumor.
7 There are three common radiographic modalities used to diagnose small bowel tumors which include
CT scan, MRI and CT, or MR enterography. NETs also benefit from octreotide scanning as a
functional scan to detect metastasis.
8 Chromogranin A tends to be the most sensitive indicator of recurrence during surveillance of NET,
and sensitivity and specificity depends on the functionality of the tumor.
9 Gastrointestinal stromal tumors (GISTs) arise from pacemaker cells (Interstitial cells of Cajal) of the
small intestine and, based on mutations in the c-kit proto-oncogene region of the tyrosine kinase
gene, respond to imitanib (tyrosine kinase inhibitor) monoclonal antibody. Surgical resection
remains the only curative method of treatment.
10 Melanoma is the most common extraintestinal malignancy with predilection to metastasize to the
small bowel.
INTRODUCTION
1 The small bowel can give rise to both malignant and benign neoplasms. It comprises about 75% of the
entire length of the gastrointestinal tract and provides about 90% of its mucosal surface area, but
surprisingly these neoplasms represent less than 5% of the cancer affecting the entire gastrointestinal
tract.1 Even so, small bowel cancer causes significant morbidity and mortality because of its potential to
metastasize and to invade critical structures in the abdomen and retroperitoneum. The main types of
malignancy include adenocarcinoma, neuroendocrine (carcinoid), lymphoma, and sarcoma (GIST).
Several benign neoplasms such as lipomas, hamartomas, leiomyomas, and desmoid tumors are found in
the small intestines. Recent large database queries have demonstrated that the most common
malignancy is now carcinoid. Adenocarcinoma formerly was the most common, but the rising incidence
of carcinoid tumors has recently surpassed it.2,3 The relative inaccessibility of the small bowel
endoscopically presents several difficulties in diagnosis, results in a delay in diagnosis, and yields
advanced disease or metastatic disease at the time of treatment. There is some utility for upper
endoscopy (EGD), but the progress in Pillcam endoscopy and small bowel enteroscopy has improved the
ability to diagnose, and possibly treat, these neoplasms. Exploratory laparoscopy can also be utilized for
diagnosis and in the treatment of these tumors. Once diagnosed, management varies based on the type
1316
booksmedicos.org
of neoplasm. Metastatic tumors to the small bowel are rare, but direct invasion, and carcinomatosis
tends to be the common presentation for nonprimary tumors. Operative treatment with extended
resection is not possible with the small bowel like the extent of resection that can be performed in the
colon. Now, treatment modalities and multidisciplinary approaches may offer improved survival.
EPIDEMIOLOGY
2 The American Cancer Society estimates that 6,900 new cases of small bowel cancer will be seen in
2015 with an estimated 1,100 deaths.4 The incidences increased from the 2008 query estimating 6,110
new cases of small bowel cancer and about the same number of deaths, approximately 1,110.5 These
reports indicate a rising incidence of small bowel cancers, and are directly caused by the increasing
incidence of carcinoid tumors of the small bowel.2 This trend is occurring not only in the United States,
but across the world. A recent review of cancer incidence showed a rising incidence of small bowel
carcinoid tumors in England. The same rising incidence is demonstrated in the United States, along with
a change in the distribution of the carcinoid tumors along the length of the small bowel.3
In the population below the age of 40, the incidence of small bowel neoplasms is low. The incidence
for males and females is essentially the same. Sporadic, nonfamilial cancer occurs rarely in young
patients.
PATHOGENESIS
With respect to the entire gastrointestinal tract, small bowel cancers are relatively rare. This raises the
question as to why the region of the GI tract with the largest surface area has the lowest rate of cancer.
Several factors have been identified as potential explanations; (1) the small bowel has liquid contents
with an alkaline pH exposing the mucosa to a decrease in mechanical and chemical inflammation, (2)
transit through the small bowel is rapid, thus shortening the time carcinogens are in contact with the
mucosal surface, (3) there is a rapid turnover in epithelial cells in the mucosa outpacing the potential
growth and development of neoplastic cells, (4) there is lower luminal bacterial load, particularly of
anaerobes, which results in less total production of potential carcinogens, (5) the small bowel mucosa
has an apparent enhanced ability to metabolize and/or detoxify certain dietary components or
breakdown products that may be carcinogenic, and (6) the elaborate lymphoid tissue network
surrounding the small bowel, and in particular, its ability to secrete immunoglobulin A, which might
confer an increased immunologic-related tumor control.1
3 The discrepancy between the number of small bowel adenocarcinomas and colorectal
adenocarcinomas has pushed the research to a molecular level. There is substantial effort toward
identifying the pathways for the mutation resulting in these cancers. These pathways include K-ras, E-
cadherin, β-catenin, and p-53. The largest study of small bowel adenocarcinomas, n = 21, analyzed a
variety of genes known to be involved with tumor mutagenesis in nonhereditary and nonperiampullary
small bowel adenocarcinomas. The outcomes showed that all tumors presented with the hMLH1 and
hMSH2 (usually absent in mismatch repair defective inherited tumors) genes in the tumor nuclei. No
APC gene mutations were detected. One specimen had a replication error (RER). β-Catenin was
expressed in 17 specimens, 8 specimens had decreased or no expression of E-cadherin, and 5 specimens
had overexpression of p-53.6 This finding illustrates that the pathway to cancer that small bowel
adenocarcinoma follows is different from the colorectal pathway.
PREDISPOSITION TO SMALL BOWEL CANCER

There are several predisposing risk factors for development of small bowel cancers. These include
genetic and environmental factors.
Familial Adenomatous Polyposis

These patients have hundreds, and even thousands, of adenomas in their gastrointestinal tract, and have
a 100% transformation rate to colorectal cancer if untreated. Interestingly, the leading cause of death
for patients with familial adenomatous polyposis (FAP) is not the progression of colorectal cancer, due
to the fact that most of the patients undergo a total colectomy. It is actually the malignant
1317
booksmedicos.org
transformation of the periampullary adenoma to adenocarcinoma.1
Crohn Disease
Crohn disease is a significant risk factor to develop small bowel adenocarcinoma. The duration of
disease, distal jejunal or ileal disease, early age of diagnosis, fistulizing-type disease, and male gender
all contribute to a higher risk for development of small bowel adenocarcinoma.7 The relative risk was
reported as 33 (95% CI: 15.9 to 60.9).8 The areas particularly susceptible are where longstanding
inflammation has caused stricture formation. In these areas, the tumor tends to occur after at least 10
years of inflammation, and commonly contains signet-ring cell features similar to those found in colon
cancer due to ulcerative colitis.
Celiac Disease
There is an increased risk for small bowel lymphomas as well as small bowel adenocarcinoma with
those patients affected by celiac disease. Lymphomas tend to be both T-cell and non-Hodgkin
lymphomas.9
Peutz–Jeghers Syndrome
This is an autosomal dominant syndrome characterized by hamartomatous polyps in the gastrointestinal
tract and mucocutaneous melanin pigmentation. The increased risk of cancer is for breast, ovarian,
testicular, pancreas, stomach, esophagus, and others. The mutation has been identified on the
serine/threonine kinase 11 (STK 11) gene. Meta-analysis of Peutz–Jeghers syndrome indicated a relative
risk for small bowel cancer of 520 when compared to the general population.10
Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant gene that is associated
with the mutation of mismatch repair genes. There is an increased risk to develop small bowel cancer
with a relative risk of greater than 100 in carriers for the gene mutation.11
Other Familial Syndromes

Multiple endocrine neoplasia type 1 (MEN-1), von Hippal–Lindau syndrome, and neurofibromatosis type
1 all carry increased risk for developing neuroendocrine, or carcinoid tumors.9
Dietary and Lifestyle Predisposition

There are several indicators to the increased risk of developing small bowel cancer including cigarette
smoking, increased BMI/obesity, red meat consumption, and alcohol consumption.9
CLINICAL PRESENTATION
4 The majority of these tumors, whether benign or malignant, are typically asymptomatic and are
encountered incidentally. The biggest factor relating to the way small bowel tumors present is the size
and location within the small bowel. Generally, tumors less than 4 cm are asymptomatic. This is even
truer with benign lesions. The most common presenting symptoms are weight loss (30% to 50%),
nausea, vomiting, anemia, and abdominal pain.9 Late detection of asymptomatic malignant tumors
results in metastases in about 50% of patients at the time of diagnosis.12 Ulceration, perforation (in
cases of lymphoma), obstruction, or bleeding are the most common presenting symptoms.13
Intussusception or volvulus can occur rarely. NETs can present as functional syndromes, such as
“carcinoid syndrome” with flushing, diarrhea, and tachycardia with late valvular dysfunction due to
fibrotic scarring induced by serotonin (Table 51-1).
DIAGNOSIS
Examining the small bowel with accuracy is a difficult process. Upper and lower gastrointestinal
endoscopy provides little information because of the limited access to the vast amount of mucosal
surface. Colonoscopic intubation of the ileocecal valve is ideal but is not possible in about 5% to 10% of
the patients.14 Even with this intubation, only the most distal 25 cm of the terminal ileum can be
1318
booksmedicos.org
surveyed. During upper endoscopy (EGD) the duodenum is visualized in the proximal portion typically
leaving the distal duodenum and the rest of the small bowel unevaluated. In certain cases, and with
maximal effort, the endoscope can be advanced beyond the ligament of Treitz. However, the risk of
duodenal injury increases due to pressure in the curve of the duodenum. Nevertheless, both of these
procedures are indicated to begin the workup. The entire small bowel needs to be evaluated for a source
of the symptoms. Newer modalities have been developed to facilitate evaluation of the small bowel.
Table 51-1 Complications Resulting From Small Bowel Tumors
CAPSULE ENDOSCOPY
CE is an ingestible miniature camera that is capable of producing images throughout the small bowel to
depict its entire mucosal lining. CE was introduced first in 2000. CE is used most commonly to evaluate
the small bowel for a source of occult gastrointestinal bleed (OGIB).
Generally, CE is safe and widely used as a diagnostic test.15 The only contraindications to its use are
patients having swallowing disorders or bowel obstruction, with the possibility of capsule retention.
There is a 2% capsule retention rate in most series.16 Other limitations to CE are that it is time
consuming; there is no biopsy potential, and no therapeutic capability.
A large meta-analysis completed by Triester et al.17 demonstrated the incremental yield of CE over
enteroscopy and small bowel barium radiography to be 35% and 59%, respectively. Although not
statistically significant, the rate of identifying lesions was higher with CE. This is not surprising given
CE’s ability to evaluate more mucosal surface area than other modalities. Lewis et al. performed a meta-
analysis of CE compared to small bowel barium swallow, EGD, colonoscopy, and small bowel
enteroscopy. Detection rate for CE was 87% and missed lesion rate was 10%. The combination of the
other 4 modalities yielded a 13% detection rate and missed lesion rate of 73%. Both large meta-analyses
demonstrate the CE capability and superiority.18
There are several capsules in use around the world. For example, the Given M2A imaging CE (Given
Imaging; Yokneam, Israel) is a pill-shaped capsule measuring 11 mm × 26 mm. Within the capsule, the
contents consist of a light source, an imaging chip, a battery source, and a radio transmitter with an
internal antenna. Its visual field is 140 degrees and is magnified 8 times. This capsule travels through
most of the small bowel with peristalsis and is excreted in the feces. The camera is able to take two
images every second and transmits image to an external recording device. The capsule has a battery life
lasting between 6 and 8 hours. At the completion of the study there are 50,000 images. There is
software available to help the interpreter evaluate for a suspected bleeding source. There is no
consensus on preprocedural bowel preparation, but some advocate for bowel prep. Prokinetics may be
beneficial because there is a 20% incomplete small bowel transit.19
SMALL BOWEL ENTEROSCOPY

The difficulty to evaluate the small bowel is based on its location and length. The scope needed to
1319
booksmedicos.org
properly evaluate it is too long to have manual control of the tip. The bowel lies freely in the peritoneal
cavity with essentially no fixation. Navigation with an endoscope has been traditionally difficult for this
reason. Fixation points allow for proper evaluation of the foregut and colon in traditional endoscopy,
but this is not the case for small bowel. DE utilizes a fixation point provided by the scope and the small
bowel is brought to the viewing tip of the scope. Traditional endoscopy utilizes pushing the endoscope
through the gastrointestinal tract which is impossible without external intraoperative manipulation of
the bowel over the scope. Using this new method for evaluation has provided endoscopists with a steep
learning curve and added length of time to complete the evaluation.
5 The disadvantages of CE are difficulty with orientation, inability to biopsy, possible obstruction,
and capsule retention. Small bowel enteroscopy, DAE, or DE, are excellent alternative modalities.
DE allows the operator to obtain biopsies and to perform therapeutic interventions. There are three
methods for DE available today.
Double-Ballon Enteroscopy
This technique was developed in 2001 by Hironi Yamamoto,20 and introduced into Korea in 2004 where
it found its way to the United States. This endoscope consists of a balloon at the tip of an endoscope that
has a length of 140 cm. An overtube, also containing a balloon at the tip, fits over the scope to employ a
push-and-pull technique.21 This allows for examination of 240 to 360 cm. While the overtube balloon is
inflated, the scope is advanced with its balloon deflated. The inflated overtube balloon will allow for a
fixation point for the scope to maneuver through the small bowel. Once a significant advancement has
occurred, the endoscope balloon is inflated, and the overtube balloon deflated. The overtube then slides
along the endoscope to the end of the scope. The overtube balloon is reinflated to provide another
fixation point as the endoscope balloon is taken down and advanced once more. This outlines the push
technique as the endoscope is advanced with the overtube balloon inflated. The pull technique is when
both balloons are inflated and the endoscopist pulls back on both. This will reset the ability to start the
push technique again. This progression continues until the entire small bowel is evaluated.
The two most common enteroscope systems used have scope diameters of 8.5 mm and 9.3 mm with
working channels of 2.2 mm and 2.8 mm. The working channels allow for the therapeutic and
diagnostic options provided by these systems.
Double-balloon enteroscopy (DBE) is the most studied method to date and shows a diagnostic yield of
60% to 80% in patients with occult GI bleeding and other small bowel pathologies.22 However, it may
not be feasible in all patients and success rates vary from 16% to 86%.20,23 This variation is due to
differing patient populations across the world and the specific disease processes.
The main limitations to DBE are the invasive nature and prolonged duration of the procedure. The
complication rate overall is reported as 0.8% but can be higher while performing therapeutic procedures
such as electrocautery for a GI bleed, polypectomy, or dilation. The main complications are pancreatitis,
ileus, and perforation.24–26
Single-Balloon Enteroscopy
This system was developed in 2007 and is similar to DBE, but the distinguishing trait is that this system
lacks the endoscope balloon. There is still a balloon on the overtube used over the scope. Substituting in
the endoscope balloon’s place, the scope tip is hooked to hold the scope fixed to aid in the advancement
of the overtube. Overall, the concept is the same as to fix a portion of the small bowel to allow for
advancement of the endoscope.
The overtube is referred to as the splinting tube which has a hydrophilic coating that is activated with
application of 30 mL of water. Radiopaque material is present at the tip to aid in the advancement with
fluoroscopy.
Spiral Enteroscopy
Also in 2007, spiral enteroscopy (SE) was introduced which provides potential benefits with regard to
shorter procedure time. A raised spiral on the exterior of the scope pulls the small bowel over the scope
as it advances. This scope is 118 cm in length and has a diameter of 9.8 mm. The raised spiral grooves
are 16 mm high. Clockwise rotation of the scope will advance the scope and counterclockwise rotation
will withdraw the scope.
Studies for SE demonstrate shorter insertion depths with faster procedure times. There is variation in
the insertion depth varying from 176 cm to 262 cm.27,28 The complication rate is noted to be 0.3% with
1320
booksmedicos.org
a perforation rate of 0.27%.22 Overall, the device is simple to use with a learning curve of 5 cases.22,29
Exploratory Laparoscopy
The role of laparoscopy has improved the management of small bowel lesions over the last decades.30,31
The advantages of DAE and imaging have been discussed at length, but the role for laparoscopic
assessment of the peritoneal cavity for small bowel tumors plays a significant role in both diagnosis and
treatment. Furthermore, the improvements in laparoscopy and surgeons abilities with a laparoscope
have enabled minimally invasive management of small bowel tumors. Johnson et al.32 evaluated all
small bowel obstructions in a single institution requiring surgery. Successful completion of a
laparoscopic approach was possible in 32% of patients (conversion to an open procedure was necessary
in 40% of patients, with 20% of the conversions secondary to tumor. Small bowel was resected in 8% of
the laparoscopic cases, 64% of the converted cases, and 41% of the case done completely open. Length
of stay of patients with a purely laparoscopic approach was 7.7 days versus 11 days in the converted
cases and 11.4 in the purely open cases.
There are distinct advantages to laparoscopy when the ability of the surgeon allows this approach.
Direct visualization of the small bowel on the extraluminal side adds significant value to the
management of small bowel tumors. Complete evaluation of the small bowel can be obtained
laparoscopically by examining the entire small bowel in a systematic approach in order to visualize all
aspects of the small bowel including the mesentery. In conjunction with endoluminal approaches, like
small bowel enteroscopy, lesions can be located, biopsied, and if needed, resected.
The laparoscopic approach is limited by the extent of the disease process being investigated. Local
spread of small bowel tumors will likely affect directly adjacent small bowel or other nearby organs.
This invasion can make it impractical to proceed laparoscopically if one is to provide the patient with
the best outcome. Also, most common tumors of the small bowel affect the mucosal surface only and
extraluminal visual examination may be inadequate to identify the lesion. Exceptions to this would be
utilizing small bowel enteroscopy to tattoo the lesion which can be easily seen from the extraluminal
side. This would also facilitate a sound oncologic resection of the tumor. Hand-assisted laparoscopy is
also helpful if palpation is essential and a small incision is desired.
A laparoscopic case should be converted to an open technique if conditions prevent oncologically
sound technique in order to provide the patient with the best outcome.
MANAGEMENT
Benign
Adenomas are benign lesions that have malignant potential. This tends to follow the malignant
degeneration seen in polyps of the large bowel, described in 1990,33 and most commonly seen with
periampullary tumors.34 Interestingly, the distribution of adenomas tends to follow the small bowel’s
exposure to bile, making the most common location immediately distal to the papilla in the second
portion of the duodenum and progressively decreases in the more distal intestine.35
Hamartomas are benign vascular tumors with a low malignant potential and usually associated with
Peutz–Jeghers syndrome.13 Lipomas are encountered as a single mass or as multiple and are usually
encountered incidentally. Hemangiomas are rare benign tumors in the small bowel that present as GI
bleeding.
The only reason for operative management of a benign small bowel lesion is to control symptoms.
Mass effect causing intussusception or obstruction, hemorrhage, or a questioned presence of malignancy
generates the need for local resection of the lesion. The diagnostic dilemma is the most common reason
for resection of an incidentally found mass on contrast study or endoscopy. Hemangiomatous lesions can
be resected or managed with angiographic embolization. The use of angiographic isolation and
intraoperative angiographic methylene blue injection can be very helpful to guide resection of a
bleeding field of small bowel angiomas.
Malignant
Discovery of small tumors is rare. Within the group of malignant tumors found in the small bowel, there
are four main types. The most recent data from a single-institution tumor registry show that carcinoid
tumors of the small bowel have surpassed the incidence for adenocarcinomas of the small bowel.1 A
total of 1,260 tumors were examined and their distribution throughout the small bowel was discussed.
1321
booksmedicos.org
Carcinoid tumors (33%), adenocarcinomas (30%), lymphoma (16%), GIST (7%), and other cell types
found (13%). The authors separated the different tumor types based on location within the small bowel,
which changed the order of the most common tumors seen in each portion.
Neuroendocrine Tumors
NETs of the small bowel have increased in incidence significantly over the last 40 years, and mirror the
overall increase in gastrointestinal NETs throughout the entire gastrointestinal tract. This is reflected in
the recent SEER data ranking gastrointestinal NETs second, only behind colorectal cancer, as the most
common cancer of the GI tract.36 This has also been shown in Sweden37 and in England.3 NETs arise
from a diffuse neuroendocrine system made up of secretory cells, called enterochromaffin cells, causing
the propensity for these tumors to produce vasoactive substances. NETs, formerly known as carcinoid
tumors, can be almost benign or very aggressive. Carcinoid syndrome was characterized in 1954 by
Thorson et al. who associated the presence of the metastatic carcinoid tumor with the presence of some
abnormal symptoms.38 They related the increased production of serotonin causing systemic effects such
as diarrhea, flushing, bronchospasm, cutaneous vasomotor symptoms, and cardiovascular dysfunction.
Serotonin was actually extracted 1 year earlier from carcinoid tumors and labeled as the active
ingredient in the symptoms.39,40 Serotonin is derived from its precursor tryptophan, and when in
circulation, it elicits particular symptoms. The liver will inactivate serotonin to make 5-
hydroxyindoleacetic acid (5-HIAA) which is excreted by the kidney.41
Table 51-2 Pathologic Classification of Neuroendocrine Tumors
The presentation of NETs comes from two basic components of the tumor. First, the tumor sizes can
elicit effects such as obstructive symptoms or abdominal pain. Second, the hormonal secretion of the
tumors can lead to symptoms, such as carcinoid syndrome. About 50% of NETs present in the ileum1
and the majority of those are in the distal 60 cm of the ileum.41 Most commonly these tumors
metastasize to the liver, mesentery, and peritoneum.42 The intraluminal effects of these tumors usually
leads to the obstructive symptoms and the desmoplastic reaction of the small bowel mesentery produces
the abdominal pain associated with the tumor burden.
6 Metastasis of small bowel NETs is related to primary tumor size. A literature review of 185 patients
with small bowel NET showed an 85% nodal metastasis and 47% distant metastasis with tumors greater
than 2 cm. With tumors between 1 and 1.9 cm, 70% had nodal metastasis and 19% had distant
metastasis. With tumors less than 1 cm, there was 12% nodal metastasis and 5% distant metastasis.43
Even though small NETs can metastasize, the risk of metastases does correlate with size of the primary
tumor. This is influenced by the early invasion of bowel wall lymphatics and blockage of the lymphatics
in the mesentery, forcing cells to flow retrograde into lymphatics along the bowel.
The mitotic rate and Ki-67 index are measured in order to provide the histologic grade of these
tumors, which correlates closely with clinical behavior. These measurements categorize the tumors into
one of three categories by grade; low, intermediate, and high. The 5-year survival rates are 79%, 74%,
and 40%, respectively. Low and intermediate grade typically fall into the well-differentiated category
and high grade is considered poorly differentiated (Table 51-2). Resection to maximally debulk the
tumor, or maximize cytoreduction, is the only chance for cure in NETs.
A formal TNM staging classification has recently been instituted. This stratifies tumors into localized,
locally advanced, and metastatic categories with associated 5-year survivals of 95%, 84%, and 51%,
respectively (Table 51-3). Shortly after, in 2007, the American Joint Committee on Cancer adopted a
TNM staging system proposed by the European Neuroendocrine Tumor Society (ENETS) specifically for
tumors of the lower jejunum and ileum. This factored out the poorer prognosis of the tumors in other
parts of the body such as the colon, rectum, and appendix44 (Tables 51-4 and 51-5). Five-year survival
1322
booksmedicos.org
rates were much different showing 100% for stage I and stage II cancers, 91% for stage III cancers, and
72% for stage IV cancers. Survival rates were slightly improved with presentation of another 270 NETs
by Jann et al.45
7 Generally, diagnosis is made based on radiographic findings in conjunction with tumor markers.
There are three common radiographic modalities used to diagnose these tumors, which include CT scan
and MRI enterography and octreotide scanning.
Abdominal CT can help locate the primary tumor, but three-phase CT should be used for optimal
evaluation of liver metastasis. The clinician should be mindful of the affinity of NETs to metastasize to
the liver, especially in the setting of physical findings consistent with neuroendocrine peptide secretion.
The arterial phase and the portal venous phase are typically the phases that maximize the ability to
locate the metastatic lesions because NETs are typically rich in vascularity.46 For the same reason, MRI
can also be used to locate and evaluate metastatic lesions to the liver.
Table 51-3 5-Year Survival Rates by Carcinoid Location (1973–1997)a
Table 51-4 Proposal for a TNM Classification for Endocrine Tumors of Lower
Jejunum and Ileum
NETs often express somatostatin receptors rendering them detectable by imaging with radiolabeled
forms of somatostatin called octreotide.47 This was discovered during the refinement of the octreoscan,
or SRS (somatostatin receptor scintigraphy). Five subtypes of somatostatin receptors have been
identified and the somatostatin analogs from the octreotide scan bind with subtypes 2 and 5 which are
present in 70% to 90% of NETs.48 With the progression of diagnostic ability came the use of single-
photon emission computed tomography (SPECT) to enhance the accuracy of differentiating areas of
pathologic and physiologic uptake in the abdomen. This is a full-body scan that enables visualization of
somatostatin uptake throughout the entire body.
Further use of radiolabeled markers has brought about advances in positron emission tomography
with use of functional radiotracers for imaging. The advantages to this platform are the higher spatial
resolution than the octreotide scanning. This also offers advantages for detecting smaller lesions than
other scanning methods. Octreotide, MBIG, and PIET scanning are used for follow-up of patients and
staging of patients for distant disease when planning aggressive, multiorgan resections.
1323
booksmedicos.org
Making the diagnosis of small bowel NET is often late in its course and the chances of metastatic
lesions being present are high because of this. However, surgical management is still an option for
patients in cases of localized tumor burden and distant metastasis. Survival outcomes are better for
those patients with stage I and stage II diseases, as previously discussed, and surgical excision of the
primary tumor and local node metastasis is still the only curative therapy for these patients.49 The
primary focus in any instance with the presence of NET is to control the functional disorder associated
with the tumor present, such as carcinoid syndrome. Several options are applicable to the tumor itself
once any functional disorder is controlled and treated. These include close surveillance of indolent
tumors, radiofrequency ablation (RFA) therapy for liver metastases, systemic therapy with somatostatin
analogs or interferon, or cytotoxic or molecular targeted therapies. These are all options that can be
used and have never been compared in a controlled comparison, making these therapies highly
individualized.
Table 51-5 Disease Staging for Endocrine Tumors of Lower Jejunum and Ileum
8 Chromogranins are glycoproteins that are stored in secretory vesicles within neuroendocrine
tissue.41 There are three distinct types named chromogranin A, B, and C. Chromogranin A tends to be
the most sensitive indicator of a NET with varied sensitivity and specificity. For instance, false positives
are noted in patients with atrophic gastritis, renal insufficiency, inflammatory bowel disease, and
patients taking proton pump inhibitors.50,51 Since chromogranin A has a low specificity, it is not used as
a screening tumor marker for NETs, but can be used in those patients with an established diagnosis to
assess disease progression and response to therapy in surgical resection.41
Surgical management with resection and the use of RFA still provides the best survival benefit for all
patients with localized and advanced NET.52,53 However, if needed, debulking procedures have been
shown to be effective in improving symptoms52 with greater than 90% resection. Planning for a two-
step approach for radical resection to achieve complete resection has been shown to be effective.54 With
high tumor grades, recurrence rates can be as high as 81%.55 Transarterial chemoembolization (TACE)
has been shown to be highly effective against nonresectable diffuse liver lesions to reduce symptoms.53
Medical management of NET includes a wide variety of agents including somatostatin analogs
(octreotide) and peptide receptor radionucleotide therapy (PRRT), chemotherapeutic agents
(doxorubicin–streptozotocin, dacarbazine, temozolomide, oxaliplatine, or interferon), monoclonal
antibody therapy (bevacizumab), mTOR inhibitors (temsirolimus and everolimus), and multikinase
inhibitors (sunitinuib, sorafenib, and pazopanib).
A combination of both medical and surgical management is outlined in Algorithm 51-1.
Since carcinoid can develop in all areas of the intestine, surveillance with endoscopy is important.
Scanning with CT/MRI of the liver can guide reexploration and resection. Octreotide scanning, MBIG,
or PET scanning can be helpful in controversial cases of possible metastases.
Small Bowel Adenocarcinoma

Small bowel adenocarcinomas represent the second-most common cancer of the small bowel with an
incidence of 7.3 cases per million worldwide.2,56,57 Small bowel adenocarcinoma, along with colorectal
cancer, is more common in developed countries, and has higher incidence rates in North America and
Western Europe.58 Adenocarcinoma can be found throughout the entire small bowel, 56% is found in
the duodenum.2 Goodman et al. performed an examination of 26 population-based cancer registries to
find that the overall age-adjusted incidence rates for small bowel adenocarcinoma favored men over
women (7.7 to 5.1), and both men and women exhibited the same trend with regard to race. Black
populations had an age-adjusted incidence rate of about twice the rate of white individuals, and the
Hispanic population followed. The lowest incidence is in the Asian/Pacific Islander population.59
1324
booksmedicos.org
Algorithm 51-1. Management algorithm for patients with advanced neuroendocrine tumors (NETs) of the gastrointestinal tract.
mTOR, mammalian target of rapamycin; PPI, proton pump inhibitor; RFA, radiofrequency ablation; TAE, transarterial
embolization. (Walter T, Brixi-Benmansour H, Lombard-Bohas C, et al. New treatment strategies in advanced neuroendocrine
tumours. Dig Liver Dis 2012;44(2):95–105.)
Presentation for small bowel adenocarcinoma is very nonspecific with the most common symptom on
presentation being abdominal pain (45% to 76%).57 Other common symptoms include nausea and
vomiting, weight loss, fatigue and anemia, and GI bleeding.60,61 Interestingly, with the indolent
presentation of these cancers, patients can recall symptoms for long periods of time prior to diagnosis.
Talamonti et al.61 were able to identify a mean duration of symptoms at presentation at 10 months.
Simple laboratory testing can identify abnormalities that can indicate bleeding, and there are no
specific tumor markers associated with a diagnosis of small bowel adenocarcinoma. Carcinoembryonic
antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) are elevated in only about 30% to 40% of
patients.62 Radiologic and endoscopic modalities provide the best method for detecting small bowel
adenocarcinoma. Unfortunately, these modalities can fail to make a diagnosis given the nonspecific
nature of the presenting symptoms.
Evaluation of the small bowel in order to make a diagnosis of small bowel adenocarcinoma can
include upper GI swallow study with small bowel follow-through or enteroclysis. The major
disadvantage to these modalities is the inability to assess extraluminal spread given the often late
presentation. The use of CT and MR with enterography has drastically improved the ability to detect
these cancers. The sensitivity rate for detecting small bowel tumors was 84.7% and a specificity of
96.9% when using CT enterography.63 Using MR enterography (MRE) for detecting small bowel tumors
has a sensitivity of 91% and a specificity of 95%.64
Endoscopic evaluation has been discussed elsewhere in this chapter, but EDG plays an important role
in detecting small bowel adenocarcinomas because of the high rate of incidence in the duodenum.
The prognosis of small bowel adenocarcinoma varies. Prognosis is directly related to the tumor
staging as it is the single most important prognostic indicator.60 There are several factors that are
related to the poor prognosis aside from advanced staging, including poor differentiation, positive
margins after resection, duodenal location, male gender, elderly age, and black ethnicity.57 Optimal
diagnostic lymph node harvest at the time of surgery has been identified as requiring either 8 or 10 or
more nodes for accurate assessment.65,66 Patients can be staged (Table 51-6) and their disease-specific
survival rates can be assessed based on the tumor site (Fig. 51-1) and change based on the number of
1325
booksmedicos.org
lymph nodes examined (Fig. 51-2) and the number of positive lymph nodes (Fig. 51-3).
Table 51-6 Disease-Specific Survival According to Disease Stage, Total Number

of Lymph Nodes Assessed, and Total Number of Positive Lymph
Nodes
Surgical management is the mainstay of therapy for small bowel adenocarcinoma with locoregional
disease.57 It has been known for almost 2 decades that resection of duodenal adenocarcinomas yields a
56% survival at 5 years with complete surgical resection and 0% survival at 5 years without resection.67
Duodenal adenocarcinomas can be managed with pancreaticoduodenectomy or with segmental resection
for the distal third and fourth portions for resectable tumors. Nodal involvement should prompt
adjuvant therapy, but otherwise observation is sufficient (Algorithm 51-2). Jejunal and ileal
adenocarcinomas should be managed with similar principles of segmental resection and regional lymph
node dissection, with a right hemicolectomy for tumors involving the distal ileum.57
Medical management of small bowel adenocarcinoma consists of adjuvant therapy which is aimed
toward controlling recurrence of adenocarcinoma at distant sites. Distant recurrence predominates over
the high locoregional recurrence for duodenal adenocarcinomas.57 Poultsides et al. recently showed in a
series of 122 patients who had a pancreaticoduodenectomy for duodenal adenocarcinoma, the first site
of recurrence was distant 59% of the time, locoregional 19% of the time, and both in 22% of the
cases.68 Adjuvant therapies involve 5-flourouracil/capecitabine, FOLFOX/CAPOX, FOLFIRI, or
gemcitabine.
Lymphoma
There is an abundant amount of lymphoid tissue in the small bowel, especially in the terminal ileum.
Lymphomas account for about 15% to 20% of small intestine neoplasms.12 This mirrors the malignant
transformation distribution patterns throughout the small intestine with regard to lymphoma. SEER
database analysis from 1975 to 2003 shows a distribution of 60% to 65% in the ileum, followed by 20%
to 25% in the jejunum, and 6% to 8% in the duodenum.69 However, secondary lymphoma is much more
common than primary lymphoma because the gastrointestinal tract is the most common site for
extranodal disease.13
1326
booksmedicos.org
Figure 51-1. These Kaplan–Meier curves illustrate disease-specific survival stratified by (A) disease stage, (B) subsite in the small
bowel for stage I and II diseases, and (C) subsite in the small bowel for stage III disease. Codes for the duodenum (C17.0),
jejunum, (C17.1), and ileum (C17.2) are from the International Classification of Diseases for Oncology and Related Health
Problems 10th Revision. (Overman MJ, Hu CY, Wolff RA, et al. Prognostic value of lymph node evaluation in small bowel
adenocarcinoma: Analysis of the surveillance, epidemiology, and end results database. Cancer 2010;116(23):5374–5382.)
The typical clinical presentation of small bowel lymphoma is nausea, vomiting, abdominal pain, and
weight loss. Severe symptoms, such as obstruction, intussusceptions, or perforation are rare.12
1327
booksmedicos.org
Figure 51-2. These Kaplan–Meier curves illustrate disease-specific survival stratified by (A) the total number of lymph nodes
assessed (TLN) in patients with stage I and II diseases and (B) the TLNs assessed in patients with stage III disease. (Overman MJ,
Hu CY, Wolff RA, et al. Prognostic value of lymph node evaluation in small bowel adenocarcinoma: Analysis of the surveillance,
epidemiology, and end results database. Cancer 2010;116(23):5374–5382.)
Several types of lymphoma can occur in the small bowel. However, the most commonly encountered
lymphoma is diffuse large B-cell lymphoma. Despite the incidence of lymphoma in the small intestine,
surgery is typically not the method for management. These patients should undergo resection in
situations of obstruction or bleeding, and should still receive chemotherapy.12 Immunoproliferative
small intestinal disease occurs in patients who are chronically immunosuppressed as a result of infection
by Helicobacter pylori and Campylobacter jejuni. Antibiotic therapy for these bacteria usually results in
regression of immunoproliferative small intestinal disease. Most of these patients relapse and will need
radiation and chemotherapy with nutritional support.70,71
Gastrointestinal Stromal Tumor

9 GISTs are the most mesenchymal tumors of the small bowel. GISTs are found in the stomach (60% to
70%), small intestine (20% to 30%), and in the duodenum (4% to 5%).72 GISTs are known to arise from
the interstitial cells of Cajal, which are described as the gastrointestinal pacemakers.73 Coincidentally,
that same year GISTs were termed gastrointestinal pacemaker cell tumors, Hirota et al.74 recognized the
c-kit proto-oncogene which codes for a tyrosine kinase inhibitor, as the genetic mutation leading to
GISTs. As a result, there has been a dramatic shift in the way GISTs are managed.
1328
booksmedicos.org
Figure 51-3. These Kaplan–Meier curves illustrate disease-specific survival stratified by (A) the number of positive lymph nodes
(PLN) and (B) the lymph node ratio (LNR) in tertiles. (Overman MJ, Hu CY, Wolff RA, et al. Prognostic value of lymph node
evaluation in small bowel adenocarcinoma: Analysis of the surveillance, epidemiology, and end results database. Cancer
2010;116(23):5374–5382.)
The diagnosis of small bowel GISTs is similar to that of other small bowel tumors; however, the GIST
is unique with regard to the submucosal origin and its likelihood to grow in size away from the lumen
of the small bowel. This also makes it difficult to make a diagnosis with intraluminal biopsy. A study by
Bümming et al. in 2006 demonstrated that only one-third of diagnoses are made with biopsies, and that
the most common method of detection was endoscopy and CT scan.75 Most commonly, patients with
GISTs present with vague abdominal symptoms, pain, GI bleeding from a mucosal erosion, or an
abdominal mass.76
GISTs do not have the malignant pattern predicted in other types of cancers based on histopathology
alone. Several factors influence malignant behavior including tumor size, mitotic rate, tumor location,
kinase mutational status, and occurrence of tumor rupture. Mitotic rate and tumor size are the most
commonly acceptable indices for prognosis.72
Tumor size and location dictate the type of treatment. Complete surgical resection remains the only
method for curative treatment, and simple negative margins are needed, as wide margins have not
shown significant benefit.72 Small segmental resection of the small bowel is adequate because GISTs
rarely metastasize to lymph nodes. Lymph node dissection is not warranted. En bloc resection should be
done for locally advanced GISTs.72 Overall 5-year survival rate for patients with complete resection of
GISTs is 50% to 65%.72,76–78
1329
booksmedicos.org
Algorithm 51-2. Algorithm showing the management of patients with small bowel adenocarcinomas. The treatment strategy
depends on disease stage and involves en bloc resection for locoregional disease and systemic chemotherapy for metastatic disease.
All current recommendations are based on case series, retrospective reviews or nonrandomized prospective trials because of an
absence of any randomized data. 5-FU, 5-fluorouracil; CAPOX, capecitabine and oxaliplatin; FOLFIRI, 5-FU, leucovorin and
irinotecan; FOLFOX, 5-FU, leucovorin and oxaliplatin; KRAS-WT, KRAS wild-type; PS, performance status; XRT, radiation therapy.
(Elias D, Lefevre JH, Duvillard P, et al. Hepatic metastases from neuroendocrine tumors with a “thin slice” pathological
examination: they are many more than you think. Ann Surg 2010;251(2):307–310.)
Patients have a defined risk for recurrence and may benefit from adjuvant therapy. The Modified
NIH–Fletcher GIST Risk Assessment Criteria is presented in Table 51-7. Other risk assessment tools are
available such as Armed Forces Institute of Pathology Classification and the Memorial Sloan-Kettering
Cancer Center Prognostic Nomogram. Adjuvant therapy utilizes imatinib (Gleevec). This drug is used in
the treatment algorithms for patients with advanced or metastatic GIST or with resectable GIST.
Algorithm 51-3A shows these algorithms. Imatinib is a competitive inhibitor for multiple tyrosine kinase
inhibitors and was originally recommended for chronic myelogenous leukemia treatment. It became
first-line treatment for GIST once it was recognized to disrupt the KIT oncogene in GISTs.79 Shortly after
that, imatinib was approved for use in unresectable or metastatic disease shown in Algorithm 51-3B.80,81
A randomized prospective study was done in 2009 to evaluate imatinib for the use in adjuvant therapy,
showing significant improvement in 5-year recurrence-free survival, 98% versus 83%, respectively, in
the treatment group over placebo.82 The NCCN guidelines in the management of GISTs provide a
standard algorithm.83
Table 51-7 Modified NIH–Fletcher GIST Risk Assessment Criteria
1330
booksmedicos.org
Algorithm 51-3. Treatment algorithms for patients with (A) advanced/metastatic GIST and (B) resectable GIST. GIST indicates
gastrointestinal stromal tumor. (Mullady DK, Tan BR. A multidisciplinary approach to the diagnosis and treatment of
gastrointestinal stromal tumor. J Clin Gastroenterol 2013;47(7):578–585.)
METASTATIC TUMORS TO THE SMALL BOWEL

10 Metastasis to the small bowel occurs in two different ways, either from distant spread or direct
invasion from a nearby organ malignancy. The most common are from breast cancer and melanoma.
Melanoma is the most common extraintestinal malignancy with predilection to metastasize to the small
bowel (Fig. 51-4).84 Patients with metastatic melanoma to the small bowel often present with other
extraintestinal metastasis.85 Primary tumors of intraperitoneal organs such as colon, ovary, uterus, and
stomach metastasize to the small bowel.84
Figure 51-4. Metastatic melanoma to small bowel resecting en bloc.
Patients with small bowel metastasis are usually offered palliative systemic chemotherapy. Other
palliative measures can be considered on a case-by-case basis including surgical resection, internal
bypass, or usage of an endoscopically placed stent.9
References
1. Hatzaras I, Palesty JA, Abir F, et al. Small-bowel tumors: epidemiologic and clinical characteristics
1331
booksmedicos.org
of 1260 cases from the connecticut tumor registry. Arch Surg 2007;142(3):229–235.
2. Bilimoria KY, Bentrem DJ, Wayne JD, et al. Small bowel cancer in the United States: changes in
epidemiology, treatment, and survival over the last 20 years. Ann Surg 2009;249(1):63–71.
3. Ellis L, Shale MJ, Coleman MP. Carcinoid tumors of the gastrointestinal tract: trends in incidence in
England since 1971. Am J Gastroenterol 2010; 105(12):2563–2569.
4. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60(5):277–300.
5. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008; 58(2):71–96.
6. Wheeler JM, Warren BF, Mortensen NJ, et al. An insight into the genetic pathway of
adenocarcinoma of the small intestine. Gut 2002;50(2):218–223.
7. Feldstein RC, Sood S, Katz S. Small bowel adenocarcinoma in Crohn’s disease. Inflamm Bowel Dis
2008;14(8):1154–1157.
8. Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in
patients with Crohn’s disease. Aliment Pharmacol Ther 2006;23(8):1097–1104.
9. Reynolds I, Healy P, McNamara DA. Malignant tumours of the small intestine. Surgeon 2014;12(5),
263–270.
10. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz–
Jeghers syndrome. Gastroenterology 2000;119(6):1447–1453.
11. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with hereditary nonpolyposis
colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110(4):1020–1027.
12. Cheung DY, Choi MG. Current advance in small bowel tumors. Clin Endosc 2011;44(1):13–21.
13. Williamson JM, Williamson RC. Small bowel tumors: pathology and management. J Med Assoc Thai
2014;97(1):126–137.
14. Lieberman DA, Faigel DO, Logan JR, et al. Assessment of the quality of colonoscopy reports: results
from a multicenter consortium. Gastrointest Endosc 2009;69(3 Pt 2):645–653.
15. Hale MF, Sidhu R, McAlindon ME. Capsule endoscopy: current practice and future directions. World
J Gastroenterol 2014;20(24):7752–7759.
16. Liao Z, Gao R, Xu C, et al. Indications and detection, completion, and retention rates of small-bowel
capsule endoscopy: a systematic review. Gastrointest Endosc 2010;71(2):280–286.
17. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of the yield of capsule endoscopy
compared to other diagnostic modalities in patients with obscure gastrointestinal bleeding. Am J
Gastroenterol 2005;100(11):2407–2418.
18. Lewis BS, Eisen GM, Friedman S. A pooled analysis to evaluate results of capsule endoscopy trials.
Endoscopy 2005;37(10):960–965.
19. Sachdev MS, Ismail MK. Capsule endoscopy: a review. South Med J 2008; 101(4):407–414.
20. Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a nonsurgical steerable double-balloon
method. Gastrointestinal Endoscopy 2001;53(2):216–220.
21. Monkemuller K, Fry LC, Bellutti M, et al. Balloon-assisted enteroscopy: unifying double-balloon and
single-balloon enteroscopy. Endoscopy 2008;40(6):537; author reply 539.
22. Riccioni ME, Bizzotto A, Cianci R. How can we compare apples and oranges? Am J Gastroenterol
2010;105(11):2504; author reply 2504–2505.
23. Ell C, May A. Mid-gastrointestinal bleeding: capsule endoscopy and push-and-pull enteroscopy give
rise to a new medical term. Endoscopy 2006;38(1):73–75.
24. Heine GD, Hadithi M, Groenen MJ, et al. Double-balloon enteroscopy: indications, diagnostic yield,
and complications in a series of 275 patients with suspected small-bowel disease. Endoscopy
2006;38(1):42–48.
25. May A, Nachbar L, Ell C. Double-balloon enteroscopy (push-and-pull enteroscopy) of the small
bowel: feasibility and diagnostic and therapeutic yield in patients with suspected small bowel
disease. Gastrointest Endosc 2005;62(1):62–70.
26. Mensink PB, Haringsma J, Kucharzik T, et al. Complications of double balloon enteroscopy: a
multicenter survey. Endoscopy 2007;39(7):613–615.
27. Akerman PA, Agrawal D, Chen W, et al. Spiral enteroscopy: a novel method of enteroscopy by
using the endo-ease discovery SB overtube and a pediatric colonoscope. Gastrointest Endosc
2009;69(2):327–332.
1332
booksmedicos.org
28. Buscaglia JM, Dunbar KB, Okolo PI 3rd, et al. The spiral enteroscopy training initiative: results of a
prospective study evaluating the discovery SB overtube device during small bowel enteroscopy
(with video). Endoscopy 2009;41(3):194–199.
29. Nagula S, Gaidos J, Draganov PV, et al. Retrograde spiral enteroscopy: feasibility, success, and
safety in a series of 22 patients. Gastrointest Endosc 2011; 74(3):699–702.
30. Cunningham JD, Vine AJ, Karch L, et al. The role of laparoscopy in the management of
intussusception in the Peutz–Jeghers syndrome: case report and review of the literature. Surg
Laparosc Endosc 1998;8(1):17–20.
31. Canin-Endres J, Vine AJ, Karch L, et al. Laparoscopically assisted intestinal resection in 88 patients
with Crohn’s disease. Surg Endosc 1999;13(6):595–599.
32. Johnson KN, Chapital AB, Harold KL, et al. Laparoscopic management of acute small bowel
obstruction: evaluating the need for resection. J Trauma Acute Care Surg 2012;72(1):25–30;
discussion 30–1; quiz 317.
33. Sellner F. Investigations on the significance of the adenoma-carcinoma sequence in the small bowel.
Cancer 1990;66(4):702–715.
34. Scott-Coombes DM, Williamson RC. Surgical treatment of primary duodenal carcinoma: a personal
series. Br J Surg 1994;81(10):1472–1474.
35. Chow JS, Chen CC, Ahsan H, et al. A population-based study of the incidence of malignant small
bowel tumours: SEER, 1973–1990. Int J Epidemiol 1996;25(4):722–728.
36. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and
prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol
2008;26(18):3063–3072.
37. Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide
epidemiologic study from Sweden. Cancer 2001;92(8):2204–2210.
38. Thorson A, Biorck G, Bjorkman G, et al. Malignant carcinoid of the small intestine with metastases
to the liver, valvular disease of the right side of the heart (pulmonary stenosis and tricuspid
regurgitation without septal defects), peripheral vasomotor symptoms, bronchoconstriction, and an
unusual type of cyanosis; a clinical and pathologic syndrome. Am Heart J 1954;47(5):795–817.
39. Lembeck, F. [Detection of 5-hydroxytryptamine in carcinoid metastases]. Naunyn Schmiedebergs
Arch Exp Pathol Pharmakol 1954;221(1):50–66.
40. Erspamer V, Asero B. Identification of enteramine, the specific hormone of the enterochromaffin
cell system, as 5-hydroxytryptamine. Nature 1952; 169(4306):800–801.
41. Strosberg J. Neuroendocrine tumours of the small intestine. Best Pract Res Clin Gastroenterol
2012;26(6):755–773.
42. Strosberg J, Gardner N, Kvols L. Survival and prognostic factor analysis of 146 metastatic
neuroendocrine tumors of the mid-gut. Neuroendocrinology 2009;89(4):471–476.
43. Rorstad O, Klöppel G, Couvelard A, et al. Prognostic indicators for carcinoid neuroendocrine
tumors of the gastrointestinal tract. J Surg Oncol 2005; 89(3):151–160.
44. Rindi G, Klöppel G, Couvelard A, et al. TNM staging of midgut and hindgut (neuro) endocrine
tumors: a consensus proposal including a grading system. Virchows Arch 2007;451(4):757–762.
45. Jann H, Roll S, Couvelard A, et al. Neuroendocrine tumors of midgut and hindgut origin: tumor-
node-metastasis classification determines clinical outcome. Cancer 2011;117(15):3332–3341.
46. Paulson EK, McDermott VG, Keogan MT, et al. Carcinoid metastases to the liver: role of triple-
phase helical CT. Radiology 1998;206(1):143–150.
47. Krenning EP, Bakker WH, Kooij PP, et al. Somatostatin receptor scintigraphy with indium-111-
DTPA-D-Phe-1-octreotide in man: metabolism, dosimetry and comparison with iodine-123-Tyr-3-
octreotide. J Nucl Med 1992;33(5):652–628.
48. Oberg K, Eriksson B. Nuclear medicine in the detection, staging and treatment of gastrointestinal
carcinoid tumours. Best Pract Res Clin Endocrinol Metab 2005;19(2):265–276.
49. Walter T, Brixi-Benmansour H, Lombard-Bohas C, et al. New treatment strategies in advanced
neuroendocrine tumours. Dig Liver Dis 2012;44(2):95–105.
50. Conlon JM. Granin-derived peptides as diagnostic and prognostic markers for endocrine tumors.
Regul Pept 2010;165(1):5–11.
51. Sanduleanu S, De Bruïne A, Stridsberg M, et al. Serum chromogranin A as a screening test for
1333
booksmedicos.org
gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur J Clin Invest
2001;31(9):802–811.
52. Gurusamy KS, Pamecha V, Sharma D, et al. Palliative cytoreductive surgery versus other palliative
treatments in patients with unresectable liver metastases from gastro-entero-pancreatic
neuroendocrine tumours. Cochrane Database Syst Rev 2009;(1):Cd007118.
53. Oberg K., Ferone D, Kaltsas G, et al. ENETS Consensus Guidelines for the Standards of Care in
Neuroendocrine Tumors: biotherapy. Neuroendocrinology 2009;90(2):209–213.
54. Kianmanesh R, Sauvanet A, Hentic O, et al. Two-step surgery for synchronous bilobar liver
metastases from digestive endocrine tumors: a safe approach for radical resection. Ann Surg
2008;247(4):659–665.
55. Elias D, Lefevre JH, Duvillard P, et al. Hepatic metastases from neuroendocrine tumors with a “thin
slice” pathological examination: they are many more than you think. Ann Surg 2010;251(2):307–
310.
56. Lu Y, Frobom R, Lagergren J. Incidence patterns of small bowel cancer in a population-based study
in Sweden: increase in duodenal adenocarcinoma. Cancer Epidemiol 2012;36(3):e158–e163.
57. Raghav K, Overman MJ. Small bowel adenocarcinomas–existing evidence and evolving paradigms.
Nat Rev Clin Oncol 2013;10(9):534–544.
58. Haselkorn T, Whittemore AS, Lilienfeld DE. Incidence of small bowel cancer in the United States
and worldwide: geographic, temporal, and racial differences. Cancer Causes Control
2005;16(7):781–787.
59. Goodman MT, Matsuno RK, Shvetsov YB. Racial and ethnic variation in the incidence of small-
bowel cancer subtypes in the United States, 1995–2008. Dis Colon Rectum 2013;56(4):441–8.
60. Halfdanarson TR, McWilliams RR, Donohue JH, et al. A single-institution experience with 491 cases
of small bowel adenocarcinoma. Am J Surg 2010; 199(6):797–803.
61. Talamonti MS, Goetz LH, Rao S, et al. Primary cancers of the small bowel: analysis of prognostic
factors and results of surgical management. Arch Surg 2002;137(5):564–570; discussion 570–571.
62. Zaanan A, Costes L, Gauthier M, et al. Chemotherapy of advanced small-bowel adenocarcinoma: a
multicenter AGEO study. Ann Oncol 2010;21(9):1786–1793.
63. Van Weyenberg SJ, Meijerink MR, Jacobs MA, et al. MR enteroclysis in the diagnosis of small-
bowel neoplasms. Radiology 2010;254(3):765–773.
64. Pilleul F, Penigaud M, Milot L, et al. Possible small-bowel neoplasms: contrast-enhanced and water-
enhanced multidetector CT enteroclysis. Radiology 2006;241(3):796–801.
65. Nicholl MB, Ahuja V, Conway WC, et al. Small bowel adenocarcinoma: understaged and
undertreated? Ann Surg Oncol 2010;17(10):2728–2732.
66. Overman MJ, Hu CY, Wolff RA, et al. Prognostic value of lymph node evaluation in small bowel
adenocarcinoma: analysis of the surveillance, epidemiology, and end results database. Cancer
2010;116(23):5374–5382.
67. Barnes G Jr, Romero L, Hess KR, et al. Primary adenocarcinoma of the duodenum: management
and survival in 67 patients. Ann Surg Oncol 1994;1(1):73–78.
68. Poultsides GA, et al. Duodenal adenocarcinoma: clinicopathologic analysis and implications for
treatment. Ann Surg Oncol 2012;19(6):1928–1935.
69. Schottenfeld D, Beebe-Dimmer JL, Vigneau FD. The epidemiology and pathogenesis of neoplasia in
the small intestine. Ann Epidemiol 2009;19(1):58–69.
70. Lecuit M, Lortholary O. Immunoproliferative small intestinal disease associated with
Campylobacter jejuni. Med Mal Infect 2005;35 Suppl 2:S56–S58.
71. Nagashima R, Takeda H, Maeda K, et al. Regression of duodenal mucosa-associated lymphoid tissue
lymphoma after eradication of Helicobacter pylori. Gastroenterology 1996;111(6):1674–1678.
72. Lai EC, Lau SH, Lau WY. Current management of gastrointestinal stromal tumors–a comprehensive
review. Int J Surg 2012;10(7):334–340.
73. Kindblom LG, Remotti HE, Aldenborg F, et al. Gastrointestinal pacemaker cell tumor (GIPACT):
gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am
J Pathol 1998;152(5):1259–1269.
74. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit in human gastrointestinal
stromal tumors. Science 1998;279(5350):577–580.
1334
booksmedicos.org
75. Bümming P, Ahlman H, Andersson J, et al. Population-based study of the diagnosis and treatment
of gastrointestinal stromal tumours. Br J Surg 2006;93(7):836–843.
76. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence
patterns and prognostic factors for survival. Ann Surg 2000;231(1):51–58.
77. Nikfarjam M, Kimchi E, Shereef S, et al. Surgical outcomes of patients with gastrointestinal stromal
tumors in the era of targeted drug therapy. J Gastrointest Surg 2008;12(11):2023–2031.
78. Krajinovic K, Germer CT, Agaimy A, et al. Outcome after resection of one hundred gastrointestinal
stromal tumors. Dig Surg 2010;27(4):313–319.
79. Heinrich MC, Rubin BP, Longley BJ, et al. Biology and genetic aspects of gastrointestinal stromal
tumors: KIT activation and cytogenetic alterations. Hum Pathol 2002;33(5):484–495.
80. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic
gastrointestinal stromal tumours: a phase I study. Lancet 2001;358(9291):1421–1423.
81. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced
gastrointestinal stromal tumors. N Engl J Med 2002;347(7):472–480.
82. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of
localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled
trial. Lancet 2009;373(9669):1097–1104.
83. Mullady DK, Tan BR. A multidisciplinary approach to the diagnosis and treatment of
gastrointestinal stromal tumor. J Clin Gastroenterol 2013; 47(7):578–585.
84. Coco C, Rizzo G, Manno A, et al. Surgical treatment of small bowel neoplasms. Eur Rev Med
Pharmacol Sci 2010;14(4):327–333.
85. Retsas S, Christofyllakis C. Melanoma involving the gastrointestinal tract. Anticancer Res
2001;21(2b):1503–1507.
1335
booksmedicos.org
SECTION G: PANCREAS
1336
booksmedicos.org
Chapter 52
Pancreas Anatomy and Physiology

Taylor S. Riall
Key Points
1 The pancreas is both an endocrine and exocrine organ.

2 The primary function of the exocrine pancreas is to synthesize and secrete enzymes necessary for
digestion.
3 The primary function of the endocrine pancreas is regulation of body energy, primarily through
control of carbohydrate metabolism. Pancreatic endocrine hormones also play a critical role in the
complex regulation of pancreatic secretion and digestion.
4 Congenital anomalies of the pancreas largely result from failure of rotation or fusion of the ventral
and dorsal pancreatic buds.
5 The pancreatic islets of Langerhans are composed of four major cell types – alpha (A), beta (B), delta
(D), and pancreatic polypeptide (PP or F) cells which primarily secrete glucagon, insulin,
somatostatin, and PP, respectively.
6 The different types of islet cells are not evenly distributed throughout the pancreas leading to a
differential distribution of functional neuroendocrine tumors. In addition, resection of different parts
of the pancreas has differing endocrine effects.
7 Pancreatic endocrine secretion also regulates pancreatic exocrine secretion. Insulin stimulates
pancreatic exocrine secretion, amino acid transport, and synthesis of protein and enzymes, whereas
glucagon acts in a counter-regulatory fashion, inhibiting the same processes.
8 Tests of pancreatic exocrine function include the secretin test, 24-hour fecal fat determination,
dimethadione (DMO) test, the Lundh test meal, the triolein breath test, and the paraaminobenzoic
acid (PABA) test. These tests help differentiate steatorrhea due to pancreatic insufficiency from other
digestive disorders.
9 Exogenous administration of somatostatin inhibits the release of insulin, glucagon, growth hormone,
and pancreatic polypeptide.
10 Knowledge of the relationship of the pancreas to surrounding structures including the stomach,
duodenum, distal bile duct, hepatic arterial blood supply, splenic artery and vein, celiac axis,
superior mesenteric artery and vein, portal vein, spleen, adrenal glands, colon and kidneys is critical
in preventing injury to these structures during pancreatic surgery.
11 Resectability in pancreatic cancer in the absence of metastatic disease depends on the extent of
involvement of the tumor with the major vascular structures including the superior mesenteric
artery, superior mesenteric vein (SMV), portal vein, and celiac axis.
INTRODUCTION
1 The pancreas is a digestive organ with both exocrine and endocrine function. The exocrine pancreas
constitutes 80% of the pancreatic mass and comprises acinar and ductal cells.
2 Acinar cells synthesize and secrete over 20 enzymes into the complex pancreatic ductal network,
which then delivers them to the duodenum. The pancreatic secretions are alkaline and provide the
optimal environment for the enzymes to carry out their digestive function in the small intestine.
3 The pancreatic endocrine cells are organized in discrete groups throughout the pancreas, called
islets of Langerhans. The islets directly secrete hormones including insulin, glucagon, and somatostatin,
directly into the blood stream in endo crine fashion. The primary function of the endocrine pancreas is
regulation of body energy, primarily through control of carbohydrate metabolism. Pancreatic endocrine
hormones also play a critical role in the complex regulation of pancreatic secretion and digestion.
1337
booksmedicos.org
The pancreas lies transversely in the retroperitoneum at the level of the second lumbar vertebrae.
Understanding of the embryology of the pancreas is critical for recognizing rare congenital anomalies,
understanding their significance, and treating them appropriately. In addition, when performing
pancreatic and other upper abdominal operations, it is critical to understand the close relationship of the
pancreas to adjacent organs (duodenum, stomach, spleen, transverse colon, bile duct, and left adrenal
gland) and major vessels (celiac axis, superior mesenteric artery, superior mesenteric vein (SMV),
splenic artery and vein, portal vein, inferior mesenteric vein, and vena cava). Knowledge of the normal
pancreatic exocrine and endocrine physiology provides insight into the pathologic processes and
subsequent treatments that can affect the normal function of the pancreas.
EMBRYOLOGY
Normal Pancreatic Embryology
The pancreas begins developing during the fifth week of gestation. Pancreatic development begins at
the junction of the foregut and midgut as two endodermal pancreatic buds, the dorsal bud and the
ventral bud. The dorsal and ventral buds comprise endoderm covered in splanchnic mesoderm. Both the
acinar and islet cells differentiate from the endodermal cells found in the embryonic buds while the
splanchnic mesoderm eventually develops into the dorsal and ventral mesentery.
The dorsal bud forms first and is larger. It ultimately forms much of the head, body, and tail of the
pancreas. As the duodenum grows and rotates, the ventral bud rotates clockwise (Fig. 52-1) and fuses
with the dorsal bud forming the uncinate process and inferior head of the pancreas. In the majority of
cases, the duct in the ventral bud fuses with the duct in the dorsal bud to become the main pancreatic
duct (duct of Wirsung), which drains the majority of the pancreas into the duodenum through the major
papilla, or ampulla of Vater. The proximal duct of the dorsal bud forms the lesser or minor pancreatic
duct (duct of Santorini) which drains into the duodenum through the minor papilla proximal to the
ampulla of Vater.
1338
booksmedicos.org
Figure 52-1. A–D: Schematic drawings of the successive stages in the development of the pancreas from the fifth through the
eighth weeks. E–G: Diagrammatic transverse sections through the duodenum and the developing pancreas. Growth and rotations
(arrows) of the duodenum bring the ventral pancreatic bud toward the dorsal bud and they subsequently fuse. The bile duct
initially attaches to the ventral aspect of the duodenum and is carried around to the dorsal aspect as the duodenum rotates. The
main pancreatic duct is formed by the union of the distal part of the dorsal pancreatic duct and the entire ventral pancreatic duct.
The endocrine function of the pancreas begins during gestation, whereas the exocrine function does
not begin until after birth. The first glucagon-producing cells are seen in 3-week-old embryos and the
first islets appear at approximately 10 weeks. During this early developmental period, predominantly
glucagon-positive islet cells initially appear in the tail of the pancreas. Early glucagon-positive
endocrine cells convert to nonepithelial cells and lose connection with the lumen and tight junctions.
Subsequently, there is a major amplification of endocrine cell numbers, particularly B cells, which
produce insulin.
1339
booksmedicos.org
Figure 52-2. Anatomic configuration of the intrapancreatic ductal system. A: The classic anatomy is present in 60% of cases, where
the accessory duct drains into the minor papilla and the main duct drains into the ampulla of Vater. B: The accessory pancreatic
duct is blind and does not drain into the duodenum in 30% of cases. C: A lack of communication between the two ducts, which
occurs in 10% of cases, is referred to as pancreas divisum. When this occurs the main pancreatic duct drains into the duodenum
through the minor papilla. D: Pancreaticogram obtained on ERCP through cannulation of the minor papilla in a patient with
pancreas divisum; the main duct drains into the minor papilla. E: MRCP on the same patient. The main pancreatic duct drains into
the minor papilla and the common bile duct drains into the ampulla of Vater.
Surgical Significance of Congenital Pancreatic Abnormalities

4 Abnormalities in the rotation and fusion of the pancreas during embryonic development can result in
specific congenital anomalies that have surgical significance. In approximately 60% of people, rotation
1340
booksmedicos.org
and fusion occur normally resulting in the classic anatomy seen in Figure 52-2A. The dorsal and ventral
ducts fuse to form the main pancreatic duct which drains the majority of the pancreas into the ampulla
of Vater. The lesser duct, formed from the proximal duct of the dorsal bud, drains into the duodenum at
the minor papilla.
In approximately 30% of cases, the ventral and dorsal ducts fuse and drain normally into the
duodenum at the ampulla of Vater. However, there is atrophy of the accessory or minor duct with a
blind end and drainage into the duodenum (Fig. 52-2B). As this blind duct still communicates with the
main pancreatic duct, this is of little to no clinical significance and most often found only at autopsy.
In 5% to 14% of cases, the fusion of the ventral and dorsal pancreatic ducts is incomplete (Fig. 52-2C–
E).1–3 As a result of the incomplete fusion, the majority of the pancreas is drained into the duodenum
through the minor papilla. This is called pancreas divisum. Only the small remnant duct of the ventral
bud drains the uncinate process into the duodenum via the ampulla of Vater. Whether or not pancreas
divisum causes pancreatitis and abdominal pain is unclear.1,4,5 It is often asymptomatic. However,
mucosal stenosis at the minor papilla may lead to cystic dilatation of the dorsal duct resulting in
pancreatitis and pain.1,6–8 Pancreatitis or abdominal pain due to pancreas divisum is a diagnosis of
exclusion, and other etiologies for the pancreatitis should be thoroughly investigated. If no other causes
of pancreatitis are identified in the setting of abdominal pain, elevated amylase levels, and pancreas
divisum, the anomaly is considered causative and an endoscopic or operative papillotomy of the minor
papilla and accessory duct is indicated. Recurrent acute pancreatitis or chronic pancreatitis with chronic
pain attributed to pancreas divisum is most often seen in young females.
Annular pancreas is a rare congenital anomaly of the pancreas first recognized in 1818. Early autopsy
and surgical series estimate the incidence to be approximately 3 in 20,000.9,10 However, with better
imaging modalities such as computed tomography (CT), magnetic resonance cholangiopancreatography
(MRCP), and endoscopy, the incidence is thought to be closer to 1 in 1,000.11–13 Annular pancreas is
thought to result from abnormal fusion of the ventral pancreatic bud to the duodenum, leading to
improper rotation of the ventral bud around the duodenum.14 This failure of rotation leads to a thin
band of normal pancreatic parenchyma completely surrounding the second portion of the duodenum
(Fig. 52-3A–C). This band is in continuity with the head of the pancreas and causes variable degrees of
duodenal compression and stenosis. This abnormal ring of pancreatic tissue may contain a pancreatic
duct. Therefore, the surgeon must be aware of this anomaly; if annular pancreas is incidentally
encountered during an operation, it should not be divided. Division of the abnormal ring can result in
pancreatic fistula or obstruction of pancreatic ductal drainage.
1341
booksmedicos.org
Figure 52-3. Annular pancreas. A: CT scan of a patient with annular pancreas. There is a ring of pancreatic tissue surrounding the
duodenum, with a narrowed duodenal lumen. B: EGD image in the same patient. Note narrowing of the duodenal lumen with no
mucosal lesion consistent with external compression by the annular pancreas. C: Intraoperative photo of an annular pancreas. Note
the dilated duodenum after the pylorus, the ring of pancreatic tissue surrounding the duodenum just distal to the dilation, and the
decompressed distal duodenum.
Annular pancreas can present at varying time points from in utero to adulthood.13 When diagnosed in
utero, the most common presentation is polyhydramnios due to duodenal obstruction. Newborns present
most commonly with duodenal obstruction shortly after birth, as evidenced by low birth weight and
feeding intolerance. In people who present in utero or in childhood, it is more commonly associated
with other congenital anomalies including Down syndrome, cardiac anomalies, and other intestinal
anomalies. Duodenal bypass (duodenoduodenostomy or gastrojejunostomy) is the treatment of choice in
children.
Fifty percent of cases of annular pancreas occur in adults. Adults are less likely to present significant
obstruction and less likely to require surgical intervention. If they do present with obstruction,
treatment is similar to that in children. In adults, annular pancreas is more commonly associated with
pancreas divisum and pancreatic neoplasia than in children.13 Heterotopic pancreas is pancreatic tissue
outside the bounds of the normal pancreas without anatomic or vascular connections to the pancreas
itself. Heterotopic pancreas occurs in 0.5% to 14% of autopsy series. The heterotopic pancreatic tissue is
functional and can occur in a variety of sites including the stomach, duodenum, ileum, umbilicus, colon,
appendix, gallbladder, and even within a Meckel diverticulum. This tissue is usually submucosal and
uniformly contains acini and ducts. Up to one-third contains islet cells. Heterotopic pancreas is usually
an incidental finding, but can present with ulceration, obstruction, or intussusception, in which case
treatment is directed at the presenting symptoms and may require resection. In incidental and
asymptomatic cases, no treatment is required. The heterotopic pancreas is susceptible to the same
diseases as normal pancreas and can even undergo malignant transformation.15,16
EXOCRINE AND ENDOCRINE STRUCTURE

The exocrine structures of the pancreas account for 80% to 90% of the pancreatic mass while the
endocrine structure accounts for approximately 2% of the pancreatic mass. The remainder of the
pancreas comprises extracellular matrix, blood vessels, and major ductal structures.
Exocrine Structure
The exocrine structure of the pancreas is composed of two main components: the acinar cells and the
ductal network. The acinar cells produce and secrete the enzymes and zymogens responsible for
digestion. The acinar cells are pyramidal cells with an apex that faces the pancreatic ductal network.
Approximately 20 to 40 acinar cells cluster together to form the functional unit called an acinus (Fig.
52-4A,B). Zymogen granules within the acinar cells contain the digestive enzymes for secretion into the
ductal system. Located more centrally within the acinus, the centroacinar cell secretes alkaline fluid (pH
8.0) into the pancreatic ductal system. The acinus drains initially into small intercalated ducts, which
join to form interlobular ducts that also secrete fluid and electrolytes (Fig. 52-4A). These interlobular
ducts form secondary ducts that drain into the main pancreatic ductal system and eventually the
duodenum at the ampulla of Vater.
1342
booksmedicos.org
Figure 52-4. Histologic anatomy of the acinus. A: Low-magnification view of a portion of the pancreas. B: High-magnification
view of a single acinus. The acinar cells, containing zymogen granules, are pyramidal cells with an apex that faces the pancreatic
ductal network. Twenty to 40 acinar cells that cluster together to form the functional unit called an acinus. The centroacinar cell,
also present within the acinus, functions to secrete fluid and electrolytes of the correct pH into the pancreatic ductal system. The
acinus drains into small intercalated ducts, which join to form interlobular ducts that also secrete fluid and electrolytes. These
interlobular ducts form secondary ducts that drain into the main pancreatic duct.
Endocrine Structure
5 The pancreatic islet cells are of neural crest origin and part of the family of amine precursor uptake
and decarboxylation (APUD) cells. Each pancreatic islet is approximately 40 to 900 mm and contains an
average of 3,000 cells. The islets are composed of four cell types. These cell types are differentially
distributed both throughout the pancreas and within the islets. Table 52-1 describes the cell types, their
hormonal products, and their location within the islet and the pancreas.
B (or beta) cells are located centrally within the islets. They constitute approximately 70% of the islet
cell mass. The main secretory product of B cells is insulin, but they also excrete amylin and
cholecystokinin. A (or alpha) cells and F cells are located peripherally within the islets and constitute
10% and 15% of the islet cell mass, respectively. Glucagon is secreted by A cells, which is the major
counter-regulatory hormone to insulin in glucose homeostasis. F cells secrete pancreatic polypeptide. D
cells are evenly distributed throughout the islet and constitute 5% of the islet cell mass.17 They can be
further divided into D cells which secrete somatostatin and D2 cells which secrete vasoactive intestinal
peptide (VIP). E (or epsilon cells) and C cells comprise <1% of the islet mass and secrete substance P
and serotonin. They are of minimal clinical significance.
6 The distribution of endocrine cell types is not uniform throughout the pancreas. B and D cells are
concentrated in the tail of the pancreas, whereas A cells (as well as C and E cells) are evenly distributed
and F cells are concentrated in the pancreatic head and uncinate process. As such, resection of the
pancreatic body and tail removes more of the insulin-producing cells and is more likely to cause
endocrine insufficiency (diabetes). This distribution also has clinical relevance with regard to the
location of endocrine neoplasms when they occur.
The islet cells have a rich blood supply supporting their endocrine role. The afferent arteriole enters
1343
booksmedicos.org
the islet in an area of discontinuity in the non-B cells surrounding the periphery. The afferent arteriole
then breaks into a capillary bed within the islet. Blood exits the islet through an efferent collecting
venule. The hormones from the islet cells are secreted directly into this rich capillary network within
the islet.
7 The most critical role of the pancreatic islet cells is the secretion of insulin and glucagon to
maintain glucose homeostasis. Pancreatic endocrine secretion also regulates pancreatic exocrine
secretion. Insulin stimulates pancreatic exocrine secretion, amino acid transport, and synthesis of
protein and enzymes, whereas glucagon acts in a counter-regulatory fashion, inhibiting the same
processes. The role of somatostatin is controversial. Somatostatin may have a direct inhibitory effect on
pancreatic acinar cells, which possess somatostatin receptors. It may also act through an inhibitory
effect on islet B cells.
PANCREATIC PHYSIOLOGY
Exocrine Function
The pancreas secretes 1.5 to 3 L of a pancreatic fluid daily. The enzymes and zymogens play a major
role in the digestive activity of the gastrointestinal tract. Pancreatic fluid is alkaline (pH 7.6 to 9.0) and
carries over 20 proteolytic enzymes and zymogens to the duodenum. The enzymes are released into the
duodenum in their inactive state; the fluid serves to neutralize gastric acid and provides an optimal
milieu for the function of these enzymes.
Pancreatic secretion is regulated via an intimate interaction of both hormonal and neural pathways
that integrate the function of the pancreas, biliary tract, and small intestine. Vagal (parasympathetic)
afferent and efferent pathways strongly affect pancreatic secretion. The secretion of enzyme-rich fluid is
largely dependent on the vagal stimulation, whereas fluid and electrolyte secretion are more dependent
on the direct hormonal effects of the secretin and cholecystokinin (CCK). Parasympathetic stimulation
also causes the release of VIP, which also serves to stimulate secretin secretion.18
Table 52-1 Pancreatic Endocrine Cell Types
Many neuropeptides also influence pancreatic secretion in an inhibitory fashion. These include
somatostatin, pancreatic polypeptide, peptide YY, calcitonin gene–related peptides, neuropeptide Y,
pancreastatin, enkephalin, glucagon, and galanin. While these neuropeptides are known to play a role in
regulation of pancreatic secretion, the mechanisms of action and the intricate interplay between the
neuropeptides is not fully understood.18
Bicarbonate Secretion
Bicarbonate is the most physiologically important ion secreted by the pancreas. Bicarbonate is formed
from carbonic acid by the enzyme carbonic anhydrase. The secretion of water and electrolytes
originates in the centroacinar and intercalated duct cells (Fig. 52-4). These cells secrete 20 mmol of
1344
booksmedicos.org
bicarbonate per liter in the basal state and up to 150 mmol/L in the maximally stimulated state.18 The
bicarbonate secreted from the ductal cells is primarily derived from the plasma. Chloride efflux through
the cystic fibrosis transmembrane conductance regulator (CFTR) leads to depolarization and bicarbonate
entry through the sodium bicarbonate cotransporter.18 As a result, chloride secretion varies inversely
with bicarbonate secretion; the sum of these two anions balances the sodium and potassium cations and
remaining constant and equal to that of the plasma.
Both secretin and VIP stimulate bicarbonate secretion by increasing intracellular cyclic AMP, which
acts on the CFTR.18 Gastric acid is the primary stimulus for release of secretin. Secretin is released from
the duodenal mucosa in response to a duodenal lumen pH of less than 3.0 due to gastric acid.
The duodenum and jejunum release CCK in response to the presence of long-chain fatty acids, some
essential amino acids (methionine, valine, phenylalanine, and tryptophan), and gastric acid. CCK is
weak direct stimulator of bicarbonate secretion, but it acts as a neuromodulator and potentiates the
stimulatory effects of secretin. Gastrin and acetylcholine are also weak stimulators of bicarbonate
secretion.19 Bicarbonate secretion is inhibited by atropine (vagal stimulation) and can be reduced by
50% after truncal vagotomy.20 Islet cell peptides including somatostatin, pancreatic polypeptide,
glucagon, galanin, and pancreastatin are thought to inhibit exocrine secretion.
Enzyme Secretion
Pancreatic enzymes originate in the acinar cells, which are highly compartmentalized. Proteins are
synthesized in the rough endoplasmic reticulum, processed in the Golgi apparatus, and then targeted to
the appropriate cell compartment (zymogen granules, lysosomes, etc.). The acinar cells secrete enzymes
that fall into three major enzyme groups: amylolytic enzymes, lipolytic enzymes, and proteolytic
enzymes. Amylolytic enzymes such as amylase hydrolyze starch to oligosaccharides and the disaccharide
maltose. Lipolytic enzymes such as lipase, phospholipase A, and cholesterol esterase function work in
conjunction with bile salts to digest fats and cholesterol. Proteolytic enzymes include endopeptidases
(trypsin and chymotrypsin) and exopeptidases (carboxypeptidase). Endopeptidases act on the internal
peptide bonds of proteins and polypeptides and exopeptidases act on the free carboxy- and amino-
terminal ends of proteins. Proteolytic enzymes are secreted as inactive precursors. Enterokinase cleaves
the lysine–isoleucine bond in trypsinogen to create the active enzyme trypsin. Trypsin then activates the
other proteolytic enzyme precursors.18
The different pancreatic enzymes are not secreted in fixed ratios. They change in response to dietary
alterations and stimuli such as gastric acid, hormones, and neuropeptides. When enzyme secretion is
absent or impaired, malabsorption or incomplete digestion occurs, leading to fat and protein loss
through the gastrointestinal tract. This is seen in patients with acute and chronic pancreatitis (who have
destruction of the exocrine pancreas) and in patients who have undergone surgical resection of all or
part of the pancreas. These patients often present with weight loss and steatorrhea secondary to
malabsorption of nutrients. These signs and symptoms can be corrected by oral replacement of
pancreatic enzymes with meals.
The nervous system initiates pancreatic enzyme secretion. This involves extrinsic innervation by the
vagus nerve and subsequent innervation by the intrapancreatic cholinergic fibers. The
neurotransmitters, acetylcholine and gastrin-releasing peptide activate calcium-dependent release of
zymogen granules.18 In addition, CCK is a predominant regulator of enzyme secretion, doing so through
activation of specific membrane-bound receptors and calcium-dependent second messenger pathways.
Secretin and VIP weakly stimulate acinar cell secretion directly, but also potentiate the effect of CCK on
acinar cells (Fig. 52-5). Insulin is required locally and serves in a permissive role for secretin and CCK
to promote exocrine secretion.18
Through the secretion of the three classes of enzymes, the pancreas regulates complete digestion of
carbohydrates, fats, and proteins. Autodigestion of the pancreas by these proteolytic enzymes is
prevented by packaging of proteases in an inactive precursor form and by the synthesis of protease
inhibitors including pancreatic secretory trypsin inhibitor (PSTI), serine protease inhibitor, kazal type 1
(SPINK1), and protease serine 1 (PRSS1). These enzymes are found in the acinar cell and loss of these
protective mechanisms can lead to activation, autodigestion, and acute pancreatitis. Mutations in the
SPINK1 and PRSS1 genes are known to cause one of the aggressive familial forms of chronic
pancreatitis, leading to recurrent episodes of pancreatitis, with associated exocrine and endocrine
insufficiency.21,22
1345
booksmedicos.org
Figure 52-5. Schematic diagram of the acinar cell, demonstrating receptors for exocrine secretagogues and their intracellular bases
of action. Six distinct classes of receptors are known, with principal ligands shown. CCK, cholecystokinin; VIP, vasoactive intestinal
peptide; CRGP, calcitonin gene–related peptide; DAG, diacylglycerol.
Table 52-2 Characteristic Results of Secretin Testing: Volume, Bicarbonate

Concentration, and Enzyme Secretion Changes in Pancreatic Disease
Processes
Tests of Pancreatic Exocrine Function

8 Several tests are useful in the assessment of pancreatic exocrine function. Such tests are useful in both
diagnosing and determining the etiology of exocrine insufficiency (chronic pancreatitis, malnutrition,
cancer, and Zollinger–Ellison syndrome) (Table 52-2). Steatorrhea from pancreatic exocrine dysfunction
is the result of lipase deficiency and is usually not present until lipase secretion is reduced by 90%. The
secretin test, the dimethadione test (DMO) and the Lundh test require duodenal intubation. The classic
test of pancreatic exocrine function is the secretin test.23 A patient fasts overnight. A double-lumen tube
is then placed in the duodenum. Basal collections are performed for 20 minutes and analyzed for total
volume, bicarbonate output, and enzyme secretion. An intravenous bolus of 2 units of secretin per
kilogram is given and four collections every 20 minutes are analyzed for volume, bicarbonate levels,
and enzyme levels.
Normal values for the standard secretin stimulation test are 2.0 mL of pancreatic fluid per kilogram
per hour, bicarbonate concentration of 80 mmol/L, bicarbonate output of >10 mmol/L in 1 hour, and
1346
booksmedicos.org
amylase secretion of 6 to 18 International Units/kg. The maximal bicarbonate concentration provides
the greatest discrimination between normal subjects and patients with chronic pancreatitis.24 The results
of the secretin stimulation test for different pancreatic disease processes is shown in Table 52-2.
The pancreas metabolizes the anticonvulsant drug trimethadione to its metabolite, DMO. After
placing a double-lumen tube in the duodenum, patients are given 0.45 g of trimethadione three times
daily for 3 days. Secretin is given through the double-lumen tube to maximally stimulate pancreatic
secretion. To measure pancreatic exocrine function, the duodenal output of DMO is analyzed.25
The Lundh test directly measures pancreatic enzyme secretion in response to a meal of carbohydrate,
fat, and protein. A patient fasts overnight, then has a double-lumen duodenal tube placed. After basal
duodenal fluid collection, patients are given a meal consisting of 18 g of corn oil, 15 g of casein, and 40
g of glucose in 300 mL of water. Duodenal fluid is collected every 30 minutes for 2 hours and analyzed
for trypsin, amylase, and lipase. This test relies on endogenous secretin and CCK secretion and may be
abnormal in diseases involving the intestinal mucosa.
N-benzoyl-1-tyrosyl paraaminobenzoic acid (BT-PABA) is cleaved by chymotrypsin to form
paraaminobenzoic acid (PABA), which is then excreted in the urine. The PABA test is performed by
administering 1 g of BT-PABA in 300 mL of water orally. Urine is then collected for 6 hours. Patients
with chronic pancreatitis excrete less than 60% of the ingested dose of PT-PABA.
Suspected pancreatic exocrine dysfunction can also be confirmed giving patients a test meal and
measuring serum levels of the islet cell hormone pancreatic polypeptide (PP). Basal and meal-stimulated
levels of serum PP are reduced in severe chronic pancreatitis and after extensive pancreatic resection.
After an overnight fast, a test meal of 20% protein, 40% fat, and 40% carbohydrate is ingested. The
normal basal range of PP is 100 to 250 pg/mL. In severe chronic pancreatitis, the basal levels are often
less than 50 pg/mL. The normal response to a meal is a rise in PP levels to 700 to 1,000 pg/mL for 2 to
3 hours after the meal. In severe disease, this response is decreased to less than 250 pg/mL. PP release
depends on intact pancreatic innervation and can also be decreased after truncal vagotomy, antrectomy,
or in the setting of diabetic autonomic neuropathy.
The triolein breath test is a noninvasive test of pancreatic exocrine insufficiency or malabsorption, but
does not differentiate between the two.26 25 g of 14C-labeled corn oil (triglycerides) are given to the
patient orally. The metabolite, 14C-carbon dioxide, can be measured in the breath 4 hours after
administration. Patients with disorders of fat digestion or malabsorption exhale less than 3% of the dose
per hour. The test can be repeated after pancreatic enzyme replacement. Patients with pancreatic
insufficiency will achieve a normal rate of excretion of 14C-carbon dioxide, whereas patients with
enteric disorders (malabsorption) show no improvement.
Many tests can help differentiate between steatorrhea caused by pancreatic exocrine insufficiency
versus malabsorption (Table 52-3). The secretin test, the PABA test, and PP will be normal in intestinal
malabsorption and abnormal in pancreatic insufficiency. The fecal fat test measures intraluminal
digestion products. Fecal fat content is measured over a 24-hour time period. If the fecal fat is elevated
to more than 20 g this indicates pancreatic insufficiency, whereas steatorrhea in the presence of low
levels of fecal fat (<20 g) indicates intestinal dysfunction. A reduction of fecal fat can be used to
demonstrate adequate replacement of pancreatic enzymes in patients with exocrine insufficiency.
However, this test is time consuming and disliked by patients and pancreatic enzyme replacement is
often titrated based on symptom relief if the clinical situation leads to a high index of suspicion for
pancreatic exocrine insufficiency (i.e., long-standing chronic pancreatitis) or once the diagnosis of
pancreatic insufficiency is made.
Table 52-3 Differential Diagnosis of Intestinal and Pancreatic Steatorrhea
1347
booksmedicos.org
Serum amylase, lipase, and trypsinogen are not elevated in the physiologic state. As amylase is found
in organs other than the pancreas (salivary glands, liver, small intestine, kidneys, and fallopian tubes),
serum amylase levels may be elevated in both pancreatic and nonpancreatic diseases (Table 52-4). When
pancreatic disease is suspected, the measurement of serum amylase and lipase levels serve as a useful
screening test. Assays for the isoenzymes of amylase can be performed, but are unreliable in
determining whether the source of amylase is pancreatic or nonpancreatic and are not widely used. It
has been shown that serum lipase is a more accurate biomarker of acute pancreatitis than serum
amylase, with 19% of patients with acute pancreatitis having normal serum amylase levels, but only 3%
having normal serum lipase levels.27 Unlike amylase and lipase, serum trypsinogen is made only by the
pancreas and may serve as a better marker for acute pancreatitis. Trypsinogen can also be measured in
the urine and serves as a specific screening test for acute pancreatitis.28,29 All three markers are cleared
by the kidneys so in the setting of acute renal failure, all may be falsely elevated. These levels do not
measure actual endocrine function, but are commonly used to diagnose acute pancreatitis and monitor
its resolution.
In the case of acute pancreatitis, serum amylase and lipase levels are usually elevated and peak within
24 hours of the onset of symptoms. They return to normal within 2 to 4 days if the inflammation
resolves. In cases of severe necrotizing pancreatitis, pancreatic ductal obstruction, and pseudocyst
formation, amylase and lipase levels can remain elevated for much longer periods of time. In this case,
elevated levels often reflect amylase-rich fluid within peripancreatic collections and not ongoing acute
inflammation.
While amylase and lipase levels are elevated in over 85% of patients with acute pancreatitis, their
elevation is far less common in chronic pancreatitis, where the exocrine function of the pancreas may be
impaired. Amylase levels may be normal in patients with acute pancreatitis if there is a delay in their
diagnosis or if their pancreatitis is related to hypertriglyceridemia, which can falsely decrease the serum
amylase levels.24
Endocrine Function
The primary function of the endocrine pancreas is regulation of carbohydrate metabolism, primarily
through regulation of insulin and glucagon secretion through a variety of feedback and regulatory
mechanisms. Insulin promotes glucose transport into cells, inhibits glycogenolysis and fatty acid
breakdown, and stimulates protein synthesis. Glucagon is the major counter-regulatory hormone to
insulin. Glucagon secretion leads to elevated blood glucose levels through stimulation of glycogenolysis
and gluconeogenesis.
Insulin Synthesis, Secretion, and Action

Insulin is a 56-amino-acid polypeptide with a molecular weight of 6 kD. It consists of two polypeptide
chains (A and B) joined by two disulfide bridges. Insulin is synthesized by the B cells within the islets of
Langerhans. Insulin is an anabolic hormone, promoting glucose transport into all cells except B cells,
hepatocytes, and central nervous system cells. It also inhibits glycogenolysis and fatty acid breakdown
but stimulates protein synthesis.
Table 52-4 Pancreatic and Nonpancreatic Causes of Hyperamylasemia
1348
booksmedicos.org
Figure 52-6. Synthesis of insulin. Proinsulin is synthesized by the endoplasmic reticulum and packaged within the secretory
granules of the B cell. There it is cleaved into insulin and C peptide. Equimolar amounts of insulin and C peptide are secreted into
the bloodstream.
The amino acid sequence varies among species, but the location of the disulfide bridges are highly
conserved and are critical for its biologic activity. When pancreatic B cells are stimulated, proinsulin
(precursor peptide to insulin) is synthesized in the endoplasmic reticulum and transported to the Golgi.
In the Golgi, the proinsulin is packaged into granules where it is cleaved into insulin and the residual
connecting peptide, C peptide (Fig. 52-6). The granules are then released directly into the bloodstream.
Defects in the synthesis and cleavage of insulin can lead to rare forms of diabetes mellitus such as
Wakayama syndrome and proinsulin syndrome.30
The secretion of insulin is tightly regulated by nutrient, neural, and hormonal factors. In response to
glucose, the predominant nutrient regulator, insulin is secreted in two phases. The first phase is a short
burst of stored insulin that lasts 4 to 6 minutes. This is followed by a sustained secretion of insulin,
which requires active synthesis of the hormone within the islet cell. The B cell is sensitive to even small
changes in glucose concentration and is maximally stimulated at concentrations of 400 to 500 mg/dL.
Insulin is released in an oscillatory or pulsatile pattern controlled by an internal pacemaker which is
present even in isolated islet cells.31 Insulin has a short half-life of 7 to 10 minutes after secretion. Forty
percent to 70% of insulin secreted into the portal venous system is metabolized by hepatocytes on the
first pass through the liver. Excess insulin is then slowly metabolized by the liver, kidneys, and skeletal
muscles. Insulin is not taken up by brain cells or red blood cells.
Insulin binds to a 300-kD glycoprotein cell surface receptor. Stimulation of the insulin receptor is
dependent upon insulin concentration. Insulin resistance, present in type II diabetes, can be the result of
decreased numbers of receptors or a decreased affinity for insulin. Glucose is actively transported across
1349
booksmedicos.org
cell membranes throughout the body by glucose transporters. There are several classes of glucose
transporters with varying affinities for glucose. The GLUT-2 transporter located on B cells has a low
affinity for glucose. This results in low rates of transport at physiologic concentrations of glucose but an
increased rate of transport at higher concentrations, with subsequent higher insulin secretion rates.32
The loss of B-cell GLUT-2 transporter can contribute to the development of diabetes mellitus.33
Through the enteroinsular axis, the release of enteric hormones in response to glucose potentiates
insulin secretion. As such, orally administered glucose has a greater effect on insulin secretion than an
equivalent amount of glucose administered intravenously. Gastric inhibitory polypeptide (GIP) is an
important regulator of insulin secretion.34 Additional gut peptides and hormones that stimulate insulin
secretion include glucagon, glucagon-like peptide-1, and CCK, while somatostatin, amylin, and
pancreastatin inhibit insulin secretion. Nutrients including certain amino acids (arginine, lysine, and
leucine) and free fatty acids also regulate insulin secretion. Sulfonylurea compounds, which act
independently of glucose concentration, also stimulate insulin secretion and are used in the treatment of
type II diabetes, where the primary defect is peripheral insulin resistance and not insulin production or
decreased islet-cell mass.
Parasympathetic and sympathetic innervation also influences B-cell activity. Both cholinergic and b-
sympathetic fibers stimulate insulin secretion, whereas s-sympathetic fibers are inhibitory. A loss of
pancreatic innervation in the setting of pancreatic transplantation can therefore result in changes in the
pattern and quality of insulin secretion. There is a significant secretory reserve of insulin within the
pancreas. Destruction or removal of 80% of the pancreatic islet cell mass is necessary before endocrine
dysfunction becomes clinically apparent in the form of type I (insulin-dependent) diabetes.35
Glucagon Synthesis, Secretion, and Action

Glucagon, secreted by the islet A, is a single-chain, 29-amino-acid polypeptide with a molecular weight
of 3.5 kD. Glucagon is the major catabolic hormone, elevating blood glucose levels through stimulation
of glycogenolysis and gluconeogenesis in the liver. Like epinephrine, cortisol, and growth hormone,
glucagon is considered a stress hormone because it increases metabolic fuel in the form of glucose
during stress. Secretion of pancreatic glucagon is tightly controlled by neural, hormonal, and nutrient
factors. Like insulin, glucose is the primary regulator, but the two hormones respond to glucose in
reciprocal fashion. Glucose has a strong suppressive effect on glucagon secretion. The two hormones are
counter-regulatory and function together to tightly control blood glucose levels. Excess glucagon can
lead to hyperglycemia, whereas insufficient glucagon can lead to profound hypoglycemia. For this
reason, the diabetes resulting from total pancreatectomy is very brittle and difficult to control due to
the lack of endogenous glucagon to balance exogenously administered insulin.
Glucagon secretion is also stimulated by the amino acids arginine and alanine. Through paracrine
effects within the islets, both insulin and somatostatin have a suppressive effect on glucagon secretion.
The neural regulation of glucagon parallels that of insulin, with cholinergic fibers being strongly
stimulatory, b-sympathetic fibers being weakly stimulatory, and a-sympathetic fibers being inhibitory.
Dysfunctional A-cell secretion of glucagon may play a role in the elevation of blood sugar in diabetes.
Somatostatin Synthesis, Secretion, and Action

9 Somatostatin is a 14-amino-acid polypeptide weighing 1.6 kD. The role of endogenous somatostatin is
unclear; it has not been proven to directly influence the secretion of other peptide hormones from islet
cells. However, exogenous administration of somatostatin has been shown to inhibit the release of
insulin, glucagon, growth hormone, and pancreatic polypeptide. Exogenous somatostatin administration
has also been shown to inhibit gastric, pancreatic, and biliary secretion.
Both short- and long-acting synthetic peptides that mimic somatostatin pharmacologically have been
developed. Somatostatin analogues are more potent inhibitors of growth hormone, glucagon, and
insulin secretion than the natural hormone. They have been used to treat both exocrine and endocrine
disorders of the pancreas. For example, in hormone-producing islet cell tumors which express
somatostatin receptors, octreotide can effectively suppress the hormonal symptoms associated with the
disease process and slow the progression of tumors.36 There has been significant debate about the role
of prophylactic somatostatin analogs in the prevention of pancreatic fistula formation after pancreatic
surgery. A 2007 meta-analysis has shown that prophylactic octreotide reduces pancreatic fistula
formation following elective pancreatic surgery37 and a more recent randomized, controlled trial
demonstrated that pasireotide given before surgery and for 7 days after surgery reduced the incidence
of clinically significant postoperative fistulas, leaks, and abscesses.38 A recent meta-analysis of pooled
1350
booksmedicos.org
data from randomized trials failed to show any advantage of somatostatin analogs for accelerating
fistula closure after pancreatic surgery.39
Pancreatic Polypeptide Synthesis, Secretion, and Action

Pancreatic polypeptide is a 36-amino-acid polypeptide secreted by the F cells of the pancreatic islet. The
physiologic role of pancreatic polypeptide remains unclear. It has been shown to inhibit pancreatic
exocrine secretion and gallbladder emptying. Cholinergic innervation predominantly regulates
pancreatic polypeptide secretion. In diabetes and normal aging pancreatic polypeptide secretion is
increased resulting in increased circulating pancreatic polypeptide levels.
Other Peptide Products

Other peptides are secreted within the pancreatic islet. These include neuropeptides such as VIP,
galanin, amylin, pancreastatin, chromogranin A, and serotonin, which are believed to play a role in the
regulation of islet cell secretion. Amylin, a 36-amino-acid polypeptide, is secreted by the B cells, but not
in equimolar amounts to proinsulin. Amylin inhibits secretion of insulin and its uptake in the periphery.
Amylin has been found to be deposited in the pancreas of patients with type II diabetes and has been
implicated in the pathogenesis of the disease. Pancreastatin is another peptide found in large amounts in
the pancreas. It is a derivative of chromogranin A, but its physiologic significance is unknown.
Chromogranin A is produced by most neuroendocrine tumors and is a good marker for diagnosis and
recurrence of pancreatic neuroendocrine tumors.
Tests of Pancreatic Endocrine Function

The most widely used tests of pancreatic endocrine function measure the body’s ability to utilize
glucose. The oral glucose tolerance test provides an indirect assessment of the insulin response to an
oral glucose load; it measures the glucose profile and not the actual insulin response. After an overnight
fast, two basal blood samples are drawn and glucose levels are analyzed. Patients are then given an oral
glucose load of 40 g/m2 over 10 minutes. Blood samples are then drawn every 30 minutes for 2 hours.
The fasting glucose level should be less than 110 mg/dL. Fasting levels between 110 and 126 mg/dL are
considered borderline, and fasting levels above 126 mg/dL are diagnostic of diabetes. The 2-hour
glucose level should be below 140 mg/dL. Two-hour levels between 140 and 200 mg/dL are borderline,
and 2-hour levels over 200 mg/dL are again diagnostic of diabetes mellitus. The test takes into account
the gastrointestinal influences of glucose metabolism and can be affected by antecedent diet, drug use,
exercise, and patient age.
The intravenous glucose tolerance test can be used to eliminate gastrointestinal influences on glucose
metabolism. After basal glucose levels are obtained, this test is performed in similar fashion to the oral
glucose tolerance test, except the glucose load is delivered as an intravenous bolus of 0.5 g/kg over 2 to
5 minutes. Blood is then drawn every 10 minutes for an hour. The disappearance of glucose per minute
(K value) is calculated. A K value of 1.5 or higher is normal. The results are age adjusted, as the
response to the intravenous glucose load decreases with age.
An insulinoma is a pancreatic neuroendocrine tumor that secretes insulin. The gold standard for
diagnosis of insulinoma is the 72-hour monitored fast. This test documents Whipple triad of
hypoglycemia, neuroglycopenic symptoms concurrent with hypoglycemia, and resolution of symptoms
with administration of glucose. It also allows the clinic to rule out surreptitious administration of
exogenous insulin. Within the B cell, proinsulin is cleaved into insulin and C-peptide prior to secretion.
Therefore, both insulin and C-peptide levels can be measured in the blood stream and should be present
in a 1:1 ratio. Surreptitious administration of exogenous insulin can be differentiated from insulinoma
by the absence of C-peptide in the case of the exogenously administered insulin. Patients are fasted in a
monitored setting. All nonessential medications are stopped and patients can only drink water, black,
decaffeinated coffee, and diet sodas. Glucose and insulin levels as well as neuroglycopenic symptoms
are closely monitored. The criteria for discontinuing the fast include serum glucose levels less than 45
mg/dL and the patient must be symptomatic. The 72-hour fast is highly sensitive for insulinoma and a
patient rarely finishes this test without an unequivocal diagnosis. Urine should also be screened for the
presence of sulfonylureas and other oral hypoglycemic medications.
The intravenous arginine test and tolbutamide response test are used to help in diagnosis of more rare
hormone-secreting pancreatic neuroendocrine tumors. After an overnight fast, a patient is given a 30-
minute intravenous infusion of 0.5 g/kg of arginine, which stimulates secretion of islet cell hormones.
Blood samples are taken every 10 minutes and radioimmunoassays are performed for the hormone in
1351
booksmedicos.org
question. This test is most useful for glucagon-secreting tumors and is not commonly used. Elevations of
plasma glucagon levels to over 400 pg/mL are diagnostic for glucagonoma.
Tolbutamide is a sulfonylurea that stimulates insulin secretion and secretion of other pancreatic
endocrine hormones. After fasting overnight, blood samples are drawn and a patient is given 1 g of
tolbutamide intravenously. Blood glucose is monitored for 1 hour and blood samples are drawn to
determine levels of the hormone of interest. Sustained hypoglycemia with hypersecretion of insulin is
diagnostic of insulinoma. Somatostatin levels more than twice as high as the normal values of the
particular assay used are considered diagnostic of somatostatinoma.
PANCREATIC ANATOMY
The pancreas lies in the retroperitoneum at the level of the second lumbar vertebrae. It lies obliquely
and transversely from its most caudal point at the duodenal C-loop on the right to its most cranial point
in the splenic hilum on the left. The pancreas is composed of four anatomic parts: the head (including
the uncinate process), the neck, the body, and the tail (Fig. 52-7).
Figure 52-7. Normal pancreatic anatomy. The pancreatic head lies within the C-loop of the duodenum. The main pancreatic duct
and common bile duct run through the head of the pancreas and drain into the duodenum at the ampulla of Vater. The superior
mesenteric artery and vein lie posterior to the pancreatic neck.
Relationship to Adjacent Structures

The pancreatic head is further subdivided into the head and uncinate process. The head and uncinate
process lie within the C-loop of the duodenum and include all the pancreatic parenchyma to the right of
the superior mesenteric vessels. The pancreatic head is attached to the medial aspect of the descending
and third portion of the duodenum and the two organs share a blood supply. The uncinate process
projects from the inferior portion of the pancreatic head medially to the left, then posterior to the
superior mesenteric vessels. The inferior vena cava, right renal artery and vein, and left renal vein lie
posterior to the uncinate process and pancreatic head. The bile duct runs through the posterior and
superior aspect of the pancreatic head, joining the pancreatic duct and draining into the duodenum
medially at the ampulla of Vater (Fig. 52-7).
The pancreatic neck is the portion of pancreatic tissue that overlies the superior mesenteric artery and
vein anteriorly. The anterior surface of the pancreatic neck lies directly posterior to the pylorus of the
stomach. The body of the pancreas continues left from the pancreatic neck. The anterior surface of the
pancreatic neck, body, and tail are covered with peritoneum and forms the floor of the omental bursa
within the lesser sac. The stomach overlies the pancreatic body/lesser sac anteriorly. The posterior
surface of the pancreatic body is not peritonealized and directly contacts the aorta, left adrenal gland,
left kidney, and left renal artery and vein. The body of the pancreas is the portion overlying the second
lumbar vertebrae. The tail of the pancreas begins anterior to the left kidney and extends superolaterally
1352
booksmedicos.org
to the hilum of the spleen. The splenic artery and vein run along the posterior surface of the pancreas.
The tail of the pancreas is in close proximity to the spleen and splenic flexure of the colon.
Pancreatic Ductal Anatomy

The main pancreatic duct, or duct of Wirsung, begins in the pancreatic tail. It most commonly runs
within the posterior aspect of the pancreatic parenchyma, midway between the superior and inferior
border of the gland. In the head of the pancreas, the pancreatic duct turns inferiorly at the genu of the
pancreatic duct and joins the common bile duct, draining into the second portion of the duodenum at
the ampulla of Vater. A common channel may exist between the common bile duct and main pancreatic
duct and it varies in length across the population. At the level of the ampulla of Vater, the pancreatic
duct is anterior and inferior to the common bile duct. At the ampulla of Vater, the sphincter of Oddi
prevents reflux of duodenal contents into the bile duct and pancreatic duct. This sphincter of Oddi is
controlled by a variety of neural and hormonal factors that regulate relaxation and constriction.
A normal main pancreatic duct is 2 to 4 mm in diameter and has a ductal pressure of approximately
15 to 30 mm Hg. This is higher than the pressure in the common bile duct (7 to 17 mm Hg) and serves
to prevent reflux of bile into the pancreatic ductal system. There are over 20 side branches of the main
pancreatic duct throughout the pancreas providing drainage of acinar units. The accessory pancreatic
duct, or duct of Santorini, is more variable than the main pancreatic duct. It typically drains the
uncinate process and inferior portion of the pancreatic head into the duodenum at the minor papilla,
proximal to the ampulla of Vater.
Arterial Blood Supply

The pancreatic blood supply arises from the celiac axis and superior mesenteric artery. The celiac axis
arises from the abdominal aorta and most commonly gives rise to the splenic artery, the left gastric
artery, and the common hepatic artery (Fig. 52-8A). The splenic artery courses along the posterior
surface of the pancreatic body and tail and gives rise to more than 10 branches which supply the
pancreatic body and tail. The first branch of the splenic artery is the dorsal pancreatic artery; it arises
close to the origin of the splenic artery and supplies blood to the proximal body. Further distally, the
great pancreatic artery supplies the midportion of the body and the caudal pancreatic artery supplies the
pancreatic tail.
The head of the pancreas is supplied by both the celiac and superior mesenteric artery (SMA). The
gastroduodenal artery is the first branch off the common hepatic artery. Distal to the first portion of the
duodenum, the gastroduodenal artery becomes the superior pancreaticoduodenal artery and divides into
anterior and posterior branches. The SMA gives rise to the inferior pancreaticoduodenal artery, which
also divides into anterior and posterior branches. The inferior and superior pancreaticoduodenal arcades
form an extensive collateral network with the superior pancreaticoduodenal arcades, supplying both the
duodenum and head of the pancreas. Anteriorly these arcades lie in the groove between the pancreas
and duodenum. Posteriorly, they cross the common bile duct. The arterial blood supply of ampulla of
Vater is from three pedicles off the superior and inferior pancreaticoduodenal arteries. The posterior
pedicle, located at 11 o’clock, arises from the superior pancreaticoduodenal artery. The ventral
commissural pedicle, located at 1 o’clock, arises from both arcades. Finally, the inferior pedicle at 6
o’clock arises from the anterior branch of the inferior pancreaticoduodenal artery. Near the head of the
pancreas, branches arising from the splenic artery form collaterals with the inferior pancreaticoduodenal
arcades.
1353
booksmedicos.org
Figure 52-8. 3D CT reconstructions of (A) Normal arterial supply to the pancreas, (B) Replaced right hepatic artery arising from
the superior mesenteric artery, (C) Replaced common hepatic artery arising from the superior mesenteric artery and (D) Replaced
left hepatic artery arising from the splenic artery.
Variations or anomalies in the pancreatic and biliary blood supply are found in 20% to 30% of people.
In most cases, all or part of the hepatic arterial blood supply does not arise from the celiac axis. As
much of the pancreatic blood supply is derived from the hepatic arterial blood supply, these variations
lead to variations in the pancreatic blood supply. In approximately 20% of patients, the replaced right
hepatic artery arises from the superior mesenteric artery (Fig. 52-8B) in the retropancreatic position and
traverses the upper edge of the uncinate process, then runs posterolateral to the portal vein. In this case,
a pulse remains in the hepatoduodenal ligament and the gastroduodenal artery can arise from the
replaced right or the left hepatic artery. The right hepatic artery can also originate from the right
gastric in 2% of cases or from the gastroduodenal artery in 6% of cases.
The entire hepatic arterial supply can be replaced, with the common hepatic artery originating from
the SMA instead of the celiac axis (Fig. 52-8C). In this case, there is no hepatic arterial pulse medially in
the hepatoduodenal ligament. The replaced common hepatic artery runs anterior to the portal vein, but
posterior to the bile duct and gives rise to a gastroduodenal branch, which is also posterior to the bile
duct. In approximately 10% of cases, the left hepatic artery can be aberrant, most commonly arising
from the left gastric artery instead of the proper hepatic artery.
Venous Drainage
The venous drainage of the pancreas follows the arterial blood supply and is eventually returned to the
portal circulation and delivered back to the liver. There are four main routes of venous drainage in the
pancreas. In the pancreatic head the superior venous arcades drain either directly into the portal vein
superiorly or laterally. The anterior and inferior pancreaticoduodenal arcades drain directly into the
infrapancreatic SMV. There are rarely any anterior branches from the pancreatic head and neck into the
1354
booksmedicos.org
superior mesenteric and portal veins. When they do occur, it is most commonly at the superior border
of the pancreatic neck.
The body and tail of the pancreas has many venous tributaries that drain into the splenic vein, which
joins the SMV posterior to the pancreatic neck forming the portal vein (PV). The three named
tributaries of the splenic are the inferior pancreatic vein, the caudal pancreatic vein, and the great
pancreatic vein. The inferior mesenteric vein (IMV) does not drain the pancreas, but joins the splenic
vein posterior to the pancreatic body. The PV then drains the intestinal blood supply to the liver.
Lymphatic Drainage
Throughout the pancreas there is a rich periacinar network of lymphatic vessels which drain to five
major nodal groups: superior, inferior, anterior, posterior, and splenic.40 The superior nodal group runs
along the superior border of the pancreas and celiac trunk. They drain the superior portion of the
pancreatic head. The inferior nodal group along the inferior border of the head and body of the
pancreas drain the inferior pancreatic head and uncinate process, eventually draining to the superior
mesenteric and paraaortic lymph nodes. The anterior lymphatics drain to the prepyloric and infrapyloric
nodes. The posterior lymph nodes include the distal common bile duct and ampullary lymphatics and
drain directly into the paraaortic lymph nodes. Finally, the splenic lymph nodes drain the lymphatics of
the pancreatic body and tail into the interceliomesenteric lymph nodes.
The Japanese Pancreas Society has classified the pancreatic lymphatic drainage into 18 lymph node
stations (Table 52-5).42 The greater and lesser curves of the stomach drain into lymph node stations 1
through 4. The anterior lymphatics described above drain into lymph node stations 5 and 6. The
superior nodal group includes lymph node stations 7 through 9 along the left gastric artery, common
hepatic artery, and celiac axis. The posterior lymph nodes include lymph node stations 12 (and all
subdivisions) and 13, while the inferior nodal group comprises stations 14 through 17. The splenic
lymph node group corresponds to Japanese lymph node stations 10 and 11.
Innervation
The innervation to the pancreas is derived from the vagus and thoracic splanchnic nerves as well as
peptidergic neurons that secrete amines and peptides.43 Parasympathetic and sympathetic fibers for
ganglia along the celiac axis and superior mesenteric artery, which give rise to the pancreatic branches
reach the pancreas by passing along the arteries from the celiac axis and superior mesenteric arteries.
The parasympathetic nerves stimulate both exocrine and endocrine secretion, while the sympathetic
fibers have a predominantly inhibitory effect (Fig. 52-9).44 The peptidergic neurons secrete hormones
including somatostatin, VIP, calcitonin gene–related peptide (CGRP), and galanin. While the peptidergic
neurons influence exocrine and endocrine secretion, their precise physiologic role is unclear. The
pancreas also has a rich network of afferent sensory fibers.
Table 52-5 Japanese Lymph Node Stations
1355
booksmedicos.org
SURGICAL SIGNIFICANCE OF PANCREATIC ANATOMY
10 Knowledge of the anatomy and anatomical variants can give clues to the diagnosis of pancreatic
disease based on signs and symptoms. In addition, an understanding of the pancreatic anatomy in
relation to adjacent structures is essential when performing operative procedures on the pancreas or
surrounding structures including the duodenum, bile duct, and spleen.
1356
booksmedicos.org
Figure 52-9. Schematic diagram of the neurohormonal control of the exocrine cells. Visceral receptors line the ductule system and
carry the sensation of pain to the spinal cord. Sympathetic fibers first synapse in the celiac plexus after traveling through the
thoracic ganglia and splanchnic nerves. Postganglionic fibers then synapse on intrapancreatic arterioles. Parasympathetic
preganglionic fibers travel through the celiac plexus after leaving the vagus nerves and course with vessels and ducts to synapse on
postganglionic fibers near acinar cells, islet cells, and smooth muscle cells of major ducts. Stimulation of these parasympathetic
fibers results in an immediate release of pancreatic enzymes. Secretin and CCK first enter the pancreas through the capillary
network of the islet cells, and then enter the separate capillary network of the acinar tissue through the insuloacinar portal vessels.
Glucagon, somatostatin, pancreatic polypeptide, and insulin from the islets cells reach the acinar tissue immediately after release.
In this way, the islet cells can influence the acinar tissue responses to CCK and secretin.
Pancreatic Anatomy and Pancreatic Cancer

Approximately, 75% of pancreatic adenocarcinomas occur in the pancreatic head at the genu of the
pancreatic duct.45 As a result, people who develop cancer in the head of the pancreas most commonly
present with obstructive jaundice secondary to occlusion of the intrapancreatic bile duct by tumor,
leading to earlier diagnosis. People with body and tail tumors present with abdominal pain and other
vague abdominal symptoms, often leading to a delay in diagnosis. Nearly 85% of resected pancreatic
tumors are in the head, neck, or uncinate process of the pancreas.46
Similarly, patients with cancer in the pancreatic head often have invasion of the adjacent duodenum.
They may present with or develop signs and symptoms of duodenal or gastric outlet obstruction. In
patients with unresectable disease, late gastric outlet obstruction in patients requiring
gastrojejunostomy or duodenal stenting occurs in 10% to 20% of patients. A prospective, randomized
trial demonstrated that the addition of prophylactic gastrojejunostomy in addition to
hepaticojejunostomy significantly reduced gastric outlet obstruction in patients with unresectable
disease undergoing open biliary bypass.47 However, in the modern era, biliary stenting is so effective
that operative hepaticojejunostomy for unresectable disease is rarely indicated. In the setting of isolated
gastric outlet obstruction in unresectable disease, duodenal stenting is an option. When successful this
can avoid surgery and its negative impact on the remaining quality of life. In a meta-analysis of trials
1357
booksmedicos.org
comparing endoscopic stenting to gastrojejunostomy, stenting was associated with shorter time to oral
intake and shorter length of stay, with similar complication rates, and decreased mortality.48
11 The ability to resect a pancreatic cancer depends on the presence or absence of metastatic disease
and the extent of local vascular involvement. Pancreatic cancers are classified as resectable, borderline
resectable, or unresectable (including locally advanced unresectable disease and metastatic disease).
Table 52-6 shows the 2014 National Comprehensive Cancer Network definitions for resectable,
borderline resectable, and unresectable disease.49 Tumors are considered resectable if they have: (1) no
distant metastases, (2) no radiographic evidence of SMV or PV distortion, and (3) clear fat planes
around the celiac axis, hepatic artery, and SMA (Fig. 52-10A).
Table 52-6 Criteria for Resectability in Pancreatic Cancer
Tumors are considered borderline resectable if they have: (1) no distant metastases, (2) venous
involvement of the SMV or PV with distortion or narrowing of the vein or occlusion of the vein with
suitable vessel proximal and distal, allowing for safe resection and replacement, (3) gastroduodenal
artery encasement up to the hepatic artery with either short segment encasement or direct abutment of
the hepatic artery, without extension to the celiac axis, and (4) tumor abutment of the SMA not to
exceed greater than 180 degrees of the circumference of the vessel wall (Fig. 52-10B).
Tumors are considered to be locally unresectable if there is: (1) no distant metastatic disease, (2)
greater than 180 degrees SMA encasement, (3) any celiac axis abutment, (4) unreconstructable
SMV/portal occlusion, (5) invasion or encasement of the aorta or inferior vena cava (IVC), and (6)
nodal involvement outside the field of resection. Patients with any distant metastatic disease, most
commonly to the liver or lymph nodes outside the field of resection, or the presence of peritoneal
carcinomatosis are considered unresectable.
Pancreatic head cancers may also involve adjacent organs including the hepatic flexure of the colon,
the gallbladder, or the stomach. If there are no distant metastases, resection of these organs en bloc is
indicated. For cancers in the body and tail without distant metastasis, involvement of the splenic artery
and/or vein does not preclude resection as these vessels are normally taken during the operation.
However, involvement of the celiac axis or superior mesenteric artery precludes resection. Involvement
of adjacent organs including the left kidney, left adrenal, spleen, and left colon can be resected if
involved with tumor and there is no distant disease.
Knowledge of the normal pancreatic blood supply is critical in order to perform an adequate cancer
operation. As the duodenum and head of pancreas share a blood supply, it is necessary to remove these
organs en bloc when performing an operation for carcinoma. While the duodenum can be preserved in
resections performed for benign disease (duodenum-preserving pancreatic head resection), this is not
the case in patients with cancer. Likewise, for cancers in the body and tail of the pancreas it is necessary
1358
booksmedicos.org
to resect the spleen and its blood supply since it shares a blood supply with the tail of the pancreas. For
benign diseases of the pancreatic tail, the spleen can be preserved.
There has been significant debate regarding the extent of lymph node dissection necessary in patients
undergoing curative resection for pancreatic cancer. Table 52-5 shows the difference in extent of
lymphadenectomy between the standard and radical procedure. The standard procedure includes the
bile duct (station 12b2) and cystic duct lymph nodes (station 12c), the posterior (station 13) and
anterior (station 17) pancreaticoduodenal lymph nodes, the SMV nodes (station 14v), and the nodes on
the right side of the superior mesenteric artery (station 14b). Radical resection adds a distal
gastrectomy (stations 3, 4, 5, and 6) and a retroperitoneal dissection extending from the right renal
hilum to the left lateral border of the aorta horizontally with samples of celiac nodes, and from the
portal vein to below the third portion of the duodenum vertically (lymph node stations 16a1, 16b2, and
9). In the United States, standard resection is most commonly performed.
Figure 52-10. A: Resectable pancreatic head cancer. There is a clear plane between the tumor and both the superior mesenteric
artery and superior mesenteric vein. B: Borderline resectable pancreatic cancer. Involvement of the superior mesenteric vein with
distortion and narrowing; tumor abutment of the superior mesenteric artery less than 80 degrees of the circumference.
Awareness of the common anatomic variants in biliary and pancreatic arterial supply is necessary to
prevent major vascular injury and damage to the hepatic blood supply during pancreatic resection. The
gastroduodenal artery is the largest named artery taken during pancreaticoduodenectomy. In the case of
a replaced right hepatic artery arising from the superior mesenteric artery, the gastroduodenal artery
can arise from this replaced vessel and enter the pancreas posterior to the bile duct. In addition, this
replaced right hepatic artery courses to the liver lateral to the bile duct and can easily be injured during
dissection of the pancreatic uncinate process off of the superior mesenteric vessels. A replaced right
hepatic artery often supplies the entire right lobe of the liver causing significant hepatic ischemia if
injured. In the case of a replaced right hepatic artery, there will still be a pulse medially in the
hepatoduodenal ligament from the left hepatic artery, but this will supply only the left lobe of the liver.
In the case of a replaced common hepatic artery, the entire hepatic blood supply will be from the
SMA. There will be no pulse medially in the hepatoduodenal ligament. The replaced vessel will again be
posterior and lateral to the bile duct and at risk of injury if not correctly identified. Given the closer
proximity of the replaced vessels to the pancreatic head and uncinate process, these replaced vessels
may also be more prone to direct involvement by tumor. If injured or involved with tumor and
resected, these often require reconstruction to restore adequate hepatic blood supply.
Due to the rich afferent sensory fiber network within the pancreas, abdominal pain and back pain are
common presenting symptoms in patients with pancreatic cancer. As pancreatic cancer progresses, the
nervous plexuses along the celiac axis in the retroperitoneum can be invaded by a tumor causing the
characteristic intractable back pain. In this setting, celiac ganglion blockade (sympathectomy) or
neurolysis using alcohol can provide significant pain relief by interrupting these somatic fibers. A celiac
block can be performed endoscopically,50 percutaneously, or intraoperatively. Endoscopic ultrasound
(EUS)- or CT-guided celiac plexus neurolysis should be considered first-line therapy in patients with pain
secondary to unresectable, locally advanced pancreatic cancer.51 Celiac blockade has been shown to
reduce pain in patients with unresectable pancreatic cancer undergoing operative bypass procedures for
obstructive jaundice and duodenal obstruction.52,53
Pancreatic Anatomy and Pancreatitis
1359
booksmedicos.org
The intrapancreatic location of the distal common bile duct is critical to many pancreatic disease
processes. Gallstone pancreatitis, the second most common cause of pancreatitis in the United States, is
caused by gallstones passed into the common bile duct. These gallstones can obstruct the duct distally
and lead to transient obstruction of the pancreatic duct with resulting reflux of pancreatic juice and bile
into the pancreatic duct, causing pancreatitis.
In benign pancreatic diseases such as chronic pancreatitis, disease in the pancreatic head may cause
benign biliary strictures and jaundice, whereas disease in the body and tail more often presents with
abdominal pain. Pancreatic ductal anatomy and the presence or absence of ductal dilation dictate the
choices for operative management. In the setting of a dilated pancreatic duct, drainage procedures may
impact pancreatic pain and recurrent acute episodes. Conversely, in the setting of small duct disease,
ablative therapy with resection (duodenum-preserving pancreatic head resection,
pancreaticoduodenectomy, and distal pancreatectomy) is the treatment of choice when medical
management fails.
Figure 52-11. Large pancreatic pseudocyst in the lesser sac. The pseudocyst is compressing the stomach anteriorly.
In the setting of acute or chronic pancreatitis, ductal disruption can lead to the formation of a
pancreatic pseudocyst. In many cases, these pseudocysts occur anterior to the pancreas in the lesser sac
(Fig. 52-11). This often leads to early satiety and abdominal pain. When large pseudocysts abut the
stomach, drainage can be achieved with endoscopic or operative cystgastrostomy.
Trauma and Pancreatic Injury

The pancreatic body lies anterior to the second lumbar vertebra deep in the retroperitoneum. In cases of
blunt abdominal trauma, specifically deceleration injury, the pancreatic body is crushed against the
second vertebral body and can be transected at this point. In trauma patients with elevated amylase and
lipase levels, the trauma surgeon should be aware of this possibility and obtain cross-sectional
pancreatic imaging to rule out ductal disruption. In the case of complete ductal disruption distal
pancreatectomy or drainage of the pancreas into the intestine may be necessary.
Penetrating injury to the duodenum or pancreas often involves major vascular injury and in many
cases is not survivable. In the case of injury to the IVC, the pancreas and duodenum must be mobilized
out of the retroperitoneum (Kocher maneuver) in order to expose the vessels.
DIAGNOSTIC APPROACH TO PATIENTS WITH PANCREATIC DISEASE

Pancreatic Imaging (Studies of Pancreatic Structure)
If pancreatic disease is suspected, the pancreas can be imaged by several radiographic modalities
including plain abdominal x-rays, upper gastrointestinal series, abdominal ultrasonography, CT MRCP,
endoscopic retrograde cholangiopancreatography (ERCP), and EUS.
Abdominal Plain Films

Plain films of the abdomen may be useful in patients with acute and chronic pancreatitis. In patients
with acute pancreatitis, the most common finding on plain film include a generalized ileus with air fluid
levels, a localized ileus or “sentinel loop” of jejunum or duodenum in the area of the inflamed pancreas,
1360
booksmedicos.org
or a cutoff of the colon due to distention of the transverse colon. In the setting of acute pancreatic fluid
collections or pseudocysts, one may see an actual mass on plain film with displacement of the stomach
or duodenum.24 These findings are not sensitive or specific for acute pancreatitis, but in the setting of
elevated amylase and lipase and associated abdominal symptoms can provide support for the diagnosis
and an indication for more sensitive pancreatic imaging studies.
In the setting of chronic pancreatitis the most common finding on plain film is the presence of
calcifications within the pancreas. These are most commonly seen at the level of the second lumbar
vertebrae, where the pancreas lies in the retroperitoneum.
Upper Gastrointestinal Series

In the setting of a mass or mass effect on plain film, an upper gastrointestinal series can demonstrate
displacement of the stomach or duodenum by a retroperitoneal mass. Displacement or narrowing of the
duodenal C-loop suggests the presence of a pancreatic mass. However, the character of the mass
(inflammatory, neoplastic, cystic, etc.) cannot be further defined on upper gastrointestinal series.24 For
this reason, upper gastrointestinal series has been largely replaced by ultrasound and other cross-
sectional imaging modalities such as CT or MRCP.
Ultrasonography
Abdominal ultrasound can be useful in the setting of acute pancreatitis, chronic pancreatitis, pancreatic
cystic lesions, pancreatic pseudocysts, and pancreatic cancer. In acute pancreatitis, the abdominal
ultrasound may demonstrate gallstones, suggesting a potential etiology. In addition, the ultrasound can
identify an enlarged pancreas, pancreatic edema and peripancreatic fluid collections consistent with the
diagnosis of acute pancreatitis. Ultrasound can also identify pancreatic pseudocysts, cystic lesions, and
other pancreatic masses.24 Pancreatic pseudocysts usually appear as a smooth, round fluid collection
without acoustic shadowing. A pancreatic cancer is more likely to distort the underlying pancreatic
anatomy and appear as a localized, solid lesion on ultrasound, also without acoustic shadowing. Cystic
neoplasms of the pancreas can have both solid and cystic components. They can be uniloculated or
multiloculated and contain cysts of varying size. A large uniloculated neoplastic cyst is difficult to
differentiate from a pancreatic pseudocyst.
Ultrasound examination can be limited by obesity, overlying bowel gas, recently performed barium
contrast studies. Small masses or fluid collections can be easily missed. The presence of a mass on
ultrasound is an indication for more extensive workup via CT or MRCP imaging.
Computed Tomography
Contrast enhanced, multidetector helical 3D CT is the most commonly performed study for the detection
and characterization of pancreatic solid and cystic tumors. It is also useful in defining the pancreatic
anatomy in the presence of chronic pancreatitis and identifying and following the complications of acute
pancreatitis. CT is very sensitive for identifying pancreatic masses as small as 1 cm and can accurately
distinguish solid from cystic lesions. The density of the lesion on CT can provide clues as to the
diagnosis. Pancreatic adenocarcinomas are usually solid and hypodense, whereas pancreatic
neuroendocrine tumors are vascular and appear hyperdense. Both pseudocysts and cystic lesions have
components with fluid density.
CT is sensitive for the diagnosis of a malignant pancreatic adenocarcinoma. However, it is less
sensitive and accurate in the diagnosis of cystic lesions. As CT scans are more commonly performed for
a variety of indications, many cystic lesions are found incidentally. CT can be useful in identifying the
characteristics associated with malignancy including tumor size greater than 3 cm, a dilated main
pancreatic duct, and solid components within the cystic lesion.54 However, significant controversy
remains regarding observation versus resection of pancreatic cystic lesions.
Endoscopic Ultrasound
Compared to transabdominal ultrasound, EUS provides higher-resolution images of the pancreatic
parenchyma and pancreatic duct. This procedure uses a transducer fixed to an endoscope that can be
directed to the surface of the pancreas through the stomach or duodenum. EUS provides a useful adjunct
to CT in the diagnosis of mucinous cystic lesions and malignancies. Pancreatic masses and cystic lesions
can be well visualized on EUS, providing information about tumor size and invasion of major vascular
structures. While more invasive than CT, EUS can provide useful additional information. EUS allows for
fine-needle aspiration and/or biopsy, providing a tissue diagnosis, which is critical in the setting of
1361
booksmedicos.org
planned neoadjuvant therapy for pancreatic adenocarcinoma. EUS can also provide information about
pancreatic ductal anatomy without the risk of invasive ERCP, which can cause severe pancreatitis.
A list of 11 EUS criteria has been defined for the diagnosis of chronic pancreatitis. The ductal criteria
include pancreatic duct stones, echogenic ductal walls, irregular ductal walls, pancreatic duct strictures,
visible side branches, and ductal dilatation. The parenchyma criteria include echogenic strands,
echogenic foci, calcifications, lobular contour, and pancreatic cysts. Recent studies have determined that
three or more EUS criteria provides the best balance of sensitivity and specificity for histologic
pancreatic fibrosis.55
Finally, in the setting of intractable pain in unresectable pancreatic cancer, chemical neurolysis of the
celiac ganglion can be performed under EUS guidance. As with any endoscopic procedure, the risks
include perforation of the stomach and/or duodenum.
Magnetic Resonance Cholangiopancreatography

MRCP is now being used more commonly as a noninvasive way to image both the biliary and pancreatic
ducts. MRCP can provide excellent images and detect abnormalities of the common bile duct and main
pancreatic duct, but it is more limited in its ability to detect abnormalities in the secondary ducts. This
noninvasive imaging technique is very useful in high-risk patients and pregnant patients. It is also useful
in diagnosis of persistent choledocholithiasis in the setting of gallstone pancreatitis. MRCP is most
useful in settings where intervention such as biopsy or biliary drainage are unnecessary, thereby
avoiding the risk of ERCP. MRCP can be a good modality for defining pancreatic ductal anatomy in
patients with chronic pancreatitis and pancreatic pseudocysts to help plan operative management.
Endoscopic Retrograde Cholangiopancreatography

ERCP is the gold standard for providing information about pancreatic ductal anatomy. However, it is
associated with significant complications and can often be avoided by using the previously described
noninvasive tests. Five percent to 20% of patients develop clinical pancreatitis after ERCP and 25% to
75% have elevated amylase and lipase levels.24 There is no way to prevent post-ERCP pancreatitis;
however, high-pressure injection of the pancreatic duct is thought to contribute. Perforation of the
gastrointestinal tract is a potential complication of ERCP.
ERCP is performed less commonly since much of the information can now be obtained with CT,
MRCP, and/or EUS. However, it remains the procedure of choice when there is a high likelihood for the
need of therapeutic intervention. For example, in patients with persistently elevated liver function tests
in the setting of common duct stones ERCP is both diagnostic and therapeutic.
Pancreatic cancer is characterized by obstruction or stenosis of the pancreatic duct and or common
bile duct (double-duct sign). ERCP remains the primary modality for palliation of obstructive jaundice
with endostent placement. In chronic pancreatitis, the pancreatic duct may have irregularities including
stenosis, dilation, sacculation, and ectasia. Pancreatic duct stones may be present within the pancreatic
duct. Similar ductal changes can be observed immediately following acute attacks of pancreatitis.
However, these abnormalities can be detected on MRCP or CT.
References
1. Klein SD, Affronti JP. Pancreas divisum, an evidence-based review: part II, patient selection and
treatment. Gastrointest Endosc 2004;60(4):585–589.
2. Levy MJ, Geenen JE. Idiopathic acute recurrent pancreatitis. Am J Gastroenterol 2001;96(9):2540–
2555.
3. Testoni PA. Aetiologies of recurrent acute pancreatitis: acute or chronic relapsing disease? JOP
2001;2(6):357–367.
4. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: controversial clinical significance. Dig Dis
1988;6(1):30–39.
5. Delhaye M, Engelholm L, Cremer M. Pancreas divisum: congenital anatomic variant or anomaly?
Contribution of endoscopic retrograde dorsal pancreatography. Gastroenterology 1985;89(5):951–
958.
6. Cotton PB. Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis.
Gut 1980;21(2):105–114.
7. Khalid A, Slivka A. Approach to idiopathic recurrent pancreatitis. Gastrointest Endosc Clin N Am
1362
booksmedicos.org
2003;13(4):695–716, x.
8. Manfredi R, Costamagna G, Brizi MG, et al. Pancreas divisum and “santorinicele”: diagnosis with
dynamic MR cholangiopancreatography with secretin stimulation. Radiology 2000;217(2):403–408.
9. Ravitch MM, Woods AC, Jr. Annular pancreas. Ann Surg 1950;132(6):1116–1127.
10. Theodorides T. [Annular Pancreas]. J Chir (Paris) 1964;87:445–462.
11. Chevillotte G, Sahel J, Raillat A, et al. Annular pancreas. Report of one case associated with acute
pancreatitis and diagnosed by endoscopic retrograde pancreatography. Dig Dis Sci 1984;29(1):75–
77.
12. Glazer GM, Margulis AR. Annular pancreas: etiology and diagnosis using endoscopic retrograde
cholangiopancreatography. Radiology 1979;133(2):303–306.
13. Zyromski NJ, Sandoval JA, Pitt HA, et al. Annular pancreas: dramatic differences between children
and adults. J Am Coll Surg 2008;206(5):1019–1025; discussion 1025–1017.
14. Ikeda Y, Irving IM. Annular pancreas in a fetus and its three-dimensional reconstruction. J Pediatr
Surg 1984;19(2):160–164.
15. Guillou L, Nordback P, Gerber C, et al. Ductal adenocarcinoma arising in a heterotopic pancreas
situated in a hiatal hernia. Arch Pathol Lab Med 1994; 118(5):568–571.
16. Makhlouf HR, Almeida JL, Sobin LH. Carcinoma in jejunal pancreatic heterotopia. Arch Pathol Lab
Med 1999;123(8):707–711.
17. Kleinman R, Gingerich R, Wong H, et al. Use of the Fab fragment for immunoneutralization of
somatostatin in the isolated perfused human pancreas. Am J Surg 1994;167(1):114–119.
18. Greenberger N, Toskes P. Chapter 307. Acute and chronic pancreatitis (chapter). In: Fauci AS,
Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed: McGraw Hill:
http://www.accessmedicine.com/content.aspx?aid=2875598. Accessed January 4, 2009.
19. Valenzuela JE, Weiner K, Saad C. Cholinergic stimulation of human pancreatic secretion. Dig Dis Sci
1986;31(6):615–619.
20. Konturek SJ, Becker HD, Thompson JC. Effect of vagotomy on hormones stimulating pancreatic
secretion. Arch Surg 1974;108(5):704–708.
21. Oh HC, Kim MH, Choi KS, et al. Analysis of PRSS1 and SPINK1 mutations in Korean patients with
idiopathic and familial pancreatitis. Pancreas 2008; 38(2), 180–183.
22. Masamune A, Kume K, Shimosegawa T. Differential roles of the SPINK1 gene mutations in alcoholic
and nonalcoholic chronic pancreatitis. J Gastroenterol 2007;42 suppl 17:135–140.
23. Dreiling D, Wolfson P. New Insights into Pancreatic Disease Revealed by the Secretin Test (chapter). Vol
2. Philadelphia, PA: Lea and Febiger; 1979.
24. Toskes P, Greenberger N. Chapter 306. Approach to the patient with pancreatic disease (chapter).
In: Fauci AS, Braunwald E, Kasper DL, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed:
McGraw Hill: http:///www.accessmedicine.com/content.aspx?aID=2875521. Accessed January 4,
2009.
25. Noda A, Hayakawa T, Kondo T, et al. Clinical evaluation of pancreatic excretion test with
dimethadione and oral BT-PABA test in chronic pancreatitis. Dig Dis Sci 1983;28(3):230–235.
26. Goff JS. Two-stage triolein breath test differentiates pancreatic insufficiency from other causes of
malabsorption. Gastroenterology 1982;83(1 Pt 1):44–46.
27. Smith RC, Southwell-Keely J, Chesher D. Should serum pancreatic lipase replace serum amylase as
a biomarker of acute pancreatitis? ANZ J Surg 2005; 75(6):399–404.
28. Kemppainen E, Hedstrom J, Puolakkainen P, et al. Increased serum trypsinogen 2 and trypsin 2-
alpha 1 antitrypsin complex values identify endoscopic retrograde cholangiopancreatography
induced pancreatitis with high accuracy. Gut 1997;41(5):690–695.
29. Kemppainen EA, Hedstrom JI, Puolakkainen PA, et al. Rapid measurement of urinary trypsinogen-2
as a screening test for acute pancreatitis. N Engl J Med 1997;336(25):1788–1793.
30. Nanjo K, Sanke T, Miyano M, et al. Diabetes due to secretion of a structurally abnormal insulin
(insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin. J Clin Invest
1986;77(2):514–519.
31. Opara EC, Atwater I, Go VL. Characterization and control of pulsatile secretion of insulin and
glucagon. Pancreas 1988;3(4):484–487.
1363
booksmedicos.org
32. Bell GI, Kayano T, Buse JB, et al. Molecular biology of mammalian glucose transporters. Diabetes
Care 1990;13(3):198–208.
33. Orci L, Unger RH, Ravazzola M, et al. Reduced beta-cell glucose transporter in new onset diabetic
BB rats. J Clin Invest 1990;86(5):1615–1622.
34. Ebert R, Creutzfeldt W. Gastrointestinal peptides and insulin secretion. Diabetes Metab Rev
1987;3(1):1–26.
35. Leahy JL, Bonner-Weir S, Weir GC. Abnormal glucose regulation of insulin secretion in models of
reduced B-cell mass. Diabetes 1984;33(7):667–673.
36. Mulvihill S, Pappas TN, Passaro E Jr, et al. The use of somatostatin and its analogs in the treatment
of surgical disorders. Surgery 1986;100(3):467–476.
37. Alghamdi AA, Jawas AM, Hart RS. Use of octreotide for the prevention of pancreatic fistula after
elective pancreatic surgery: a systematic review and meta-analysis. Can J Surg 2007;50(6):459–466.
38. Allen PJ, Gonen M, Brennan MF, et al. Pasireotide for postoperative pancreatic fistula. N Engl J
Med 2014;370(21):2014–2022.
39. Malleo G, Pulvirenti A, Marchegiani G, et al. Diagnosis and management of postoperative
pancreatic fistula. Langenbeck’s Arch Surg. 2014;399(7):801–810.
40. Cubilla AL, Fortner J, Fitzgerald PJ. Lymph node involvement in carcinoma of the head of the
pancreas area. Cancer 1978;41(3):880–887.
41. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal
gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma,
part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg
2002;236(3):355–366; discussion 366–358.
42. Japanese Pancreas Society. Classification of Pancreatic Carcinoma, First English Edition. Tokyo:
Kanehara and Complany, Ltd.; 1996.
43. Ahren B, Taborsky GJ Jr, Porte D Jr. Neuropeptidergic versus cholinergic and adrenergic regulation
of islet hormone secretion. Diabetologia 1986; 29(12):827–836.
44. Havel PJ, Taborsky GJ Jr. The contribution of the autonomic nervous system to changes of
glucagon and insulin secretion during hypoglycemic stress. Endocr Rev 1989;10(3):332–350.
45. Yeo TP, Hruban RH, Leach SD, et al. Pancreatic cancer. Curr Probl Cancer 2002;26(4):176–275.
46. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas-616 patients: results,
outcomes, and prognostic indicators. J Gastrointest Surg 2000;4(6):567–579.
47. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for
unresectable periampullary cancer? a prospective randomized trial. Ann Surg 1999;230(3):322–328;
48. Nagaraja V, Eslick GD, Cox MR. Endoscopic stenting versus operative gastrojejunostomy for
malignant gastric outlet obstruction-a systematic review and meta-analysis of randomized and non-
randomized trials. J Gastrointest Oncol 2014;5(2):92–98.
49. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic
Adenocarcinoma. Version I.2016. Available from:
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed June 24, 2016.
50. Seicean A. Celiac plexus neurolysis in pancreatic cancer: the endoscopic ultrasound approach. World
J Gastroenterol 2014;20(1):110–117.
51. Michaels AJ, Draganov PV. Endoscopic ultrasonography guided celiac plexus neurolysis and celiac
plexus block in the management of pain due to pancreatic cancer and chronic pancreatitis. World J
Gastroenterol 2007; 13(26):3575–3580.
52. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with
unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993;217(5):447–455;
53. Gao L, Yang YJ, Xu HY, et al. A randomized clinical trial of nerve block to manage end-stage
pancreatic cancerous pain. Tumour Biol 2014;35(3):2297–2301.
54. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the
management of IPMN and MCN of the pancreas. Pancreatology 2012;12(3):183–197.
55. Chong AK, Hawes RH, Hoffman BJ, et al. Diagnostic performance of EUS for chronic pancreatitis: a
comparison with histopathology. Gastrointest Endosc 2007;65(6):808–814.
1364
booksmedicos.org
Chapter 53
Acute Pancreatitis
Jason S. Gold and Edward E. Whang
Key Points
1 In the United States, more than 75% of cases of acute pancreatitis are attributable to either
gallstones or alcohol.
2 In general, a diagnosis of acute pancreatitis can be made with the presence of two of the following
three features: (1) characteristic abdominal pain (acute onset of severe, persistent epigastric pain
often radiating to the back); (2) serum lipase (or amylase) levels at least three times greater than
the upper limit of normal; and (3) findings of acute pancreatitis on contrast-enhanced CT or MRI.
3 Approximately 80% of cases of acute pancreatitis are mild, associated with minimal systemic
derangements, and generally resolve within 5 to 7 days, even with minimaltherapy.
4 Severe acute pancreatitis accounts for about 20% of cases and is defined as acute pancreatitis
associated with one or more of the following: pancreatic necrosis, distant organ failure, and the
development of local complications such as hemorrhage, abscess, or pseudocyst.
5 The mortality rate associated with severe acute pancreatitis ranges from 10% to 20%, with half of
the deaths in the first 2 weeks as the result of SIRS-induced multisystem organ failure and the
remaining occurring later as the result of pancreatic necrosis/infection.
6 The most important component of initial management of acute pancreatitis is fluid resuscitation.
7 Early ERCP in acute pancreatitis has been subjected to extensive study. Early ERCP with stone
extraction and sphincterotomy clearly benefits the subset of patients with gallstone pancreatitis who
have cholangitis.
8 Infection of pancreatic and peripancreatic necrosis complicates 30% to 70% of cases of acute
necrotizing pancreatitis and most commonly becomes established during the second to third weeks
after onset of disease.
9 Infected necrosis is suggested by clinical signs such as persistent fever, increasing leukocytosis, and
imaging findings such as gas in peripancreatic collections. When the necessary, infected necrosis can
be confirmed by CT-guided fine needle aspiration.
10 Invasive intervention is usually indicated in the presence of infected necrosis. In contrast, sterile
necrotic collections almost never require intervention in the acute phase of necrotizing pancreatitis.
11 Procedures for the treatment of infected necrosis are best performed when collections become
walled off and demarcated from viable pancreatic tissue with at least partial liquefaction, which
typically requires a delay of 4 to 6 weeks after disease onset.
12 Drainage alone is now the initial recommended intervention for infected pancreatic necrosis. This is
most often accomplished through a percutaneous image-guided approach. When percutaneous drains
are placed, preference should be given to a retroperitoneal approach. Drainage can also be
accomplished through an endoscopic transluminal approach.
13 When required, débridement can often be performed through minimally invasive techniques.
14 Current well-accepted indications for intervention on pseudocysts and walled-off necrosis in the
absence of infection include the presence of symptoms attributable to the collection such as
intractable pain or obstruction of the stomach, duodenum or bile duct.
15 There are multiple treatment options available for the treatment of pancreatic pseudocysts and
sterile walled-off necrosis, including percutaneous aspiration, percutaneous drainage, and internal
drainage (performed transabdominally or endoscopically).
Acute pancreatitis is an acute inflammatory process of the pancreas with variable involvement of other
regional tissues or remote organ systems.1 In the United States, more than 250,000 patients are
1365
booksmedicos.org
hospitalized annually with acute pancreatitis as the primary diagnosis. It is the principal cause of
approximately 3,000 deaths per year and a contributing factor in an additional 2,500 deaths. The direct
cost attributable to acute pancreatitis exceeds $2.5 billion per year in the United States.2
CLASSIFICATION AND DEFINITIONS

A useful system for defining and classifying acute pancreatitis and its complications was recently
developed through an iterative process involving several national and international pancreas
organizations.3 This new system is a modification of widely accepted but outdated classification system
originally derived from a multidisciplinary symposium held in 1992.1 The clinically based definitions
reached by consensus are shown in Table 53-1.
PATHOLOGY AND PATHOPHYSIOLOGY

The typical pathologic correlate of mild acute pancreatitis is interstitial edematous pancreatitis, in which
the pancreatic parenchyma is edematous and infiltrated with inflammatory cells. Gross architectural
features are preserved. In contrast, in necrotizing pancreatitis variable amounts of pancreatic parenchyma
and peripancreatic fat have undergone tissue necrosis, with vascular inflammation and thrombosis being
prominent features.
Studies using experimental models suggest that prototypical molecular and cellular derangements lead
to pancreatic injury, regardless of the specific etiology or inciting event that triggers an episode of acute
pancreatitis. Among the earliest of these derangements appears to be abnormal activation of proteolytic
enzymes within pancreatic acinar cells.4 Under normal conditions, trypsinogen and other digestive
zymogens are stored in granules that are segregated from lysosomal enzymes (e.g., cathepsin B) and
acid. Early in the course of acute pancreatitis, cytoplasmic vacuoles containing activated proteolytic
enzymes appear. How the digestive enzymes are activated, and what role these vacuoles play has been
the subject of much investigation. In the prevailing model, trypsinogen is believed to be activated to
yield trypsin either by colocalization with the lysosomal hydrolase cathepsin B5 or through
autoactivation due to a moderately acidic pH6. It has been noted that the cytoplasmic vacuoles
appearing in the acinar cell in experimental acute pancreatitis share expression of proteins with
autophagosomes. Autophagosomes are vacuoles that degrade cellular components such as organelles in
the process of autophagy. Highlighting the possible importance of autophagy in the development of
pancreatitis, mice lacking expression of the autophagy-related gene Atg5 in the pancreas fail to exhibit
prototypical features of acute pancreatitis.7
CLASSIFICATION
Table 53-1 Terms Used in the Classification of Acute Pancreatitis
1366
booksmedicos.org
Figure 53-1. Schematic diagram depicting activation of proteolytic enzymes, possibly through colocalization of zymogen granules
and lysosomes, and subsequent rupture of zymogen granules releasing the activated enzymes into the cytoplasm of the pancreatic
acinar cell. The activated enzymes then undergo disordered basolateral discharge from the acinar cell into the pancreatic
parenchyma.
Acinar cell injury induced by active trypsin allows it to be released into the pancreatic parenchyma
(Fig. 53-1) where it activates more trypsin and other digestive enzymes (e.g., chymotrypsin,
phospholipase, and elastase). Trypsin can also activate the complement, kallikrein-kinin, coagulation,
and fibrinolysis cascades within the pancreatic parenchyma. Activation of these enzymes is believed to
initiate a vicious cycle in which activated enzymes cause cellular injury, an event that leads to the
release of even more destructive enzymes. This cycle can overwhelm defense mechanisms that normally
serve to limit the injurious consequences of premature trypsin activation within the pancreas (e.g.,
pancreatic secretory trypsin inhibitor–mediated inhibition of trypsin activity).
An inflammatory response is then generated in response to the initial acinar cell injury. This
inflammatory response is marked by the infiltration of the pancreatic parenchyma with immune cells
such as neutrophils, macrophages, monocytes, and lymphocytes and the release of a broad range of
proinflammatory mediators such as tumor necrosis factor (TNF) α; interleukins (IL) 1β, 6, and 8;
platelet-activating factor; chemokines (i.e., CXCL2 and CCL2); prostaglandins; and leukotrienes. The
inflammatory response, to a large extent, determines the severity of pancreatitis, and the blockade of
several components of the inflammatory response ameliorates the disease and reduces mortality in
experimental models. The understanding of how the initial acinar cell injury provokes an inflammatory
response is incomplete, but it appears that reactive oxygen species (ROS) and innate molecular pattern
1367
booksmedicos.org
recognition (i.e., damage/danger-associated pattern molecules and toll-like receptors (TLRs) as well as
the activation of transcription factors such as NF-κB play a role.8
The result of these events is pancreatic autodigestion, with injury to the vascular endothelium,
interstitium, and acinar cells. Increases in vascular permeability lead to interstitial edema.
Vasoconstriction, thrombosis, and capillary stasis can lead to ischemic (and perhaps ischemia–
reperfusion) injury and the development of pancreatic necrosis. With severe pancreatic injury, the
systemic inflammatory response syndrome (SIRS) and distant organ failure can occur. The systemic
complications are believed to be mediated by digestive enzymes and inflammatory mediators released
from the injured pancreas. For example, activated phospholipase A–induced digestion of lecithin (an
important component of pulmonary surfactant) may play a role in pathogenesis of acute respiratory
distress syndrome (ARDS) that occurs in the setting of acute pancreatitis. In addition, the circulatory
and inflammatory effects induced by acute pancreatitis are postulated to impair intestinal epithelial
barrier function, allowing for the translocation of bacteria from the intestinal lumen into the systemic
circulation. This phenomenon has been demonstrated to occur in animal models and may account for the
pathogenesis of pancreatic and peripancreatic infection that can complicate necrotizing pancreatitis.
ETIOLOGY
1 Although many etiologies of acute pancreatitis have been described, in the United States, more than
75% of cases are attributable to either gallstones or alcohol.
Gallstones
Gallstones cause approximately 35% of episodes of acute pancreatitis in the United States. In a
mechanistic model proposed over a century ago, a gallstone lodged at the papilla of Vater occludes the
ampullary orifice, leading to retrograde reflux of bile into the pancreatic duct through a common
channel shared by the common bile duct and the pancreatic duct (Fig. 53-2). Although elements of this
model have been challenged, the prevailing view is that transient or persistent obstruction of the
ampullary orifice by a gallstone or edema induced by stone passage is the inciting factor in the
pathogenesis of gallstone-induced pancreatitis. Microlithiasis refers to aggregates (<5 mm in diameter)
of cholesterol monohydrate crystals or calcium bilirubinate granules detected as “sludge” within the
gallbladder on ultrasonography or on examination of bile obtained during endoscopic retrograde
cholangiopancreatography (ERCP). An etiologic role for microlithiasis in acute pancreatitis remains
unproved; however, data derived from case-control studies suggest that cholecystectomy or endoscopic
sphincterotomy can reduce the risk of recurrent acute pancreatitis in patients with microlithiasis.
Figure 53-2. Illustration of the common channel concept. A gallstone lodged at the ampulla of Vater can cause reflux of bile into
the pancreatic duct.
Alcohol
1368
booksmedicos.org
Ethanol causes approximately 40% of cases of acute pancreatitis in the United States. Most patients with
alcohol-induced acute pancreatitis also have underlying chronic pancreatitis. Potential mechanisms by
which alcohol-induced pancreatitis include sphincter of Oddi spasm, obstruction of small pancreatic
ductules by proteinaceous plugs, alcohol-induced metabolic abnormalities (e.g., hyperlipidemia), and
direct toxic effects induced by alcohol and its metabolites (e.g., acetaldehyde, acetate, and nonesterified
fatty acids).
Other Etiologies
A wide range of other etiologies of acute pancreatitis have been identified (Table 53-2). Ongoing
investigations are beginning to reveal specific gene abnormalities (e.g., mutations in cationic
trypsinogen PRSS1, pancreatic secretory trypsin inhibitor SPINK1, and the cystic fibrosis transmembrane
conductance regulator CFTR) that can be associated with pancreatitis. Patients for whom no etiology
can be identified despite thorough evaluation are classified as having idiopathic pancreatitis.
ETIOLOGY
Table 53-2 Etiology of Acute Pancreatitis
Abdominal pain, nausea, and vomiting are the most prevalent symptoms associated with acute
pancreatitis. The pain is visceral in quality, is localized to the epigastrium, often radiates to the back,
and may be alleviated with the patient leaning forward. Abdominal tenderness is the most prevalent
sign of acute pancreatitis. Tachycardia and hypotension may result from intravascular hypovolemia.
Low-grade fevers are common, but high-grade fevers are unusual in the absence of intra- or
extrapancreatic infection. Jaundice may be evident in the presence of cholangitis (e.g., with gallstone-
induced pancreatitis and persistent choledocholithiasis) or liver disease (alcohol-induced pancreatitis in
a patient with cirrhosis). Evidence of retroperitoneal hemorrhage may be become apparent if blood
dissects into the subcutaneous tissues of the flanks (Grey Turner sign), umbilicus (Cullen sign), or
1369
booksmedicos.org
inguinal region (Fox sign); however, these findings are unusual. In approximately 20% of cases, acute
pancreatitis is associated with SIRS, hemodynamic lability, and/or organ failure (particularly
compromise of the cardiovascular, pulmonary, and renal systems) on presentation.
DIAGNOSIS
2 The differential diagnosis of acute pancreatitis includes other conditions causing acute upper
abdominal pain, such as biliary colic and cholecystitis, acute mesenteric ischemia, small bowel
obstruction, visceral perforation, and ruptured aortic aneurysm. Acute exacerbations of chronic
pancreatitis can also be associated with clinical features resembling those of acute pancreatitis. In
general, a diagnosis of acute pancreatitis can be made with the presence of two of the following three
features: (1) characteristic abdominal pain (acute onset of severe, persistent epigastric pain often
radiating to the back); (2) serum lipase (or amylase) levels at least three times greater than the upper
limit of normal; and (3) findings of acute pancreatitis on contrast-enhanced computed tomography (CT)
or magnetic resonance imaging (MRI).9,10 Imaging tests should be used selectively, to rule out other
diagnoses and for the indications discussed later. In cases of typical abdominal pain and confirmatory
laboratory tests, imaging is usually not needed at the time of admission.
Laboratory Tests
With pancreatic injury, a variety of digestive enzymes escape from acinar cells and enter the systemic
circulation. Of these enzymes, amylase is the most widely assayed to confirm the diagnosis of acute
pancreatitis. Amylase levels rise within several hours after onset of symptoms and typically remain
elevated for 3 to 5 days during uncomplicated episodes of mild acute pancreatitis. Because of the short
serum half-life of amylase (10 hours), levels can normalize as soon as 24 hours after disease onset. The
sensitivity of this test depends on what threshold value is used to define a positive result (90%
sensitivity with a threshold value just above the normal range vs. 60% sensitivity with a threshold value
at three times the upper limit of normal). Specificity (which also varies with the threshold values
selected) is limited because a wide range of disorders can cause elevations in serum amylase
concentration. Assays that detect increases in the serum concentration of amylase of pancreatic origin
(P-isoamylase) alone are associated with greater specificity. Increased urinary amylase concentrations
and amylase-to-creatinine clearance ratios occur with acute pancreatitis; however, these parameters
offer no advantage over serum amylase concentrations, except in the evaluation of macroamylasemia
(in which urinary amylase excretion is not increased despite elevations in serum amylase
concentration).
Serum lipase concentrations increase with kinetics similar to those of amylase. It has a longer serum
half-life than amylase, however, and may be useful for diagnosing acute pancreatitis late in the course
of an episode (at which time serum amylase concentrations may have already normalized). Although
lipase is more specific than amylase in the diagnosis of acute pancreatitis, note that lipase is produced at
a range of nonpancreatic sites, including the intestine, liver, biliary tract, and stomach, and tongue.
The magnitude of the increases in amylase or lipase concentrations has no correlation with severity of
pancreatitis. In general, the magnitude of increases in amylase concentrations tends to be greater in
patients with gallstone pancreatitis than in those with alcohol-induced pancreatitis; however, this
finding is unreliable in distinguishing between these two etiologies.
Imaging Tests
Findings on plain radiographs associated with acute pancreatitis are nonspecific and include ileus that
may be generalized or localized to a segment of small intestine (“sentinel loop”) or transverse colon
(“colon cut-off sign”), psoas muscle margins that are obscured by retroperitoneal edema, an elevated
hemidiaphragm, pleural effusions, and basilar atelectasis.
Ultrasonography may reveal a diffusely enlarged, hypoechoic pancreas. However, overlying bowel
gas (particularly prominent with ileus) limits visualization of the pancreas in a large percentage of
cases. Although ultrasonography has poor sensitivity in the diagnosis of acute pancreatitis, it plays an
important role in the identification of the etiology of pancreatitis (e.g., the detection of gallstones).
CT scanning is the most important imaging test in the evaluation of acute pancreatitis. CT findings of
mild acute pancreatitis include pancreatic enlargement and edema, effacement of the normal lobulated
contour of the pancreas, and stranding of peripancreatic fat (Fig. 53-3). In addition, dynamic CT
1370
booksmedicos.org
scanning performed after the bolus administration of intravenous contrast can demonstrate regions of
pancreas that have poor or no perfusion, as seen with pancreatic necrosis (Fig. 53-4). Detection of
necrosis plays an important role in assessment of disease severity, as discussed further later. CT can also
characterize collections and other complications associated with acute pancreatitis.
Figure 53-3. Computed tomography scan of acute interstitial pancreatitis.
Figure 53-4. Computed tomography scan of acute necrotizing pancreatitis.
MRI and magnetic resonance cholangiopancreatography (MRCP) are being used with increasing
frequency in patients with acute pancreatitis. These examinations have the potential to offer better
definition of pancreatic and biliary ductal abnormalities than CT scanning, and they are applicable in
patients for whom ionizing radiation or iodinated intravenous contrast agents used in CT scanning are
contraindicated. MRI can suggest the presence of pancreatic necrosis even without the use of
intravenous gadolinium. MRI also has the advantage of better characterizing collections associated with
acute pancreatitis, in particular with respect to differentiating solid from liquid components.
Disadvantages of MRI include high cost, limited availability, and the long duration of examinations.
ASSESSMENT OF DISEASE SEVERITY

3 Approximately 80% of cases of acute pancreatitis are mild, associated with minimal systemic
derangements, and generally resolve within 5 to 7 days, even with minimal therapy. The mortality rate
associated with mild acute pancreatitis is less than 1%.
4, 5 Approximately 20% of cases are associated with either organ failure or the development of local
complications. The mortality rate for these patients ranges from approximately 10% to 20% in
contemporary series.11–14 One-half of deaths occur within the first 2 weeks after the onset of symptoms;
these deaths are primarily the result of SIRS-induced multisystem organ failure. Most of the remaining
deaths occur beyond 2 weeks after presentation and result from complications of pancreatic necrosis,
especially infection.
1371
booksmedicos.org
Accurate prediction of severity early in the course of disease offers potential benefits in that
complications can be anticipated and detected early through the use of intensive monitoring and
frequent clinical assessment, and early and aggressive therapies can be instituted to attempt to prevent
these complications. Several methods for assessing disease severity based on clinical parameters, serum
markers, imaging, and scoring systems have been widely studied.
Revised Atlanta and Determinant-Based Classifications

An optimal system for the classification of severity of acute pancreatitis has not been universally
accepted. Nevertheless, it is widely recognized that organ failure and local complications, particularly
necrosis, are the two most important predictors of disease severity. While these two variables are often
associated, they differ as to when in the course of disease they typically arise and the manner in which
they contribute to disease severity. The early phase of acute pancreatitis (generally the first week after
onset of symptoms) is characterized by the host response to the local pancreatic injury. Disease severity
in the early phase is thus determined by organ failure resulting from the systemic inflammatory
response. Organ failure can be immediately apparent on clinical presentation, and in fact, organ failure
occurring in the early phase of disease is usually present on admission. In contrast, pancreatic necrosis,
which occurs in 5% to 10% of cases of acute pancreatitis, may not be apparent on initial presentation
and the extent of local complications can continue to evolve into the late phase of disease. Organ failure
and death in the late phase are often determined by local complications, particularly infected necrosis.3
While local complications can contribute to the mortality of patients with organ failure, there is also a
subset of patients with pancreatic necrosis without organ failure who experience significant morbidity
but have very low mortality.13
Two classification schemes based on organ failure and local complications have been proposed (Table
53-3).3,13,15 While these classification schemes are quite useful and validated in predicting mortality,11,14
their utility in predicting the course of disease on admission or within the first few days of
hospitalization is limited by the fact that local complications and the resultant organ failure occurring in
the late phase of the disease have not become apparent. Furthermore, a distinction is made between
transient organ failure and persistent organ failure. This distinction cannot be made at the time of
presentation. Similarly, the distinction between sterile necrosis and infected necrosis in the
Determinant-Based Classification cannot be made with certainty until a patient with necrotizing
pancreatitis shows signs of resolution.
Scoring Systems
The Ranson criteria, which is based on age, white blood cell count (WBC), glucose, serum lactate
dehydrogenase (LDH), and serum aspartate aminotransferase (AST) all determined on admission as well
as hematocrit drop, blood urea nitrogen (BUN), serum calcium, arterial partial pressure of oxygen
(PaO2), base deficit, and fluid requirement all determined after 48 hours, are easily tabulated, and the
resulting scores are well correlated with morbidity and mortality rates.16 The presence of three or more
of these criteria is indicative of severe acute pancreatitis. Important limitations of the Ranson criteria
are that the predictive score cannot be determined prior to 48 hours following admission and that it can
only be used once. Furthermore, because these criteria were developed using a cohort of patients for
whom alcohol was the predominant etiology of pancreatitis, their generalizability may be limited. A
similar predictive scoring system developed in Glasgow using a cohort of patients for whom gallstones
were the predominant etiology of pancreatitis is available.17
Acute Physiology and Chronic Health Evaluation (APACHE) II scores, which are based on patient age,
indices of chronic health, and physiologic parameters, can be determined at any time after admission,
can be updated continuously during the course of disease and may have greater predictive power than
Ranson scores.18 However, the complexity of calculating APACHE II (or related APACHE III) scores
limits its application in routine clinical practice.
STAGING
Table 53-3 Criteria for Assessing Severity of Pancreatitis
1372
booksmedicos.org
Recently another scoring system, the Bedside Index for Severity in Acute Pancreatitis (BISAP), based
on five relatively straightforward parameters that are obtained within the first 24 hours of hospital
admission, has been proposed. One point is assigned for the presence of each of the following: BUN
>25 mg/dL, impaired mental status, SIRS, age >60 years, and the presence of a pleural effusion.19 The
BISAP has been validated and is comparable to the Ranson criteria20,21 and the APACHE II Score19,21,22
in its prediction of mortality.
Computed Tomography Scanning

The diagnostic application of CT scanning was discussed previously. Although not required for making a
diagnosis on admission, a CT is often useful in patients who deteriorate or fail to improve. This
technique is associated with greater than 90% sensitivity in the detection of pancreatic necrosis, a
finding that is predictive of disease severity. Furthermore, CT scanning can also diagnose and
characterize collections and can indicate infection (e.g., if air bubbles are present) in some cases.
Because necrosis takes time to develop (in some patients up to 5 days), a contrast-enhanced CT scan
obtained too early in the disease course (e.g., at the time of admission) does not have predictive value
beyond clinical assessment (i.e., APACHE II or BISAP scoring).23 In addition, concerns that early
administration of iodinated intravenous contrast agents used in CT scanning may exacerbate pancreatic
injury have been raised, although these agents have not been shown to cause or exacerbate pancreatitis
in humans.24
Serum and Urinary Markers

C-reactive protein (CRP) is an easily assayed marker for which serum concentrations are well correlated
with disease severity. However, CRP levels do not become significantly elevated until 48 hours after
onset of disease; therefore, this marker is not useful for early prediction of disease severity.
Lipopolysaccharide-binding protein (LBP), a class 1 acute-phase protein that binds and transfers
bacterial lipopolysaccharide (LPS), has also been shown to correlate with disease severity but its
elevation is similarly delayed. Serum concentrations of IL-6, IL-8, neutrophil elastase, angiopoietin-2,
procalcitonin, and urinary concentrations of TAP (a product of trypsinogen activation) are also
correlated with disease severity. Because these markers become elevated within 24 hours of disease
1373
booksmedicos.org
onset, they may be relevant to early prediction strategies in the future. Currently, however, assays for
these markers are not widely available.
MANAGEMENT
The goals of management for patients with acute pancreatitis are summarized below.
Correcting Pathophysiologic Derangements and Ameliorating Symptoms

6 The most important component of initial management is fluid resuscitation. In severe pancreatitis,
third-space fluid losses can be large, with up to one-third of plasma volume being sequestered. The
failure to appropriately resuscitate these patients is associated with increased morbidity and mortality.
An indwelling urinary catheter should be placed, intravascular volume should be frequently assessed,
and aggressive fluid and electrolyte replacement should be ensured. It should be noted, however, that
adverse consequence of massive resuscitation can also complicate the course of patients with severe
pancreatitis, and some recent studies have suggested an association between overresuscitation and
increased complications and death. While the optimal fluid resuscitation strategy is not known, critically
ill patients with pancreatitis should likely be aggressively and promptly resuscitated with lactated
Ringer solution with the amount of fluid administered tailored individually based on signs of end- organ
perfusion such as stabilization of blood pressure and heart rate and production of adequate urine
output.9,10,25
Patients with potentially severe pancreatitis, as well as those for whom initial resuscitation fails, are
best managed in a dedicated intensive care unit (ICU). Central venous monitoring may facilitate fluid
management. Patients should be closely monitored for development of distant organ failure,
particularly respiratory, cardiovascular, and renal failure, so that supportive management of these
conditions (positive-pressure ventilation, administration of vasopressor agents, and hemodialysis,
respectively) can be instituted without delay.
Abdominal pain is usually ameliorated with intravenous narcotics. In the past, morphine was avoided
because of concerns that morphine-induced increases in sphincter of Oddi pressure might exacerbate an
episode of pancreatitis. However, there is no clinical evidence that morphine can induce or exacerbate
acute pancreatitis. Other analgesic agents commonly used in patients with acute pancreatitis include
meperidine and fentanyl. Evacuation of gastric contents using a nasogastric tube should be instituted if
vomiting is a prominent symptom; otherwise, it is unnecessary.
A fraction of patients with severe pancreatitis develop abdominal compartment syndrome (ACS). ACS
is defined as a life-threatening sustained elevation of intra-abdominal pressure associated with new-
onset organ failure or acute worsening of existing organ failure. ACS usually manifests with a tensely
dilated abdomen, oliguria, and increased peak airway pressures. The diagnosis and treatment of ACS is
discussed in more detail elsewhere in this book. In acute pancreatitis, ACS is associated with very severe
disease, and approximately half of patients with ACS do not survive. ACS is treated by attempting to
decrease intra-abdominal pressure. In some patients this can be accomplished by draining intra-
abdominal collections and/or decompressing the bowel with nasogastric and rectal tubes. More than
half of the patients with ACS in the setting of acute pancreatitis require a decompressive laparotomy.9,26
Minimizing Progression of Pancreatic Inflammation and Injury

Identification of strategies for interrupting the inflammatory cascades that induce pancreatic injury and
distant organ failure is an area of active investigation. Currently, the only method used in routine
clinical practice is bowel rest (nothing by mouth). The rationale underlying this approach is that
avoidance of bolus oral nutrient intake may limit stimulation of pancreatic exocrine secretion induced
by the presence of nutrients in the intestine, particularly the duodenum.
Patients with mild acute pancreatitis generally need no nutritional support, as their disease typically
resolves within 1 week. In contrast, patients with severe pancreatitis usually have a more prolonged
disease course and should begin to receive nutritional support as early as feasible. Although these
patients traditionally have been administered total parenteral nutrition (TPN), accumulating evidence
suggests that enteral nutrition is safe, is less costly, and may be associated with a lower complication
rate than TPN.27 Administration of enteral nutrition is also associated with the theoretical advantage of
helping to maintain the integrity of the intestinal mucosal barrier, thus potentially limiting or
preventing bacterial translocation. Enteral nutrients have typically been delivered to the jejunum
1374
booksmedicos.org
through nasojejunal tubes to avoid stimulating pancreatic exocrine secretion, however, randomized
controlled trials indicate that continuous feedings delivered through nasogastric tubes are equally safe
and effective.28,29 TPN is still required in many patients who do not tolerate enteral nutrition due to
ileus.
Clinical trials of agents that inhibit activated pancreatic enzymes, inhibit pancreatic secretion, or
interrupt the inflammatory cascade have yielded disappointing results. Meta-analyses of clinical trials of
gabexate mesylate (a proteinase inhibitor), somatostatin, and octreotide suggest these agents have
limited, if any, efficacy in improving outcomes in acute pancreatitis. A platelet-activating factor
antagonist, lexipafant, showed promise in an initial study but not in a subsequent larger trial and is not
currently recommended. Other adjuncts for which clinical trials have failed to demonstrate efficacy in
limiting pancreatic injury in patients with acute pancreatitis include glucagon, anticholinergics, fresh
frozen plasma, and peritoneal lavage.
Treating the Underlying Cause

7 This discussion is particularly relevant to patients with gallstone pancreatitis. There are both
theoretical and experimental rationales to believe that removal of gallstones impacted at the ampulla of
Vater early in the course of an episode of acute gallstone pancreatitis might limit disease severity. On
the other hand, most gallstones that cause acute pancreatitis readily pass into the small intestine. The
benefit of early ERCP in acute pancreatitis has been subjected to extensive study.30 It has been shown
that early ERCP with stone extraction and sphincterotomy clearly benefits the subset of patients with
gallstone pancreatitis who have cholangitis.There also may be a benefit in patients with biliary
obstruction who do not have cholangitis, although this is less clear. In patients, with cholangitis, ERCP
should be performed urgently (within 24 hours). The timing of ERCP in patients with biliary obstruction
is not clear (24 to 72 hours). It is reasonable to wait up to 48 hours for biliary obstruction to resolve.
MRCP and endoscopic ultrasound (EUS) may be reasonable to screen for persistent choledocholithiasis
in equivocal cases to prevent unnecessary intervention. In the absence of obstructive jaundice and/or
cholangitis, early ERCP is associated with high complication rates but no apparent benefits and is
therefore not recommended.
There is an approximately 18% incidence of recurrent pancreatitis or other gallstone-related
complications during the 6-week period following an episode of gallstone pancreatitis in patients who
do not undergo cholecystectomy.31 Indeed, there is a substantial incidence of recurrent pancreatitis and
gallstone-related complications in patients with biliary pancreatitis whose cholecystectomy is delayed
even 2 weeks after hospital discharge.32 Therefore, cholecystectomy should be performed during the
same hospitalization for most patients with mild gallstone pancreatitis. This strategy does not increase
operative complications, conversion to open procedures, or mortality.31 In severe biliary pancreatitis,
the risk of deferring surgery needs to be balanced against the risk of performing early surgery in
patients who are debilitated and nutritionally compromised. Endoscopic sphincterotomy is another
option, however, the high risk of recurrent gallstone-related complications and the higher mortality
compared to cholecystectomy suggest that this strategy should be reserved for patients with severe
comorbidities precluding safe surgery.31,33
Examples of other measures directed at correcting the underlying cause of pancreatitis include
cessation of drugs known to cause pancreatitis and treatment of hypercalcemia or hyperlipidemia.
Preventing and Treating Complications

Complications of acute pancreatitis include pancreatic abscesses and infected necrosis, pseudocysts and
walled-off necrosis, pancreatic ascites and fistulas, splenic vein thrombosis, and arterial
pseudoaneurysms (Table 53-4). Infected necrosis as well as pseudocysts and sterile walled-off necrosis
are discussed in detail below.
Infected Necrosis
8, 9 Infection of pancreatic and peripancreatic necrosis complicates 30% to 70% of cases of acute
necrotizing pancreatitis and most commonly becomes established during the second to third weeks after
onset of disease. Historical data suggest that mortality rates associated with untreated infected necrosis
approach 100%. Infected necrosis is suggested by clinical signs such as persistent fever, increasing
leukocytosis, and imaging findings such as gas in peripancreatic collections. When necessary, infected
necrosis can be confirmed by cultures of aspirates of fluid or necrotic tissue obtained during CT-guided
fine needle aspiration (FNA) or specimens collected during surgery. The concordance rate between
1375
booksmedicos.org
bacteriologic results of FNA and those of surgical specimens is greater than 95%.34 The peak occurrence
of infected necrosis is between 2 and 4 weeks after presentation but it may occur at any time during the
clinical course.
COMPLICATIONS
Table 53-4 Local Complications of Acute Pancreatitis
10 Invasive intervention is usually indicated in the presence of infected necrosis. In contrast, sterile
necrotic collections almost never require intervention in the acute phase of necrotizing pancreatitis. As
infected necrosis often consists of thick and tenacious materials, traditionally mechanical débridement
via an open surgical approach was the primary treatment. Recently, less invasive approaches have been
popularized. Minimally invasive approaches for the treatment of infected pancreatic necrosis are
associated with fewer complications, however the mortality rate and the length of hospital stay appear
to be predominantly determined by the disease process itself rather than the interventional approach. In
centers with the appropriate expertise, most cases of infected pancreatic necrosis can now be managed
using minimally invasive techniques.
11 Procedures for the treatment of infected necrosis are best performed when collections become
walled-off and demarcated from viable pancreatic tissue with at least partial liquefaction, which
typically requires a delay of 4 to 6 weeks after disease onset. This is especially true for débridement, as
when it is performed too early, bleeding, incomplete removal of infected necrosis, resection of vital
tissue, and loss of endocrine and exocrine function are more likely to ensue. Convincing evidence now
supports delaying intervention whenever possible. Antibiotics can often be used to temporize the
situation allowing necrotic collections to mature. A subset of patients may even be successfully treated
with antibiotics alone. Patients with clinical deterioration and signs of sepsis despite the use of
antibiotics who have clearly infected acute necrotic collections may require intervention within the first
few weeks of acute pancreatitis.9,10,35
12 Drainage alone is the initial recommended intervention for infected pancreatic necrosis. This is
most often accomplished through a percutaneous image-guided approach, which is technically feasible
in the vast majority of cases. When percutaneous drains are placed, preference should be given to a
retroperitoneal approach so that the drain tract can be used to perform video-assisted retroperitoneal
débridement (VARD, see below). Drainage can also be accomplished through an endoscopic transluminal
approach, particularly in the rare cases where a percutaneous approach is not feasible. Drainage alone
can successfully treat infected necrosis in approximately 1/3 to 1/2 of cases.9,10,35–38
13 When required, débridement can often be performed through minimally invasive techniques.
These techniques are reserved for patients without intra-abdominal catastrophes or other complications
of acute pancreatitis mandating surgical exploration. VARD and direct endoscopic necrosectomy (DEN)
are the two most widely utilized techniques for minimally invasive débridement.
VARD is usually accomplished through a retroperitoneal approach via flank incisions. The previously
placed drain tracts are dilated to insert an operative nephroscope over a wire or to place laparoscopic
ports that follow the drain tract into the retroperitoneum. Fluid that is encountered is suctioned and
submitted for culture. Hydrodissection is used liberally. Gentle débridement of solid debris can be
accomplished under direct vision through the entry site or under visualization with the videoscope. The
goal of VARD is to facilitate drainage and not necessarily to perform a complete necrosectomy.
Irrigation is usually continued postoperatively through surgically placed drains. In a multicenter
randomized controlled trial, patients with infected pancreatic necrosis were randomized to undergo
primary open necrosectomy or a step-up approach consisting of percutaneous or endoscopic drainage
followed, in most cases (65%), by VARD. Open necrosectomy was rarely used when VARD could not be
1376
booksmedicos.org
accomplished. Although mortality between the two groups did not differ, primary open necrosectomy
was associated with a higher incidence of major complications and increased cost.39
DEN is performed via transmural puncture into a necrotic collection after insertion of an endoscopic.
It is required that the collection abuts or is in close proximity to the stomach or duodenum. The
collection can be visualized as a bulge in the wall of the viscera or using EUS. The tract into the
collection is then dilated and large bore stents are placed. Mechanical débridement can be performed
with endoscopic instruments and/or irrigation. Nasocystic or percutaneous drains can be used to provide
irrigation after the procedure. Typically, multiple sessions are necessary to completely débride the
cavity. A small randomized controlled trial showed a decreased inflammatory response as well as
decreased complications for patients undergoing endoscopic transgastric necrosectomy as opposed to
VARD after failure of drainage for infected pancreatic necrosis.
Open necrosectomy may still be performed in the subset of patients not amenable to a minimally
invasive approach or in centers without expertise in these techniques. For open necrosectomy, the
abdomen is usually entered through a vertical midline or bilateral subcostal incision. The anterior
surface of the pancreas can be exposed by dividing the gastrocolic ligament (greater omentum) and
entering the lesser sac. If inflammatory changes have obliterated the lesser sac, an alternative route to
the pancreas is achieved by dividing avascular portions of the transverse mesocolon. Clearly nonviable
tissue should be débrided bluntly without attempting to perform anatomic resections. The débridement
field is irrigated with several liters of sterile saline. There are several options for assuring that all
necrotic tissue is removed after surgery. Traditionally, when the abdomen is closed, large-bore drains
are placed, and postoperatively the drains are left in place at least 7 days and until the effluent becomes
clear. This procedure is known as necrosectomy with closed drainage. Several authors prefer variants of
this procedure in which either both gauze packing and drains are placed at the time of surgery and
gradually withdrawn postoperatively (necrosectomy with closed packing) or where high-volume lavage of
the lesser sac is performed through the drains placed at the time of surgery until the effluent becomes
clear and the patient’s clinical course improves (necrosectomy with continuous lavage). Other procedures
including necrosectomy with open packing, where the retroperitoneum is marsupialized and the abdomen
left open, and necrosectomy with planned, staged relaparotomy, in which the initial operation is followed
by repeat laparotomies to change gauze packing or to perform additional débridement have fallen out
of favor but may be necessary if necrosectomy is performed early in the course of disease before clear
demarcation between necrotic and viable tissues has occurred. Modern mortality rates associated with
necrosectomy performed for infected necrosis range from 10% to 20%.40,41 On long-term follow-up,
approximately 25% of survivors develop exocrine insufficiency, and 30% develop endocrine
insufficiency. It should be noted that open necrosectomy is associated with better results in more recent
series due to improvements in ICU care and implementation of delayed timing for surgery. The results
of open necrosectomy in relation to VARD or DEN have not been directly compared after initial
drainage. Although surgical débridement is clearly indicated for infected necrosis, its role in sterile
necrosis has undergone evolution. In the past, early necrosectomy was recommended for patients with
necrotizing pancreatitis, even in the absence of documented infection. The rationale for this approach
was to prevent infection from developing and to remove the source of toxins and inflammatory
mediators. Today, it is recommended that surgery should be avoided in patients without documentation
of infected necrosis, based on favorable outcomes reported using this conservative approach.40,41
However, there remains a subset of patients with sterile necrosis who, despite prolonged supportive
care, have persistent problems, including disabling pain, malaise, and gastric outlet obstruction who
may benefit from interventions for sterile necrosis late in the course of disease.
Because of the high morbidity and mortality rates associated with infected necrosis, there has been
much investigation into the use of antibiotics as prophylaxis against infection. Initial clinical trials failed
to demonstrate a benefit of prophylactic antibiotics; however, these studies were flawed by the
inclusion of patients with mild disease who were at low risk for developing infected necrosis and the
use of antibiotics with poor penetration into the pancreas. Trials were published in the 1990s showing a
significant reduction in the incidence of pancreatic infection among patients receiving antibiotic
prophylaxis, and based on this evidence, the use of antibiotic prophylaxis in patients documented to
have necrotizing pancreatitis has become a widespread practice. Several recent trials that failed to show
a benefit for prophylactic antibiotics have now been published.42,43 Similarly, recent meta-analyses of
the available trials have failed to demonstrate a benefit for patients receiving prophylactic
antibiotics.44,45 Disadvantages of using prophylactic antibiotics include the risks of fungal superinfection
and the selection of resistant organisms. Another strategy for prophylaxis against infection in patients
1377
booksmedicos.org
with acute pancreatitis has been the administration of probiotic bacteria to reduce the load of
pathogenic bacteria in the bowel; however, prospective evaluation has yielded disappointing results.46
An algorithm for the general management of acute pancreatitis and pancreatic necrosis is shown in
Algorithm 53-1.
Algorithm 53-1. Algorithm for the management of acute pancreatitis.
Pseudocysts and Sterile Walled-Off Necrosis

Acute fluid collections develop in up to 30% to 50% of patients with acute pancreatitis. As most resolve
spontaneously, no specific treatment directed at acute fluid collections is necessary in the absence of
evidence that the fluid is infected. However, in up to 10% of patients with acute pancreatitis, these fluid
collections progress to develop a wall of fibrous granulation tissue. Until recently, predominantly liquid
collections with a well-formed wall appearing after an episode of acute pancreatitis were classified as
pseudocysts. It is now appreciated that many of the chronic collections seen after bouts of acute
pancreatitis contain variable amounts of solid materials from the necrosis of pancreatic and
peripancreatic tissues. In the new taxonomy, these collections are called walled-off necrosis. This
distinction may better indicate how these collections should be treated, however, there is no distinction
in the indication for intervention between pseudocysts and sterile walled-off necrosis.35 The walls of
these collections generally require at least 4 weeks from the onset of pancreatitis to mature. In contrast
to true cysts, pseudocysts (and walled-off necrosis) do not have epithelium-lined walls.
Most pseudocysts and sterile walled-off necrosis are asymptomatic; however, they can cause upper
abdominal pain, gastric outlet obstruction, and obstructive jaundice. Pseudocysts and walled-off necrosis
can be diagnosed on ultrasonography or CT scanning (Figs. 53-5 and 53-6). It is important to distinguish
1378
booksmedicos.org
cystic neoplasms of the pancreas from these lesions, as cystic neoplasms can be malignant or have
malignant potential. Cystic lesions of the pancreas are being diagnosed with increasing frequency due to
the routine use of CT and MRI scans. Cystic neoplams of the pancreas can usually be differentiated from
pseudocysts and walled-off necrosis by the lack of evidence for antecedent pancreatitis or pancreatic
trauma, or by the appearance on imaging studies. Pseudocysts are typically round, unilocular, and have
a dense wall. In contrast, walled-off necrosis is typically heterogeneous with liquid and nonliquid
density, with varying degrees of loculations, and is encapsulated by a well-defined wall. FNA, either by
an image-guided percutaneous approach or an EUS-guided approach, can be used in cases where it is
difficult to differentiate between pseudocysts or walled-off necrosis and cystic neoplasms. Pseudocysts
and walled-off necrosis usually contain fluid with high amylase concentrations. In contrast, most
neoplastic cysts do not communicate with the pancreatic duct and contain fluid with low amylase
concentrations. These criteria, however, lack absolute predictive power.
Figure 53-5. Computed tomography scan of pancreatic pseudocyst.
Figure 53-6. Computed tomography scan of walled-off necrosis. Arrows indicate the presence of solid material within the
collection.
14 The management of pseudocysts and walled-off necrosis continues to evolve. In the past, surgical
drainage of pseudocysts was recommended for all pseudocysts (even if asymptomatic) that persisted
beyond a 6-week period of observation. This recommendation was based on a widely quoted report
which suggested that pseudocysts that persist more than 6 weeks rarely resolve spontaneously and are
associated with high complication rates.47 However, subsequent reports suggest that the natural history
of asymptomatic pseudocysts follows a more benign course, with most pseudocysts less than 6 cm in
diameter resolving spontaneously without complications.48,49 Even large, persistent collections may
never cause symptoms or complications. Current well-accepted indications for intervention in the
absence of infection include the presence of symptoms attributable to the collection such as intractable
pain or obstruction of the stomach, duodenum, or bile duct.9,10,35,50
15 There are multiple treatment options available for the treatment of pancreatic pseudocysts and
sterile walled-off necrosis, including percutaneous aspiration, percutaneous drainage, and internal
drainage (performed transabdominally or endoscopically). The optimal indications for these procedures
1379
booksmedicos.org
are not conclusively determined. Percutaneous aspiration alone is associated with high recurrence rates.
Patients with chronic pancreatitis or pancreatic ductal abnormalities, particularly severe strictures or
discontinuity of the pancreatic duct, have a high rate of failure with percutaneous drainage of
pseudocysts. Percutaneous drainage alone should be avoided in these circumstances but may have a high
rate of success in patients with normal ducts.51 Endoscopic cystgastrostomy is an option for patients in
whom the pseudocyst or walled-off necrosis is intimately adherent to the stomach or duodenum. This
procedure is accomplished by transmural puncture of the pseudocyst, balloon dilation of the tract, and
placement of a stent connecting the pseudocyst to the stomach. A small, single-center randomized
controlled trial of surgical cystgastrostomy versus endoscopic cystgastrostomy (along with ERCP and
stenting of pancreatic duct leaks or strictures) for pseudocysts showed equal efficacy along with
decreased hospital stay and cost for the endoscopic arm.52 The treatment of symptomatic sterile walled-
off necrosis can also be accomplished endoscopically (see description of DEN above). Due to the
presence of necrotic debris within these collections, in contrast to pseudocyts, the need for multiple
stents and/or multiple procedures, often with mechanical débridement, should be expected when
walled-off necrosis is approached endoscopically. As of yet, high-quality data comparing the efficacy of
surgical versus endoscopic treatment of symptomatic, sterile walled-off necrosis are lacking.
The most commonly performed surgical procedures used to treat pseudocysts and sterile walled-off
necrosis include cystgastrostomy, cystoduodenostomy, and Roux-en-Y cystojejunostomy.
Cystgastrostomy or cystoduodenostomy is applicable if a portion of the pseudocyst wall is adherent to
the stomach or duodenum respectively allowing for the creation of an anastomosis. Otherwise, the cyst
wall can be anastomosed to a Roux limb of jejunum. These procedures, which can be performed as open
or laparoscopic operations, should be delayed until pseudocyst wall maturation occurs. Mortality rates
associated with surgical drainage procedures average less than 5%, with pseudocyst recurrence rates
averaging 10%.
References
1. Bradley EL 3rd. A clinically based classification system for acute pancreatitis. Summary of the
International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Arch
Surg 1993;128:586–590.
2. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012
update. Gastroenterology 2012;143:1179–1187.
3. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis–2012: revision of the
Atlanta classification and definitions by international consensus. Gut 2013;62:102–111.
4. Steer ML. Pathogenesis of acute pancreatitis. Digestion 1997;58 suppl 1:46–49.
5. Saluja AK, Donovan EA, Yamanaka K, et al. Cerulein-induced in vitro activation of trypsinogen in
rat pancreatic acini is mediated by cathepsin B. Gastroenterology 1997;113:304–310.
6. Leach SD, Modlin IM, Scheele GA, et al. Intracellular activation of digestive zymogens in rat
pancreatic acini. Stimulation by high doses of cholecystokinin. J Clin Invest 1991;87:362–366.
7. Hashimoto D, Ohmuraya M, Hirota M, et al. Involvement of autophagy in trypsinogen activation
within the pancreatic acinar cells. J Cell Biol 2008; 181:1065–1072.
8. Gukovsky I, Li N, Todoric J, et al. Inflammation, autophagy, and obesity: common features in the
pathogenesis of pancreatitis and pancreatic cancer. Gastroenterology 2013;144:1199–1209. e4.
9. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the
management of acute pancreatitis. Pancreatology 2013;13:e1–e15.
10. Tenner S, Baillie J, DeWitt J, et al. American College of Gastroenterology guideline: management
of acute pancreatitis. Am J Gastroenterol 2013;108:1400–1415, 1416.
11. Nawaz H, Mounzer R, Yadav D, et al. Revised Atlanta and determinant-based classification:
application in a prospective cohort of acute pancreatitis patients. Am J Gastroenterol
2013;108:1911–1917.
12. Petrov MS, Shanbhag S, Chakraborty M, et al. Organ failure and infection of pancreatic necrosis as
determinants of mortality in patients with acute pancreatitis. Gastroenterology 2010;139:813–820.
13. Petrov MS, Windsor JA. Classification of the severity of acute pancreatitis: how many categories
make sense? Am J Gastroenterol 2010;105:74–76.
14. Thandassery RB, Yadav TD, Dutta U, et al. Prospective validation of 4-category classification of
1380
booksmedicos.org
acute pancreatitis severity. Pancreas 2013;42:392–396.
15. Dellinger EP, Forsmark CE, Layer P, et al. Determinant-based classification of acute pancreatitis
severity: an international multidisciplinary consultation. Ann Surg 2012;256:875–880.
16. Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in
acute pancreatitis. Surg Gynecol Obstet 1974; 139:69–81.
17. Imrie CW, Benjamin IS, Ferguson JC, et al. A single-centre double-blind trial of Trasylol therapy in
primary acute pancreatitis. Br J Surg 1978;65:337–341.
18. Larvin M, McMahon MJ. APACHE-II score for assessment and monitoring of acute pancreatitis.
Lancet 1989;2:201–205.
19. Wu BU, Johannes RS, Sun X, et al. The early prediction of mortality in acute pancreatitis: a large
population-based study. Gut 2008;57:1698–1703.
20. Cho YS, Kim HK, Jang EC, et al. Usefulness of the Bedside Index for severity in acute pancreatitis in
the early prediction of severity and mortality in acute pancreatitis. Pancreas 2013;42:483–487.
21. Papachristou GI, Muddana V, Yadav D, et al. Comparison of BISAP, Ranson’s, APACHE-II, and CTSI
scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J
Gastroenterol 2010;105:435–441.
22. Singh VK, Wu BU, Bollen TL, et al. A prospective evaluation of the bedside index for severity in
acute pancreatitis score in assessing mortality and intermediate markers of severity in acute
pancreatitis. Am J Gastroenterol 2009; 104:966–71.
23. Bollen TL, Singh VK, Maurer R, et al. A comparative evaluation of radiologic and clinical scoring
systems in the early prediction of severity in acute pancreatitis. Am J Gastroenterol 2012;107:612–
619.
24. Johnson CD, Stephens DH, Sarr MG. CT of acute pancreatitis: correlation between lack of contrast
enhancement and pancreatic necrosis. AJR Am J Roentgenol 1991;156:93–95.
25. Fisher JM, Gardner TB. The “golden hours” of management in acute pancreatitis. Am J Gastroenterol
2012;107:1146–1150.
26. van Brunschot S, Schut AJ, Bouwense SA, et al. Abdominal compartment syndrome in acute
pancreatitis: a systematic review. Pancreas 2014;43:665–674.
27. Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in patients with
acute pancreatitis. BMJ 2004;328:1407.
28. Eatock FC, Chong P, Menezes N, et al. A randomized study of early nasogastric versus nasojejunal
feeding in severe acute pancreatitis. Am J Gastroenterol 2005;100:432–439.
29. Singh N, Sharma B, Sharma M, et al. Evaluation of early enteral feeding through nasogastric and
nasojejunal tube in severe acute pancreatitis: a noninferiority randomized controlled trial. Pancreas
2012;41:153–159.
30. Tse F, Yuan Y. Early routine endoscopic retrograde cholangiopancreatography strategy versus early
conservative management strategy in acute gallstone pancreatitis. Cochrane Database Syst Rev
2012;5:CD009779.
31. van Baal MC, Besselink MG, Bakker OJ, et al. Timing of cholecystectomy after mild biliary
pancreatitis: a systematic review. Ann Surg 2012;255:860–866.
32. Ito K, Ito H, Whang EE. Timing of cholecystectomy for biliary pancreatitis: Do the data support
current guidelines? J Gastrointest Surg 2008;12(12):2164–2170.
33. McAlister VC, Davenport E, Renouf E. Cholecystectomy deferral in patients with endoscopic
sphincterotomy. Cochrane Database Syst Rev 2007;(4):CD006233.
34. Gerzof SG, Banks PA, Robbins AH, et al. Early diagnosis of pancreatic infection by computed
tomography-guided aspiration. Gastroenterology 1987;93:1315–1320.
35. Freeman ML, Werner J, van Santvoort HC, et al. Interventions for necrotizing pancreatitis:
summary of a multidisciplinary consensus conference. Pancreas 2012;41:1176–1194.
36. Carter CR, McKay CJ, Imrie CW. Percutaneous necrosectomy and sinus tract endoscopy in the
management of infected pancreatic necrosis: an initial experience. Ann Surg 2000;232:175–180.
37. Connor S, Alexakis N, Raraty MG, et al. Early and late complications after pancreatic necrosectomy.
Surgery 2005;137:499–505.
38. Mouli VP, Sreenivas V, Garg PK. Efficacy of conservative treatment, without necrosectomy, for
1381
booksmedicos.org
infected pancreatic necrosis: a systematic review and meta-analysis. Gastroenterology 2013;144:333–
340.
39. van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for
necrotizing pancreatitis. N Engl J Med 2010;362:1491–1502.
40. Ashley SW, Perez A, Pierce EA, et al. Necrotizing pancreatitis: contemporary analysis of 99
consecutive cases. Ann Surg 2001;234:572–579.
41. Büchler MW, Gloor B, Müller CA, et al. Acute necrotizing pancreatitis: treatment strategy according
to the status of infection. Ann Surg 2000;232:619–626.
42. Isenmann R, Runzi M, Kron M, et al. Prophylactic antibiotic treatment in patients with predicted
severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology 2004;126:997–
1004.
43. Dellinger EP, Tellado JM, Soto NE, et al. Early antibiotic treatment for severe acute necrotizing
pancreatitis: a randomized, double-blind, placebo-controlled study. Ann Surg 2007;245:674–683.
44. de Vries AC, Besselink MG, Buskens E, et al. Randomized controlled trials of antibiotic prophylaxis
in severe acute pancreatitis: relationship between methodological quality and outcome.
Pancreatology 2007;7:531–538.
45. Bai Y, Gao J, Zou DW, et al. Prophylactic antibiotics cannot reduce infected pancreatic necrosis and
mortality in acute necrotizing pancreatitis: evidence from a meta-analysis of randomized controlled
trials. Am J Gastroenterol 2008;103:104–110.
46. Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute
pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–659.
47. Bradley EL, Clements JL Jr., Gonzalez AC. The natural history of pancreatic pseudocysts: a unified
concept of management. Am J Surg 1979;137:135–141.
48. Vitas GJ, Sarr MG. Selected management of pancreatic pseudocysts: operative versus expectant
management. Surgery 1992;111:123–130.
49. Yeo CJ, Bastidas JA, Lynch-Nyhan A, et al. The natural history of pancreatic pseudocysts
documented by computed tomography. Surg Gynecol Obstet 1990;170:411–417.
50. Cannon JW, Callery MP, Vollmer CM Jr. Diagnosis and management of pancreatic pseudocysts:
what is the evidence? J Am Coll Surg 2009;209:385–393.
51. Nealon WH, Bhutani M, Riall TS, et al. A unifying concept: pancreatic ductal anatomy both predicts
and determines the major complications resulting from pancreatitis. J Am Coll Surg 2009;208:790–
799.
52. Varadarajulu S, Bang JY, Sutton BS, et al. Equal efficacy of endoscopic and surgical
cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial. Gastroenterology
2013;145:583–590.
1382
booksmedicos.org
Chapter 54
Chronic Pancreatitis
Katherine A. Morgan and David B. Adams
Key Points
1 Chronic pancreatitis is heterogeneous in etiology with an increasingly recognized role of smoking

and genetic factors.
2 The most common indication for intervention in chronic pancreatitis is severe, debilitating
abdominal pain.
3 Medical and endoscopic therapies are frontline management of chronic pancreatitis, but are often
unsuccessful.
4 Surgical intervention is aimed at achieving durable pain relief with least perioperative and long term
morbidity.
5 Cutting edge therapies for chronic pancreatitis include total pancreatectomy with islet
autotransplantation and minimally invasive techniques (laparoscopic and robotic).
INTRODUCTION
Chronic pancreatitis (CP) is an inflammatory disorder of the pancreas marked by fibrotic replacement of
the pancreatic parenchyma. The clinical hallmark of disease is severe, debilitating, and recalcitrant
abdominal pain, often associated with nutritional failure. CP typically results in progressive endocrine
failure (type 3c diabetes mellitus)1 and exocrine failure (malabsorption) in afflicted patients.
Management of this challenging disorder is problematic due the complexities of disease pathogenesis,
the clinical management of pain, and attendant impairments in patient quality of life.
EPIDEMIOLOGY
CP is a significant public health concern. Its prevalence and annual incidence are estimated at 0.2% to
0.6% and 7 to 10/100,000 respectively in the United States and Europe.2 The economic impact is
notable, with estimated annual healthcare expenditures for pancreatitis in the United States in 2004
were $3.7 billion.3
ETIOLOGY
The etiology of CP is heterogeneous and multifactorial. The M-ANNHEIM classification can be utilized
to describe the (M) multiple risk factors for the development of pancreatitis including (A) alcohol
consumption, (N) nicotine use, (N) nutrition, (H) hereditary factors, (E) efferent ductal obstruction, (I)
immunologic factors, and (M) metabolic factors.4
Historically, alcohol use has been the most commonly implicated etiologic factor in CP in the Western
world, classically comprising 60% to 90% of cases in observational studies in the 1970s to the 1990s.5–7
More recent data from multiinstitutional prospective data, however, have demonstrated a lesser
contributory role from alcohol, with association in approximately 45% of cases.8 Dose and duration of
alcohol consumption have been demonstrated to be contributory to CP development, although several
more recent studies suggest that alcohol alone is not sufficient to cause CP. Byproducts from ethanol
metabolism injure acinar cells and can activate pancreatic stellate cells (PSCs) to form extracellular
matrix. Recent investigation suggests an association between pancreatitis and a locus on the X
chromosome. A risk factor for alcoholic pancreatitis on the X chromosome may partially explain the
higher incidence of alcoholic pancreatitis in men than in women, a difference that cannot be explained
1383
booksmedicos.org
solely by alcohol consumption rate differences in men and women. In women, the high-risk allele acts
as a recessive genetic disorder with consequent risk diminishment.9
1 Smoking has been determined as a significant risk factor in the development of CP. In the 1990s, a
relationship between tobacco consumption and pancreatic calcifications was noted.10 In addition, the
synergistic effects of smoking and alcohol have been described.11 More recently, a large multicenter
epidemiologic study has shown that smoking is an independent risk factor for CP in a dose-dependent
fashion.8,12 In addition, tobacco use has been shown to be a strong risk factor for the progression of
acute pancreatitis to CP, suggesting a role for smoking in pancreatic fibrogenesis.13
Genetic causes of CP have been increasingly recognized over the past couple of decades. In 1952,
Comfort and Steinberg14 described hereditary pancreatitis (HP) and in 1996, Whitcomb and colleagues
delineated a mutation in the cationic trypsinogen gene PRSS1, which results in the inappropriate
activation of trypsin and is responsible for HP.15 HP is an autosomal dominant disorder with 80%
penetrance, marked by recurrent acute pancreatitis beginning in early childhood, progression to CP in
many, and a greatly (50×) increased risk of pancreatic cancer beginning in the fifth decade. Since,
several other mutations in the PRSS1 gene have been identified. In addition, multiple other genetic foci
have been implicated as contributing agents in CP as well, primarily related to the inappropriate
activation of trypsin. Pancreas secretory trypsin inhibitor (serine protease inhibitor, kazal type 1, and
SPINK1),16 cystic fibrosis transmembrane conductance regulator gene (CFTR), chymotrypsinogen C
(CTRC),17 calcium-sensing receptor gene (CASR),18 and gamma-glutamyltransferase 1 gene (GGT1)19
have all been elucidated as conferring a susceptibility to CP development. Conversely the anionic
trypsinogen gene PRSS2 may confer a protective advantage against the development of pancreatitis.
Clearly, the etiology of pancreatitis is variable, complex, and incompletely understood.
Figure 54-1. Three-hit hypothesis for pathophysiology of chronic pancreatitis. NGF, nerve growth factor. Adapted from Whitcomb
DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013;144:1292–1302.
PATHOPHYSIOLOGY
The pathophysiology of CP is not well elucidated. A theory known as the “three-hit hypothesis” holds
that (1) a stochastic event occurs resulting in (2) inappropriate trypsin activation causing acute
pancreatitis. The patient then has (3) an unfavorable immunologic response to the inflammation
resulting in fibrosis and CP (Fig. 54-1).20 Environmental factors (e.g., alcohol and tobacco) are
implicated as the inciting events to this cascade, with potential key modulating factors including
genetics and the histologic milieu.
Insights into pathophysiology of pancreatitis have occurred through advances in cellular basic science.
PSCs are causative in pancreatic fibrogenesis. PSCs are residents of the healthy pancreas that become
activated by inflammatory cytokines during pancreatitis to become myofibroblast-like cells, producing
extracellular matrix in the interstitial space.21 In addition, several matrix metalloproteinases are
implicated in altering extracellular matrix remodeling and collagen degradation, enhancing fibrogenesis
and irreversibly altering the organ architecture to a diseased, fibrotic pancreas.22
The pathophysiology of the CP pain syndrome is not well delineated and is likely multifactorial.
1384
booksmedicos.org
Classically, pancreatic ductal obstruction due to fibrosis and resulting in elevated intraductal pressures
has been implicated as a primary cause for pain. Additionally, pancreatic capsular and parenchymal
fibrosis resulting in intracapsular hypertension and ischemia, create a “pancreatic compartment
syndrome,” and has been theorized to result in pain. More recent theories have focused on
peripancreatic neuropathy. On a histologic level, peripancreatic neuronal hypertrophy as well as
infiltration of periaxonal tissue with inflammatory cells is evident.23,24 Increased presence of the “pain
neurotransmitters” is identified including calcitonin gene-related peptide and substance P, stimulated by
nerve growth factor.25 These changes in the peripancreatic neuronal milieu may result in peripheral and
central neural sensitization and undoubtedly contribute to the CP pain syndrome. The pancreas has a
uniquely villainous role in abdominal pain syndromes. No other visceral organ can match it in terms of
pain severity. Neural remodeling precipitated by pancreas-synthesized tachykinins may lead to
centralization of pain that is precipitated by extra pancreatic stimuli. The “phantom pancreatitis” pain
that occurs after total pancreatectomy (TP) is related to centralization of pain pathways and is a
reminder of the vast intersecting neuronal web of the pancreas and the foregut.
2 The primary presentation of CP is severe, intractable epigastric abdominal pain that radiates into the
back. The classic pain is daily and constant with periods of exacerbation. Patients typically describe
pancreatitis pain as if someone is slowing twisting a knife into the epigastrium and interscapular region.
Patients often have associated gut dysfunction, with nausea, emesis, and difficulty tolerating a diet
consistently, particularly during pain episodes. Pain and nausea are frequently precipitated by ingestion
of a fatty meal or less commonly a high protein meal. Patients may develop endocrine failure
(pancreatogenic diabetes, type 3c) and exocrine pancreatic insufficiency (EPI) over time. Less often,
patients may present with an acute complication of CP such as biliary or duodenal obstruction, a
pancreatic pseudocyst, pancreatic ascites, mesenteric venous thrombosis, or mesenteric arterial
pseudoaneurysm (Table 54-1).
On physical examination, patients may generally appear malnourished and underweight. Abdominal
tenderness in the epigastrum may be elicited. Significant laboratory values to be examined include
chemistries to evaluate for dehydration and acidosis. A hepatic panel may reveal elevated alkaline
phosphatase or direct bilirubin, indicating biliary obstruction, or hypoalbuminemia from chronic
malnutrition. Serum amylase and lipase may be elevated or may be normal during pain exacerbations in
advanced disease.
Table 54-1 Complications of Chronic Pancreatitis
1385
booksmedicos.org
Figure 54-2. Contrasted CT scan in venous phase, coronal images showing (A), dilated main pancreatic duct with intraductal
stones and (B), significant fibrotic disease burden in the head of the pancreas with intraparenchymal and intraductal calcifications.
RADIOGRAPHIC EVALUATION
Radiography is useful in both diagnosis and treatment planning in CP. The most relevant imaging
modalities include contrast-enhanced computed tomography (CT), secretin-stimulated magnetic
resonance imaging with cholangiopancreatography (MRCP), endoscopic retrograde
cholangiopancreatography (ERCP), and endoscopic ultrasound (EUS).
Abdominal CT can show pancreatic parenchymal changes including edema, fibrosis, or atrophy.
Pancreatic ductal dilation may be evident, as well as intraparenchymal and intraductal calcifications
(Fig. 54-2). CT can also be helpful in recognizing intra-abdominal complications of pancreatitis such as
biliary or duodenal obstruction, pancreatic pseudocysts or ascites, or thrombosis or pseudoaneurysms of
the mesenteric vasculature. Similarly, MRCP can be very useful in showing parenchymal changes in
enhancement and secretion (T1-weighted images) and ductal anatomy (T2-weighted images),
particularly with the addition of secretin stimulation (Fig. 54-3). With the increased capabilities of MR
technology over the past couple of decades, MR imaging has largely replaced ERCP for diagnostic
imaging in CP. ERCP is the classic imaging modality for CP. The ERCP Cambridge classification system,
derived from an international consensus, remains the gold standard of CP staging (Table 54-2).26 In the
modern era, ERCP is primarily utilized as a therapeutic modality. EUS is useful for evaluation of
pancreatic parenchyma and ductal anatomy, while being less invasive than ERCP. EUS also has a
grading system to objectify and document pancreatitis disease severity, although the modality still
maintains interobserver variability (Table 54-3). With the addition of fine needle aspiration, EUS can be
helpful in the differentiation of pancreatic neoplasms from CP.27
Figure 54-3. T2-weighted magnetic resonance imaging with secretin stimulation demonstrate a pathologically dilated pancreatic
duct in the body of the pancreas (A), and cystic changes and dilated ducts in a fibrotic and inflammatory head of the pancreas (B).
1386
booksmedicos.org
Table 54-2 Cambridge Classification System for Chronic Pancreatitis by ERCP
Imaging
CONSIDERATIONS IN MANAGEMENT
3 Frontline management of CP includes risk factor modification, such as alcohol and tobacco cessation.
Primary medical interventions entail pain management, including adjunctive behavioral therapy, and
nutritional optimization, including pancreatic enzyme replacement.
Pancreatic enzymes are the mainstay of medical management of CP despite controversy about their
efficacy. Enzyme replacement is presumed to improve pain by feedback inhibition of cholecystokinin
(CCK) release from the duodenum, leading to decreased pancreatic exocrine secretions. A meta-analysis
of six randomized, placebo-controlled trials did not reveal a significant benefit for supplemental
pancreatic enzyme therapy for pain relief.28 Antioxidant therapy has been proposed as a treatment for
CP, based on the theory that antioxidants will reduce oxygen free radicals and ameliorate oxidative
stress and pancreatic acinar cell injury. Prospective randomized trials have shown conflicting results in
antioxidant therapy for CP.29
Table 54-3 EUS Criteria for Chronic Pancreatitis
Because CP pain is associated with extrapancreatic neuronal remodeling, neuromodulation with

anticonvulsant or antidepressant medications similar to gabapentin have been utilized for CP pain
management with limited success in patients with ongoing pancreatic inflammation.
Avoidance of narcotic analgesia in the management of CP pain is uniformly recommended. Analgesic
management with nonsteroidal anti-inflammatory medication, acetaminophen, and tramadol is typically
recommended. However, because the severity of pancreatic pain is so incapacitating, most patients who
are evaluated for endoscopic or surgical management have been treated with narcotic analgesics and
have developed physiologic narcotic dependence.
Behavioral therapy is a keystone of therapy in CP, particularly since many patients who are
debilitated by CP are young and have previously been in good health. Behavioral modification is
1387
booksmedicos.org
effective in modulating pain perceptions in many chronic disorders. In addition, behavioral therapy is
important in patients at risk for opioid misuse.30
Patients who have failed medical management, have continued debilitating pain or nutritional failure,
and are physiologically fit are candidates for therapeutic interventions.
ENDOSCOPIC MANAGEMENT
ERCP is the primary endoscopic modality for therapy in CP. The principle goal with ERCP is to relieve
any obstructive process. Potential maneuvers include sphincterotomy, stone extraction, stricture
dilation, and stenting.
EUS can be utilized for endoscopic pseudocyst drainage procedures and for celiac plexus neurolysis.
Percutaneous and endoscopic-guided celiac nerve blockade has been utilized to manage CP pain. Meta-
analysis studies of EUS-guided celiac plexus blockade found short-term pain relief in about one-half of
the subjects.31
In general, the endoscopic approach is undertaken prior to consideration of surgery, given the
perceived advantages of lower morbidity with a less invasive approach. Two prospective, randomized,
controlled trials have compared endoscopy and surgery in patients with obstructive CP. Dite and
colleagues randomized 72 patients with CP, pancreatic duct obstruction and pain to endoscopic or
surgical intervention. Endoscopic therapy consisted of ERCP with 52% undergoing sphincterotomy and
stenting and 23% stone removal. Operative management was 20% drainage procedure and 80%
resection. At 5-year follow-up, the surgical group had a greater proportion of patients that were pain
free (34% vs. 15%).32 In another study Cahen and colleagues from randomized 39 patients with dilated
duct CP and pain to endoscopic or surgical management. Endoscopic treatment was ERCP with
sphincterotomy and stenting, and operative therapy was a drainage procedure (longitudinal
pancreaticojejunostomy). At 5-year follow-up, the surgical group had a greater proportion of patients
that had pain relief (80% vs. 38%, p = 0.001), had larger improvements in quality of life, and
underwent fewer procedures, despite equivalent morbidity, length of stay, and preserved pancreatic
function.33,34
SURGICAL MANAGEMENT
4 Approximately two-thirds of patients with debilitating pain from CP fail medical and endoscopic
managements and are candidates for consideration for operative therapy. The primary indication for
surgical intervention in CP is intractable pain, and the goals of surgery are to effectively relieve pain
while minimizing morbidity, including minimizing perioperative complications and preserving
pancreatic parenchyma. As the underlying cause of CP pain is not well understood, operative decision-
making can be difficult. The pancreatic anatomy is the primary determinant in surgical planning.
Patients with a dilated (greater than 6 to 7 mm diameter) main pancreatic duct are assumed to have
obstructive pathology and are candidates for a drainage-type procedure (lateral pancreaticojejunostomy,
Frey procedure). In patients with a small-diameter main pancreatic duct, resection of fibrotic and poorly
drained parenchyma is undertaken. Patients with head-predominant or tail-centered disease can undergo
a directed partial resection. In patients with diffuse parenchymal involvement a TP with islet
autotransplantation may be considered (Algorithm 54-1).
Parenchymal fibrosis associated with CP may involve adjacent organs and lead to complications
requiring operative management. Other indications for surgical management of CP include terminal
biliary stenosis, duodenal stenosis, gastric variceal hemorrhage due to splenic vein thrombosis, stenosis
of the transverse colon, and symptomatic pancreatic pseudocysts. These complications are managed by a
variety of bypass or resection procedures depending on the underlying pancreatic ductal disorder.
Uncomplicated biliary stenosis is managed with biliary bypass with choledochoduodenostomy or Roux-
en-Y hepaticojejunostomy.35 When associated with an inflammatory mass in the head of the pancreas,
pancreatic head resection may be indicated. When biliary stenosis is associated with CP and a
pseudocyst in the region of the pancreatic head, pseudocyst drainage should be undertaken prior to
performing biliary bypass as this may lead to resolution of the obstruction. Duodenal stenosis is usually
associated with biliary stenosis and an inflammatory pancreatic head mass and is best managed with
resection of the head of the pancreas.36 When patient factors make resection unsafe, a double bypass is
undertaken with gastrojejunostomy and biliary bypass. Gastric varices due to splenic vein occlusion are
1388
booksmedicos.org
not an indication for operation unless associated with hemorrhage. When indicated for gastric variceal
bleeding complications, splenectomy is indicated. Preoperative splenic artery embolization or balloon
occlusion may diminish intraoperative blood loss when splenomegaly and fibrosis in the region of the
pancreatic tail make operative control of the splenic artery problematic.37 Fibrosing stenosis of the
transverse colon, a rare complication of CP, is managed with colonic resection and anastomosis or
colostomy, depending on the condition of the patient and the condition of the pancreas.38 Pancreatic
pseudocysts associated with CP and ductal obstruction are managed by addressing the underlying ductal
disorder with resection or drainage procedures.39
Lateral Pancreaticojejunostomy
Retrograde pancreatic drainage for relapsing pancreatitis was described by Puestow and Gillesby in
1958.40 A modification of this original drainage procedure that more closely resembles the modern-day
technique of the lateral pancreaticojejunostomy (LPJ) was reported by Partington and Rochelle in
1960.41 LPJ is the classic operation for pancreatic drainage and entails opening the pancreatic duct
anteriorly along its length, medially to the level of the gastroduodenal artery and laterally into the tail.
The opened pancreatic duct is then cleared of stones, including into the head, and anastomosed to a
Roux-en-Y jejunal limb for drainage.
Procedure-specific complications of note include intraoperative hemorrhage (due to splenic vein or
gastroduodenal artery injury), postoperative hemorrhage (often from the gastroduodenal artery), and
anastomotic leak (seen in 10% of cases).
Multiple retrospective single-institution case series have been reported while evaluating outcomes
with LPJ, with pain-relief rates of 48% to 91%.42–49 Morbidity rates are low (20% on average) and
endocrine and exocrine function is often preserved.50 LPJ is an effective and safe procedure for pain
relief in many patients with dilated duct pancreatitis. Recurrent pain does occur after LPJ, however,
likely due to disease in the head of the pancreas. Intraductal stone disease in the head of the pancreas
can be cleared with intraoperative pancreatoscopy and electrohydraulic lithotripsy, which has been
shown to improve outcomes (reduced readmissions, increased pain-relief rates).51 Alternatively,
combining a localized head resection with LPJ can help to reduce recidivism.
Localized Pancreatic Head Resection with Lateral Pancreaticojejunostomy

In 1987, Frey and colleagues described a localized pancreatic head resection with a lateral
pancreaticojejunostomy (LR-LPJ) with the goal of achieving pancreatic ductal drainage, resection of
damaged and poorly drained parenchyma in the head of the pancreas, and preservation of the
duodenum to minimize postoperative gastrointestinal dysfunction. The Frey procedure combines a
classic longitudinal ductotomy of the neck, body and tail of the pancreas with unroofing of the
pancreatic ducts in the head and uncinate process of the pancreas with a “coring” out of the overlying
ductal tissue and preservation of the pancreas parenchyma along the posterior and lateral margin of the
pancreas. Frey reported initially on 50 patients, describing a morbidity of 22% and a pain-relief rate of
84%.52 His outcomes have been validated in modern series, both at his own institution and at others,
with pain-relief rates of 62% to 88% and morbidity of 20% to 30% reported.53–56
Algorithm 54-1. Algorithm for operative decision-making in chronic pancreatitis. LPJ, lateral pancreaticojejunostomy; LR-LPJ,
local pancreatic head resection with lateral pancreaticojejunostomy; PD, pancreatoduodenectomy; DPPHR, duodenal-preserving
pancreatic head resection; DP, distal pancreatectomy; TPIAT, total pancreatectomy with islet autotransplantation.
1389
booksmedicos.org
Pancreatic Head Resection
Pancreatoduodenectomy (PD) for CP was described as early as 1946 by Whipple.57 In the modern era,
PD is the operation of choice for patients with complicated CP and head-dominant disease. Patients may
present with duodenal or biliary obstruction as well as obstructive pancreatopathy from an
inflammatory mass in the head of the pancreas. Outcomes for PD include pain relief in 70% to 89% of
patients, morbidity in 16% to 53%, and mortality in less than 5% in high-volume centers.58–61
The pylorus preserving pancreatoduodenectomy (PPPD) was popularized by Traverso and Longmire
in 1978 in an effort to maintain the physiologic benefits of a functional pylorus.62 PPPD has been well
adopted into pancreas surgery although the purported nutritional advantages have not been
evidenced.63–67 Some authors, however, have reported improved professional rehabilitation64 and
improved quality of life after PPPD66 as compared to classic PD.
Duodenal preserving pancreatic head resection (DPPHR) was developed by Beger and colleagues in
the 1970s in an effort to decrease the morbidity of pancreatic head resection for CP. Pain relief is
reported in 77% to 88% of patients, with professional rehabilitation rates of 63% to 69%. Morbidity and
mortality are acceptable at 28.5% and 1%, respectively.67–71 Multiple prospective randomized trials in
comparing the various methods of pancreatic head resection in CP have been undertaken mostly in
Germany over the past couple of decades, with no discernable advantage determined between them
(Table 54-4).71–76 A modification of the Beger procedure was described by the group in Berne in which
the neck of the pancreas is left intact in its course over the portal vein thereby diminishing the risk of
portal venotomy (Fig. 54-4).77,78
Distal Pancreatectomy
In patients with CP and disease localized to the body and tail of the pancreas or in patients with a main
pancreatic duct stricture in the neck or body, distal pancreatectomy (DP) can be an effective means of
pain relief. The majority of CP patients who are candidates for DP have severe inflammatory changes in
the region of the splenic hilum, making concomitant splenectomy the most prudent course. Pain-relief
rates of 57% to 84% are reported with occupational rehabilitation in 29% to 73%. Morbidity and
mortality are reported in 15% to 32% and 2% to 2.2% of cases, respectively.79–81 Postoperative
pancreatic fistula after DP is the primary morbidity of this operation and appears to be related to
patient-specific factors rather than operative technique.82 DP appears to be applicable in approximately
9% to 25% of patients in larger series of patients undergoing surgery for CP.49,83
Total Pancreatectomy
TP for CP was performed as early as 1944 by Clagett at the Mayo Clinic. Perhaps tellingly, his patient
died 10 weeks after surgery of a hypoglycemic event. TP can be an effective means of pain relief in
patients with diffuse small-duct pancreatitis, patients who have failed lesser surgeries, and patients with
hereditary pancreatitis. Excellent pain-relief rates of 72% to 100% have been described with TP, with
morbidity rates of 22% to 54% and mortality 0 to 14%. There is a requisite brittle type 3c
pancreatogenic diabetes that follows TP; however, with severe diabetic control problems in 15% to 75%
of patients, and in one series, half of late postoperative deaths were due to hypoglycemia.84,85 With TP,
there is loss of not only insulin-producing beta cells but also loss of the alpha cells and other composite
cells of the islet that produce hormones to maintain glucose homeostasis. As a result, patients may
demonstrate an unpredictable response to exogenous insulin and importantly may develop
hypoglycemic unawareness, which can be morbid.86 Thus, TP is a good option for pain relief but the
resultant diabetes is exceptionally morbid.
5 TP with islet autotransplantation (TPIAT) was described by Sutherland and colleagues at the
University of Minnesota in 1978, with the goal of ameliorating the brittle diabetes after extensive
pancreatectomy.87 TPIAT has really only been performed with any regularity, however, over the past
decade, and understanding of long-term outcomes is evolving. Pain-relief rates of 72% to 86% have
been reported and patients have a significantly improved quality of life. Morbidity rates of 47% to 55%
are reported, with 1.4% to 6% mortality, and insulin independence in 10% to 40% after islet
transplant.88–91 Insulin independence after TPIAT correlates with the number of islet equivalents per
kilogram harvested89,91 and transplanted islet function appears to be durable, with outcomes reported
for more than 13 years.92 TPIAT has been safely and effectively performed in children with hereditary
pancreatitis, with insulin independence in 55%.93 While this therapy holds promise, long-term outcomes
data are currently lacking.
1390
booksmedicos.org
Figure 54-4. Schematic drawings of extent of resection (A), and method of reconstruction (B) for a Beger procedure (1), Frey
procedure (2), and a Berne modification of the Beger procedure (3). Reproduced from Muller MW, Freiss H, Leitzbach S, et al.
Perioperative and follow-up results after central pancreatic head resection (Berne technique) in a consecutive series of patients
with chronic pancreatitis. Am J Surg 2008;196:364–372.
Table 54-4 Comparative Randomized Controlled Trials of Pancreatic Head

Resection
Laparoscopic Surgery for Chronic Pancreatitis

Laparoscopy began in pancreas surgery with laparoscopic staging for pancreatic cancer. The
development of endoscopic stapler technology in the mid-1990s allowed for pancreatic resections to be
developed. In 1996, Gagner reported his experience with laparoscopic distal pancreatectomy.94 Due to
the recent epidemic of incidentally discovered low-grade pancreatic neoplasms, experience with
laparoscopic DP has matured rapidly, and now it is currently the most commonly performed
laparoscopic pancreatic resection. A large multicenter group reported on 667 distal pancreatectomies
with 159 (24%) laparoscopic, and 14 (9%) were for CP. The authors reported lower blood loss, length
of stay and morbidity with laparoscopy, and equivalent operative times and pancreatic fistula rates.95 A
recent meta-analysis of studies reporting experience with laparoscopic DP, including greater than 1,800
cases, showed similar advantages with laparoscopy, while maintaining quality.96 While laparoscopic DP
is arguably now the standard approach to resection of benign or low-grade neoplasms its wide
application in patients with CP is still in evolution, as these cases are more technically challenging due
to the distorted anatomy and loss of tissue planes in CP. Laparoscopic LPJ has been described by several
authors and is technically feasible.97 Success rate for the minimally invasive approach in this operation
increases as the size of the pancreatic duct increases. The laparoscopic PD is being performed at many
1391
booksmedicos.org
academic centers, mostly for malignant disease, but in a few with CP. The authors report reasonable
operative times (median 357 to 368 minutes), blood loss (75 to 240 cc), morbidity (26.7% to 42%), and
pancreatic fistula rates (6.7% to 18%).98–100 The limitations of laparoscopic PD in CP are similar to
those with laparoscopic DP, with the associated technical challenges of operating on a fibrotic gland.
CONCLUSIONS
CP is a complex disease, challenging in diagnosis and management. Notable recent progress has been
made in understanding the underlying pathophysiology, including genetic causes and cellular and
biochemical mechanisms, with much still to be learned. Surgery can be beneficial in many patients with
debilitating pain from CP. Evolving surgical therapies, such as TPIAT and minimally invasive
techniques, are promising.
References
1. Rickels MR, Bellin M, Toledo FG, et al. Detection, evaluation, and treatment of diabetes mellitus in
chronic pancreatitis: recommendations from Pancreasfest 2012. Pancreatology 2013;13(4):336–342.
2. Levy P, Barthet M, Mollard BR, et al. Estimation of the prevalence and incidence of chronic
pancreatitis and its complications. Gastroenterol Clin Biol 2006;30:838–844.
3. Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: liver, biliary tract,
and pancreas. Gastroenterology 2009;136:1134–1144.
4. Schneider A, Lohr JM, Singer MV. The M-ANNHEIM classification of chronic pancreatitis:
introduction of a unifying classification system based on a review of previous classifications of the
disease. J Gastroenterol 2007;42:101–119.
5. Layer P, Yamamoto H, Kalthoff L, et al. The different courses of early and late onset idiopathic and
alcoholic chronic pancreatitis. Gastroenterology 1994;107:1481–1487.
6. Dani R, Penna FJ, Nogueira CE. Etiology of chronic calcifying pancreatitis in Brazil: a report of 329
consecutive cases. Int J Pancreatol 1986;1:399–406.
7. Marks IN, Bank S, Louw JH. Chronic pancreatitis in the Western Cape. Digestion 1973;9:447–453.
8. Cote GA, Yadav D, Slivka A, et al. Alcohol and smoking as risk factors in an epidemiology study of
patients with chronic pancreatitis. Clin Gastroenterol Hepatol 2011;9:266–273.
9. Whitcomb DC. Genetics of alcoholic and nonalcoholic pancreatitis. Curr Opin Gastroenterol
2012;28:501–506.
10. Cavallini G, Talamini G, Vaona B, et al. Effect of alcohol and smoking on pancreatic lithogenesis in
the course of chronic pancreatitis. Pancreas 1994;9:42–46.
11. Maisonneuve P, Lowenfels AB, Mullhaupt B, et al. Cigarette smoking accelerates progression of
alcoholic chronic pancreatitis. Gut 2005;54:510–514.
12. Yadav D, Hawes RH, Brand RE, et al. Alcohol consumption, cigarette smoking, and the risk of
recurrent acute and chronic pancreatitis. Arch Int Med 2009;169:1035–1045.
13. Nojgaard C, Becker U, Matzen P, et al. Progression from acute to chronic pancreatitis: prognostic
factors, mortality and natural cause. Pancreas 2011;40:1195–1200.
14. Comfort MW, Steinberg AG. Pedigree of a family with hereditary chronic relapsing pancreatitis.
15. Whitcomb DC, Gorry MC, Preston RA, et al. Hereditary pancreatitis is caused by a mutation in the
cationic trypsinogen gene. Nat Genet 1996;14:141–145.
16. Witt H, Luck W, Hennies HC, et al. Mutations in the gene encoding the serine protease inhibitor,
Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213–216.
17. Szmola R, Sahin-Toth M. Chymotrypsin C promotes degradation of human cationic trypsin: identity
with Rinderknecht’s enzyme Y. Proc Natl Acad Sci U S A 2001;104:11227–11232.
18. Felderbauer P, Hoffman P, Einwachter H, et al. A novel mutation of the calcium sensing receptor
gene is associated with chronic pancreatitis in a family with heterozygous SPINK1 mutations. BMC
Gastroenterol 2003;3:34.
19. Brand H, Diergaarde B, O’Connell MR, et al. Variation in the gamma-glutamyltransferase 1 gene
1392
booksmedicos.org
and risk of chronic pancreatitis. Pancreas 2011;40:1188–1194.
20. Whitcomb DC. Genetic risk factors for pancreatic disorders. Gastroenterology 2013;144:1292–1302.
21. Apte MV, Haber PS, Darby SJ, et al. Pancreatic stellate cells are activated by proinflammatory
cytokines: implications for pancreatic fibrogenesis. Gut 1999;44:534–541.
22. Shek FW, Benyon RC, Walker FM, et al. Expression of transforming growth factor beta 1 by
pancreatic stellate cells and its implications for matrix secretion and turnover in chronic
pancreatitis. Am J Pathol 2002;160:1787–1798.
23. Bockman DE, Buchler M, Malfetheiner P, et al. Analysis of nerves in pancreatitis. Gastroenterology
1988;94:1459–1469.
24. Buchler M, Weihe E, Fries H, et al. Changes in peptidergic innervation in chronic pancreatitis.
Pancreas 1992;7:183–192.
25. Michalski CW, Shi X, Reiser C, et al. Neurokinin-2 receptor levels correlate with intensity,
frequency, and duration of pain in chronic pancreatitis. Ann Surg 2007;246:786–793.
26. Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756–759.
27. Wallace MB, Hawes RH, Durkalski V, et al. The reliability of EUS for the diagnosis of chronic
pancreatitis: interobserver agreement among experienced endosonographers. Gastrointest Endosc
2001;53:294–299.
28. Ferrone M, Raimondo M, Scolapio JS. Pancreatic enzyme pharmacotherapy. Pharmacotherapy
2007;27:910–920.
29. Siriwardena AK, Mason JM, Sheen AJ, et al. Antioxidant therapy does not reduce pain in patients
with chronic pancreatitis: the ANTICIPATE study. Gastroenterology 2012;143(3):655–663.
30. Barth KS, Balliet W, Pelic CM, et al. Screening for current opioid misuse and associated risk factors
among patients with chronic nonalcoholic pancreatitis pain. Pain Med 2014;15(8):1359–1364.
31. Kaufman M, Singh G, Das S, et al. Efficacy of endoscopic ultrasound-guided celiac plexus block and
celiac plexus neurolysis for managing abdominal pain associated with chronic pancreatitis and
pancreatic cancer. J Clin Gastroenterol 2010;44(2):127–134.
32. Dite P, Ruzicka M, Zboril V, et al. A prospective randomized trial comparing endoscopic and
surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553–558.
33. Cahen DL, Gouma DJ, Nio Y, et al. Endoscopic versus surgical drainage of the pancreatic duct in
chronic pancreatitis. NEJM 2007;356:676–684.
34. Cahen DL, Gouma DJ, Laramee P, et al. Long-term outcomes of endoscopic vs. surgical drainage of
the pancreatic duct in patients with chronic pancreatitis. Gastroenterology 2011;141:1690–1695.
35. Leppard WM, Shary TM, Adams DB, et al. Choledochoduodenostomy: is it really so bad? J
36. Taylor SM, Adams DB, Anderson MC. Duodenal stricture: a complication of chronic fibrocalcific
pancreatitis. South Med J 1991;84:338–341.
37. Adams DB, Mauterer DJ, Vujic IJ, et al. Preoperative control of splenic artery inflow in patients
with splenic venous occlusion. South Med J 1990;83:1021–1024.
38. Adams DB, Davis BR, Anderson MC. Colonic complications of pancreatitis. Am Surg 1994 60:44–49.
39. Nealon WH, Walser E. Duct drainage alone is sufficient in the operative management of pancreatic
pseudocyst in patients with chronic pancreatitis. Ann Surg 2003;237:614–620.
40. Puestow CB, Billesby WJ. Retrograde surgical drainage of pancreas for chronic relapsing
pancreatitis. Arch Surg 1958;76:898–907.
41. Partington PF, Rochelle RE. Modified Puestow procedure for retrograde drainage of the pancreatic
duct. Ann Surg 2001;233:793–800.
42. Nealon WH, Matin S. Analysis of surgical success in preventing recurrent acute exacerbations in
chronic pancreatitis. Ann Surg 2001;233:793–800.
43. Greenlee HB, Prinz RA, Aranha GV. Longterm results of side to side pancreaticojejunostomy. World
J Surg 1990;14:70–76.
44. Sato T, Miyashita E, Yamaguchi H, et al. The role of surgical treatment for chronic pancreatitis.
Ann Surg 1986;203:266–271.
45. Bradley EL. Long term results of pancreaticojejunostomy in patients with chronic pancreatitis. Am J
Surg 1987;153:207–213.
1393
booksmedicos.org
46. Holmberg JT, Isaksson G, Ihse I. Longterm results of pancreaticojejunostomy in chronic
pancreatitis. Surg Gynecol Obstet 1985;160:339–346.
47. Sarles JC, Nacchiero M, Garani F, et al. Surgical treatment of chronic pancreatitis. Report of 134
cases treated by resection or drainage. Am J Surg 1982;144:317–321.
48. Adams DB, Ford MC, Anderson MC. Outcome after lateral pancreaticojejunostomy for chronic
pancreatitis. Ann Surg 1994;219:481–489.
49. Schnelldorfer T, Lewin DN, Adams DB. Operative management of chronic pancreatitis: longterm
results in 372 patients. JACS 2007;204:1039–1045.
50. Nealon WH, Thompson JC. Progressive loss of pancreatic function in chronic pancreatitis is delayed
by main pancreatic duct decompression. a longitudinal prospective analysis of the modified
puestow procedure. Ann Surg 1993;217:458–468.
51. Rios G, Adams DB. Does intraoperative EHL improve outcome in the surgical management of
chronic pancreatitis. Am Surg 2001;67:534–538.
52. Frey CF, Smith GJ. Description and rationale of a new operation for chronic pancreatitis. Pancreas
1987;2:701–707.
53. Frey CF, Amikura K. Local resection of the head of the pancreas combined with longitudinal
pancreaticojejunostomy in the management of patients with chronic pancreatitis. Ann Surg
1994;220:492–504.
54. Keck T, Wellner UF, Riediger H, et al. Long term outcome after 92 duodenum preserving pancreatic
head resections for chronic pancreatitis: comparison of Beger and Frey procedures. J Gastrointest
Surg 2010;14:549–556.
55. Negi S, Singh A, Chaudhary A. Pain relief after Frey’s procedure for chronic pancreatitis. Br J Surg
2010;97:187–195.
56. Pessaux P, Kianmanesh R, Regimbequ JM, et al. Frey Procedure in the Treatment of Chronic
pancreatitis. Pancreas 2006;33:354–358.
57. Whipple AO. Radical surgery for certain cases of pancreatic fibrosis associated with calcareous
deposits. Ann Surg 1946;124:991–1006.
58. Sakorafas GH, Farnell, MB, Nagorney DM, et al. Pancreatoduodenctomy for chronic pancreatitis:
long term results in 105 patients. Arch Surg 2000;135:517–523.
59. Jimenez RE, Fernandez-Del Castillo C, Rattner DW, et al. Pylorus preserving
pancreaticoduodenectomy in the treatment of chronic pancreatitis. World J Surg 2003;27:1211–
1216.
60. Russell RC, Theis BA. Pancreatoduodenectomy in the treatment of chronic pancreatitis. World J Surg
2003;27:1203–1210.
61. Vickers SM, Chan C, Heslin MJ, et al. The role of pancreaticoduodenectomy in the treatment of
severe chronic pancreatitis. Am Surg 1999;65:1108–1111.
62. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg
Gynecol Obstet 1978;146:959–962.
63. Tran KT, Smeenk HG, van Eijck CH, et al. Pylorus preserving pancreaticoduodenectomy versus
standard Whipple procedure: a prospective, randomized, multicenter analysis of 170 patients with
pancreatic and periampullary tumors. Ann Surg 2004;240:738–745.
64. Seiler CA, Wagner M, Bachmann T, et al. Randomized clinical trial of pylorus-preserving
duodenopancreatectomy versus classical Whipple resection—long term results. Br J Surg
2005;92:547–556.
65. Iqbal N, Lovegrove RE, Tilney HS, et al. A comparison of pancreaticoduodenectomy with pylorus
preserving pancreaticoduodenectomy: a meta-analysis of 2822 patients. EJSO 2008;34:1237–1245.
66. Ohtsuka T, Yamaguchi K, Ohuchida J, et al. Comparison of quality of life after pylorus preserving
pancreatoduodenectomy and Whipple resection. Hepatogastroenterology 2003;50:846–850.
67. Beger HG, Krautzberger W, Bittner R, et al. Duodenum-preserving resection of the head of the
pancreas in patients with severe chronic pancreatitis. Surgery 1985;97:467–475.
68. Beger HG, Buchler M, Bittner RR, et al. Duodenum-preserving resection of the head of the pancreas
in severe chronic pancreatitis. Early and late results. Ann Surg 1989;209:273–278.
69. Beger HG, Schlosser W, Friess HM, et al. Duodenum preserving head resection in chronic
pancreatitis changes the natural course of the disease: a single-center 26 year experience. Ann Surg
1394
booksmedicos.org
1999;230:512–519.
70. Buchler MW, Friess H, Bittner R, et al. Duodenum preserving pancreatic head resection: long term
results. J Gastrointest Surg 1997;1:13–19.
71. Klempa I, Spatny M, Menzel J, et al. Pancreatic function and quality of life after resection of the
head of the pancreas in chronic pancreatitis. a prospective, randomized comparative study after
duodenum preserving resection of the head of the pancreas versus Whipple’s operation. Chirurg
1995;66:350–359.
72. Buchler MW, Friess H, Muller MW, et al. Randomized trial of duodenum preserving pancreatic head
resection versus pylorus preserving Whipple in chronic pancreatitis. Am J Surg 1995;169:65–69.
73. Farkas G, Leindler L, Daroczi M, et al. Prospective randomized comparison of organ preserving
pancreatic head resection with pylorus preserving pancreaticoduodenectomy. Langenbecks Arch Surg
2006;391:338–342.
74. Izbicki JR, Bloechle C, Knoefel WT, et al. Duodenum preserving resection of the head of the
pancreas in chronic pancreatitis: a prospective randomized trial. Ann Surg 1995;221:350–358.
75. Izbicki JR, Bloechle C, Broering DC, et al. Extended drainage versus resection in surgery for chronic
pancreatitis: a prospective randomized trial comparing the longitudinal pancreaticojejunostomy
combined with local pancreatic head excision with the pylorus preserving pancreatoduodenectomy.
Ann Surg 1998;228:771–779.
76. Strate T, Taherpour Z, Bloechle C, et al. Long term follow up of a randomized trial comparing the
Beger and Frey procedures for patients suffering from chronic pancreatitis. Ann Surg 2005;241:591–
598.
77. Muller MW, Friess H, Leitzbach S, et al. Perioperative and follow up results after central pancreatic
head resection in a consecutive series of patients with chronic pancreatitis. Am J Surg
2008;196:364–372.
78. Gloor B, Friess H, Uhl W, et al. A modified technique of the Beger and Frey procedure in patients
with chronic pancreatitis. Dig Surg 2001;18:21–25.
79. Hutchins RR, Hart RS, Pacifico M, et al. Long term results of distal pancreatectomy for chronic
pancreatitis in 90 patients. Ann Surg 2002;236:612–618.
80. Schoenberg MH, Schlosser W, Ruck W, et al. Distal pancreatectomy in chronic pancreatitis. Dig Surg
1999;16:130–136.
81. Sakorafas GH, Sarr MG, Rowland CM, et al. Postobstructive chronic pancreatitis: results with distal
resection. Arch Surg 2001;136:643–648.
82. Schnelldorfer T, Mauldin PD, Lewin DN, et al. Distal pancreatectomy for chronic pancreatitis: risk
factors for postoperative pancreatic fistula. J Gastrointest Surg 2007;11:991–997.
83. Riediger H, Adam U, Fischer E, et al. Long-term outcome after resection for chronic pancreatitis in
224 patients. J Gastrointest Surg 2007;11:949–960.
84. Gruessner RW, Sutherland DE, Dunn DL, et al. Transplant options for patients undergoing total
pancreatectomy for chronic pancreatitis. JACS 2004;198:559–567.
85. Dresler CM, Fortner JG, McDermott K, et al. Metabolic consequences of regional (total)
pancreatectomy. 1991;214(2):131–140.
86. Rickles MR, Schutta MF, Markmann JF, et al. Beta cell function following human islet
transplantation for type I diabetes. Diabetes 2005;54:100–106.
87. Sutherland DE, Matas AJ, Najarian JS. Pancreatic islet cell transplantation. Surg Clin North Am
1978;58:365–382.
88. Morgan K, Owczarski SM, Borckardt J, et al. Pain control and quality of life after pancreatectomy
with islet autotransplantation for chronic pancreatitis. J Gastrointest Surg 2012;16:129–134.
89. Sutherland DE, Radosevich DM, Bellin MD, et al. Total pancreatectomy and islet
autotransplantation for chronic pancreatitis. JACS 2012; 214:409–424.
90. Argo JL, Contreras JL, Wesley MM, et al. Pancreatic resection with islet cell autotransplant for the
treatment of severe chronic pancreatitis. Am Surg 2008;74:530–536.
91. Rilo HR, Ahmad SA, D’Alessio D. Total pancreatectomy and autologous islet cell transplant as a
means to treat severe chronic pancreatitis. J Gastrointest Surg 2003;7:978–989.
92. Robertson RP, Lanz KJ, Sutherland DE, et al. Prevention of diabetes for up to 13 years by autoislet
transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001;50:47–53.
1395
booksmedicos.org
93. Chinnakotla S, Bellin MD, Schwartzenberg SJ, et al. Total pancreatectomy and islet
autotransplantation in children for chronic pancreatitis: indication, surgical techniques,
postoperative management, and long-term outcomes. Ann Surg 2014;97:1286–1291.
94. Gagner M, Pomp A, Herrera MF. Early experience with laparoscopic resections of islet cell tumors.
Surgery 1996;120:1051–1054.
95. Kooby DA, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of
laparoscopic and open approaches. Ann Surg 2008;248:438–446.
96. Venkat R, Edil BH, Shulick RD, et al. Laparoscopic distal pancreatectomy is associated with
significantly less overall morbidity compared to the open technique: a systematic review and meta-
analysis. Ann Surg 2012;255:1048–1059.
97. Tantia O, Jindal MK, Khanna S, et al. Laparoscopic lateral pancreaticojejunostomy: our experience
of 17 cases. Surg Endosc 2004;18:1054–1057.
98. Palanivelu C, Rajan RS, Rangarajan M, et al. Evolution in techniques of laparoscopic
pancreaticoduodenectomy. a decade long experience from a tertiary center. J HBP Surg
2009;16:731–740.
99. Kendrick ML, Cusati D. Total laparoscopic pancreaticoduodenectomy: feasibility and outcome in an
early experience. Arch Surg 2010;145:19–23.
100. Asbun HJ, Stauffer JA. Laparoscopic vs open pancreaticoduodenectomy: overall outcomes and
severity of complications using the Accordion Severity Grading System. J Amer Coll Surg
2012;215:810–819.
1396
booksmedicos.org
Chapter 55
Neoplasms of Exocrine Pancreas

Attila Nakeeb, Michael G. House, and Keith D. Lillemoe
Key Points
1 Recent evidence supports that pancreatic ductal adenocarcinoma arises from precursor lesions
referred to as pancreatic intraepithelial neoplasia (PanIN) with progression from proliferative lesions
without nuclear abnormality to carcinoma in situ, known as PanIN-3.
2 Intraductal papillary mucinous neoplasms (IPMNs) are intraductal mucin-producing tumors that
range from benign adenomas to invasive carcinoma.
3 Contrast-enhanced computed tomography (CT) is the preferred noninvasive imaging test for the
diagnosis and staging of pancreatic cancer.
4 Perioperative mortality rates following pancreatoduodenectomy have fallen to the range of 2% to
5% although perioperative complications occur in approximately 40% of patients.
5 Survival after pancreatoduodenectomy for pancreatic cancer is approximately 20% at 5 years with
factors influencing survival including tumor size, margin status, and lymph node status.
6 Adjuvant chemotherapy is beneficial for patients following resection of pancreatic cancer.
7 Endoscopic palliation of patients with incurable pancreatic cancer located in the head may require
biliary and duodenal stenting.
8 Patients found to be unresectable at laparotomy for head of pancreas cancer should be considered for
biliary bypass, gastrojejunostomy, and chemical splanchnicectomy to palliate the symptoms of
jaundice, duodenal obstruction, and pain, respectively.
INTRODUCTION
Pancreatic cancer is the fourth leading cause of cancer-related death in the United States and second
only to colorectal cancer as a cause of gastrointestinal cancer-related death. The overall 5-year survival
for patients with pancreatic cancer is 7%.1 Surgical resection offers the only chance for long-term cure.
Unfortunately, because of the late presentation, only 15% to 20% of patients are candidates for surgical
intervention. Five-year survival after pancreaticoduodenectomy (PD) is about 25% to 30% for node-
negative and 10% for node-positive disease.2 The nonspecific symptoms associated with early pancreatic
cancer, the inaccessibility of the pancreas to examination, the aggressiveness of the tumors, and the
technical difficulties associated with pancreatic surgery make pancreatic cancer one of the most
challenging diseases treated by surgeons and oncologists.
In recent years, significant advances have been made in our understanding of the pathogenesis and
clinical management of pancreatic cancer. This chapter will review the epidemiology and risk factors
associated with pancreatic cancer, discuss recent developments in the field of molecular genetics, and
provide an update on the current clinical management of pancreatic cancer.
EPIDEMIOLOGY AND RISK FACTORS

In the United States, it is estimated that nearly 48,960 new cases of pancreatic cancer will be diagnosed
with almost 40,560 people dying of the disease in 2015. Pancreatic cancer accounts for 3% of all cancers
in the United States and is responsible for 7% of all cancer deaths. The incidence of pancreatic cancer in
the United States is 12.4 per 100,000 populations. The lifetime risk for developing pancreatic cancer is
1.5%.1 The incidence of pancreatic cancer has slowly been increasing, with an average increase of 0.8%
per year over the last 10 years (Fig. 55-1). The risk for the development of pancreatic cancer is related
to age, race, sex, tobacco use, diet, and specific genetic syndromes (Table 55-1). The incidence increases
1397
booksmedicos.org
with advancing age. More than 80% of cases occur in persons between the ages of 60 and 80 years, and
pancreatic cancer is rare in people younger than 40 years. The incidence and mortality rates for
pancreatic cancer in African Americans of both sexes are higher than those in whites. The gender
differences in pancreatic cancer have been equalizing during recent years. Pancreatic cancer is still more
common in men than in women, but the incidence and mortality rates have increased in women while
they have stabilized or slightly decreased in men.
Environmental and dietary factors have also been implicated as risk factors for the development of
pancreatic cancer. The most consistently observed environmental risk for the development of pancreatic
cancer is cigarette smoking. It has been estimated that cigarette smoking can increase the risk for
pancreatic cancer between one and a half and five times. The mechanism is unknown, but carcinogens in
cigarette smoke have been shown to produce pancreatic cancers in laboratory animals. In addition,
autopsy studies have documented hyperplastic changes in pancreatic ductal cells with atypical nuclear
patterns in smokers. Alcohol consumption does not seem to be a risk factor for pancreatic cancer despite
conflicting past reports. Recent studies suggest that past studies linking pancreatic cancer to alcohol use
may have been confounded by tobacco use. Similarly, coffee consumption and exposure to ionizing
radiation have been shown not to be associated with an increased pancreatic cancer risk.
Several epidemiologic investigations have suggested that diet may play an important role in the
development of pancreatic cancer. An apparent association has been noted between pancreatic cancer
and an increased consumption of total calories, carbohydrate, cholesterol, meat, salt, dehydrated food,
fried food, refined sugar, soy beans, and nitrosamines. The risks are unproven for the ingestion of fat,
beta-carotene, and coffee. A protective effect has been reported for dietary fiber, vitamin C, fruits, and
vegetables.3
Figure 55-1. U.S. pancreatic cancer new cases, death rate, and 5-year survival. Adapted from EER Cancer Statistics Factsheets:
Pancreas Cancer. National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/statfacts/html/pancreas.html. Accessed March 10,
2016.
In addition to well-defined genetic syndromes, a number of common conditions have been thought to
be etiologic factors in the development of pancreatic cancer. An apparent association between diabetes
and pancreatic cancer has been suggested. Approximately 80% of patients diagnosed with pancreatic
cancer have impaired glucose metabolism, impaired glucose tolerance, or diabetes mellitus. It is unclear
if alterations in glucose tolerance/metabolism are a causative factor for pancreatic cancer or represent
reaction to an enlarging malignancy in the pancreas. Among patients with newly diagnosed diabetes,
0.85% went on to be diagnosed with pancreatic cancer within 3 years.4 Type II diabetes of at least 5
years duration has been shown to increase the risk of pancreatic cancer twofold.
The risk of pancreatic cancer has been shown to increase as body mass index increases. Examination
of data from the Nurses’ Health Study and the Health Professional’s follow-up study show a 1.72
relative risk (95% CI 1.19–2.48) of pancreatic cancer in patients with a BMI >30 kg/m2 as compared to
individuals with a BMI <23 kg/m2.
Chronic pancreatitis of any cause has been associated with a 25-year cumulative risk for the
development of pancreatic cancer of approximately 4%. Other conditions for which a possible
association with pancreatic cancer has been demonstrated include thyroid and other benign endocrine
tumors, cystic fibrosis, and pernicious anemia.
1398
booksmedicos.org
Most cases of pancreatic cancer have no obvious predisposing factors. However, it is believed that
between 5% and 10% of pancreatic cancers arise because of a familial predisposition. Six genetic
syndromes have been associated with an increased risk for the development of pancreatic cancer (Table
55-2). These include hereditary nonpolyposis colon cancer, familial breast cancer associated with the
BRCA2 mutation, Peutz–Jeghers syndrome (PJS), ataxia–telangiectasia syndrome, familial atypical
multiple mole–melanoma syndrome, and hereditary pancreatitis.
Table 55-1 Risk Factors for Pancreatic Cancer
Table 55-2 Genetic Syndromes Associated with Hereditary Pancreatic Cancer
MOLECULAR GENETICS
Invasive pancreatic ductal adenocarcinoma (PDAC) are genetically very complex, with wide-spread
chromosome abnormalities, numerous losses and gains of large segments of DNA, and on average, more
than 60 exomic alterations in each cancer.5 PDAC harbors an average of 63 genome alterations, of
which the majority are point mutations. Four key genes are frequently altered in PDAC: KRAS,
CDKN2A, TP53, and SMAD4 (Table 55-3). The most common gene alteration is in KRAS (Kirsten rat
sarcoma viral oncogene homolog), where mutations occur in codons 12, 13, and 61. More than 90% of
PDAC contain KRAS mutations. Point mutations of the K-ras oncogene impair the intrinsic guanosine
triphosphatase activity of its gene product; the result is a protein that is constitutively active in signal
transduction and activates various downstream signaling pathways, including the mitogen-activated
protein kinase (MAPK) cascades. Ras proteins are involved in a variety of cellular functions, including
proliferation, differentiation, and survival. Cyclin-dependent kinase inhibitor 2A gene (CDKN2A) is also
inactivated in up to 90% of PDAC, due to intragenic mutations in association with allelic loss,
homozygous deletion, or hypermethylation of the gene promoter. CDKN2A encodes a cyclin-dependent
kinase inhibitor that controls G1–S transition in the cell cycle. Inactivation of CDKN2A leads to the loss
of an important cell cycle checkpoint and therefore relatively unchecked proliferation. TP53 is one of
the most frequently mutated genes in many types of cancer, and is inactivated in about 75% of PDAC,
mainly due to point mutations or small deletions. The p53 gene product is a DNA-binding protein that
acts as both a cell-cycle checkpoint and an inducer of apoptosis. Inactivation of the p53 gene in
1399
booksmedicos.org
pancreatic cancer leads to the loss of two important controls of cell growth: regulation of cellular
proliferation and induction of cell death. SMAD4 (DPC4, SMAD family member 4 gene). SMAD4 encodes
a transcription factor that mediates signaling of the transforming growth factor-β (TGF-β) superfamily.
SMAD4 is a tumor-suppressor gene that has been identified on chromosome 18q. This chromosome has
been shown to be missing in nearly 90% of pancreatic cancers. The SMAD4 gene is inactive in almost
50% of pancreatic carcinomas. The mutation appears to be a homozygous deletion in 30% of pancreatic
cancers, and a point mutation in another 20% of tumors. SMAD4 mutations are more specific than p53
or p16 mutations for pancreatic cancer.
Table 55-3 Genetic Alterations in Pancreatic Adenocarcinomas
Germline mutations in BRCA2 and CDKN2A, and less frequently in BRCA1, PALB2 and ATM have been
identified in a small subset of patients with familial pancreatic cancer. The inactivation of BRCA2, which
encodes a protein involved in DNA damage repair, is associated with a 3.5- to 10-fold increased risk of
pancreatic cancer, as well as increased risk of breast and ovarian cancer. In addition, patients with
Lynch syndrome (caused by germline mutation in one of the mismatch repair genes MLH1, MSH2,
MSH6, or PMS2) and PJS (caused by germline mutation of the STK11 gene) are at increased risk of
pancreatic cancer. Approximately 4% of pancreatic cancers can be characterized by disorders of DNA
mismatch–repair genes.6
PATHOLOGY
Tumors of the exocrine pancreas can be classified based on their cell of origin (Table 55-4). The most
common neoplasms of the exocrine pancreas are ductal adenocarcinomas. Approximately 65% of
pancreatic ductal cancers arise in the head, neck, or uncinate process of the pancreas; 15% originate in
the body or the tail of the gland; and 20% diffusely involve the whole gland.
Solid Epithelial Tumors

Ductal Adenocarcinomas
Ductal adenocarcinomas account for more than 75% of all nonendocrine pancreatic cancers. Grossly,
they are white–yellow, poorly defined, hard masses that often obstruct the distal common bile duct or
main pancreatic duct. They are often associated with a desmoplastic reaction that causes fibrosis and
chronic pancreatitis. Microscopically, they contain infiltrating glands of varying size and shape
surrounded by dense, reactive fibrous tissue (Fig. 55-2). The epithelial cells sometimes form papillae
and cribriform structures, and they frequently contain mucin. The nuclei of the cells can show marked
pleomorphism, hyperchromasia, loss of polarity, and prominent nucleoli.
CLASSIFICATION
Table 55-4 Histologic Classification of 645 Cases of Primary Nonendocrine
Cancer of the Pancreas
1400
booksmedicos.org
Ductal adenocarcinomas tend to infiltrate into vascular, lymphatic, and perineural spaces. At the time
of resection, most ductal carcinomas have already metastasized to regional lymph nodes. In addition to
the lymph nodes, PDAC frequently metastasize to the liver (80%), peritoneum (60%), lungs and pleurae
(50% to 70%), and adrenal glands (25%). They also can directly invade the duodenum, stomach,
transverse mesocolon, colon, spleen, and adrenal glands.
1 The histologic examination of a pancreas resected for cancer frequently reveals the presence of
precursor lesions in the pancreatic ducts and ductules adjacent to the cancer. This suggests that much
like colon cancer, which arises from benign adenomas, pancreatic cancer may also demonstrate
progression to malignant from benign precursor lesions. These precursor lesions are referred to as
pancreatic intraepithelial neoplasia (PanIN). Briefly, PanIN-1A and PanIN-1B are proliferative lesions
without remarkable nuclear abnormality that have a flat and papillary architecture, respectively. PanIN-
3 is associated with severe architectural and cytonuclear abnormalities, but invasion through the
basement membrane is absent. The older term for PanIN-3 includes carcinoma in situ (CIS). PanIN-2 is
an intermediate category between PanIN-1 and PanIN-3 and is associated with a moderate degree of
architectural and cytonuclear abnormality.7 Several lines of evidence suggest that PanINs are precursors
of infiltrating pancreatic cancer: PanINs are often found in association with ductal adenocarcinomas,
three-dimensional mapping techniques that demonstrated a stepwise transformation from mild dysplasia
to severe dysplasia in pancreatic duct lesions, and PanINs demonstrate some of the same genetic
changes seen in infiltrating adenocarcinomas, most notably activating point mutations in codon 12 of K-
ras and mutations in the p16 and p53 tumor-suppressor genes.
Figure 55-2. Microscopic appearance of ductal adenocarcinoma of the head of the pancreas demonstrating glands from an
adenocarcinoma embedded in a fibrous matrix.
Adenosquamous Carcinomas
Adenosquamous carcinoma is a rare variant of ductal adenocarcinoma that shows both glandular and
squamous differentiation. This variant appears to be more common in patients who have undergone
previous chemoradiation therapy. The biologic behavior of adenosquamous carcinoma appears to be
similar to that of ductal adenocarcinoma, with similar rates of perineural invasion, lymph node
1401
booksmedicos.org
metastases, and dissemination.
Acinar Cell Carcinomas

Acinar cell carcinomas account for only 1% of pancreatic exocrine tumors. Acinar tumors are typically
smooth, fleshy, lobulated, hemorrhagic, or necrotic. Histologically, they form acini, and the cells
display an eosinophilic, granular cytoplasm. Immunohistochemical staining demonstrates expression of
trypsin, lipase, chymotrypsin, or amylase. These tumors are more common in males with a male-to-
female predominance of approximately 3:1. The age of diagnosis is usually in the fifth to seventh
decades. These tumors tend to be larger than ductal adenocarcinomas, often being larger than 10 cm.
Although data are limited, it appears that patients with acinar cell carcinoma have a slightly better
prognosis than patients with ductal carcinoma.8 Therefore, surgical resection is the treatment of choice.
Giant Cell Carcinomas

Giant cell carcinomas account for less than 1% of nonendocrine pancreatic cancers. They tend to be
large, with average diameters greater than 15 cm. Microscopically, they contain large, uninucleated or
multinucleated tumor cells, many of which are pleomorphic. The nuclei contain prominent nucleoli and
numerous mitotic figures. Giant cell carcinomas are associated with a poorer prognosis than ductal
adenocarcinomas. There is a variant of giant cell carcinoma termed giant cell carcinoma with osteoclast-
like giant cells. These lesions tend to be well circumscribed with nonpleomorphic giant cells and are less
aggressive than standard giant cell carcinomas.
Pancreatoblastoma
Pancreatoblastomas occur primarily in children ages 1 to 15 years. Pancreatoblastomas contain both
epithelial and mesenchymal elements. The epithelial component appears to arise from acinar cells. The
tumors are typically larger than 10 cm and often contain areas of degeneration and hemorrhage. The
prognosis appears to be more favorable than that for typical ductal adenocarcinoma if the tumor can be
resected.
Cystic Epithelial Tumors

Cystic neoplasms also arise from the exocrine pancreas. Cystic neoplasms are less common than ductal
adenocarcinomas, tend to occur in women, and are evenly distributed throughout the gland. Many
pancreatic and peripancreatic cysts are actually benign inflammatory pseudocysts. It is important to
identify cystic neoplasms because their management is very different from that of nonneoplastic cysts.
With advancements in imaging technology, cystic lesions of the pancreas are being detected with
increased frequency. With routine application of cross-sectional imaging to early diagnostic processes in
medicine, pancreatic cysts are often detected incidentally.9 Although many of these lesions are small
and asymptomatic, they can have malignant potential. Therefore, the management of these patients is
complex, and knowledge of pancreatic cyst natural history and predictors of neoplasia are important.
Serous Cystic Neoplasms

Serous cysts are epithelial neoplasms composed of uniform cuboidal glycogen-rich cells that usually
form numerous small cysts containing serous fluid. Serous cystadenomas or microcystic adenomas are
more common in women than in men (3:1 preponderance). These tumors can vary from a few
centimeters to more than 10 cm in size. Twenty-five percent to 30% of patients are asymptomatic;
however, most patients present with symptoms such as abdominal or epigastric pain, dyspepsia, nausea,
or vomiting. Serous cystadenomas can be located anywhere in the pancreas – head, body, or tail – and
usually do not communicate with the pancreatic ducts. Plain computed tomography (CT) shows a
honeycomb pattern of microlacunae, with thin septa separating different segments. Serous cystic
neoplasms can have a sunburst pattern of central calcification, which is seen in 10% to 30% of cases.
Grossly, they appear as spongy, well-circumscribed, multiloculated cysts. Microscopically, they consist
of a layer of simple cuboidal cells separated by dense fibrous bands. Most serous cystic neoplasms are
benign, although malignant behavior has been reported rarely (<1% with metastases to the liver or
peripancreatic lymph nodes). Symptomatic cysts or cysts that cannot be differentiated from other
potentially malignant cysts should undergo surgical excision.
Mucinous Cystic Neoplasms

Mucinous cystic neoplasms (MCNs) are neoplasms composed of mucin-producing epithelial cells
associated with an ovarian-type of stroma. These cysts usually do not communicate with the larger
1402
booksmedicos.org
pancreatic ducts. MCNs are relatively uncommon but account for almost 30% of all cystic neoplasms.
The mean age at diagnosis is between 40 and 50 years. MCNs are more common in women with a
female-to-male ratio of 9:1. Most patients with MCNs present with vague abdominal symptoms that
include epigastric pain or a sense of abdominal fullness. The majority (70% to 90%) of MCNs arises in
the body or tail of the pancreas, and only a minority (10% to 30%) involves the head of the gland.
Microscopically, the cysts are lined by tall columnar mucin-producing epithelium. These columnar cells
have basal nuclei and abundant intracytoplasmic apical mucin and can form flat sheets or papillae. The
walls of the cysts contain a very distinctive “ovarian-type” stroma. This stroma is composed of densely
packed spindle cells with sparse cytoplasm and uniform elongated nuclei. All MCNs are considered to be
premalignant lesions and should be completely resected to prevent progression to malignancy.
Invasive mucinous cystadenocarcinomas are MCNs associated with an invasive carcinoma, whereas
noninvasive mucinous neoplasms can be categorized into MCNs with low-grade dysplasia (adenoma),
MCNs with moderate dysplasia (borderline) neoplasms, and MCNs with high-grade dysplasia (carcinoma
in situ) based on the degree of architectural and cytologic atypia of the epithelial cells. In surgical series
between 15% and 30% of all MCNs are associated with invasive carcinoma. Patients with mucinous
cystadenocarcinomas tend to be 5 to 10 years older than patients with benign MCNs. The extent of
invasive and in situ carcinomas in MCNs can be very focal. Therefore, a benign diagnosis cannot be
established on biopsy alone and the lesions should be completely resected. The prognosis for patients
with resected benign or borderline tumors is excellent. Patients with mucinous cystadenocarcinoma tend
to do better than patients with ductal adenocarcinoma, with a 5-year survival of approximately 50%.
Intraductal Papillary-Mucinous Neoplasms

Intraductal papillary-mucinous neoplasms (IPMNs) are intraductal mucin-producing neoplasms with tall,
columnar, mucin-containing epithelium with or without papillary projections. These neoplasms
extensively involve the main pancreatic ducts and/or major side branches. In addition, IPMNs lack the
ovarian stroma characteristic of MCNs. Similar to the well-defined adenoma–carcinoma sequence in
PDAC (PanIN to invasive ductal carcinoma), IPMNs seem to follow a similar pattern progressing from
IPMN with low-grade dysplasia to invasive carcinoma. Microscopically, they consist of papillary
projections lined by columnar mucin-secreting cells. They show varying degrees of cellular atypia. The
noninvasive IPMNs are graded on the basis of greatest degree of dysplasia and classified into low-grade,
moderate-grade, and high-grade dysplasia or carcinoma in situ. Invasive IPMNs are either colloid or
tubular, with the latter having a worse prognosis. The mean age of patients with invasive carcinoma is
approximately 5 years older than patients with noninvasive IPMNs suggesting an approximately 5-year
lag period for progression to malignancy. Further histologic subtyping of epithelial differentiation is
based on the cell lineage, the morphology of the papillae, and the immunophenotype, and includes
classification into intestinal, gastric, pancreaticobiliary, and oncocytic subtypes.
IPMNs are subclassified as main- and branch-duct types and as a mixed type that contains elements of
both. Main-duct IPMN is characterized by involvement of the duct of Wirsung, which is dilated to more
than 1 cm in diameter. Branch-duct IPMN originates in the side branches of the pancreatic ductal system
and appears as a multilobular cystic lesion communicating with a nondilated main pancreatic duct.
Typically, branch-duct IPMN occurs in the uncinate process–head of the gland, but it can also be seen in
the neck and distal pancreas. If the main duct is dilated with synchronous involvement of the branch
ducts, it is described as a mixed IPMN.
IPMNs are usually found in individuals in their 60s to 80s. Some patients may experience symptoms
that include: abdominal pain, steatorrhea, weight loss, jaundice, diabetes, and chronic pancreatitis. A
substantial number of these lesions are also detected as incidental findings on cross-sectional imaging
studies performed for other indications. IPMNs appear to be more common in the head, neck, and
uncinate process of the pancreas but can be found diffusely throughout the whole gland. CT scans will
typically reveal a cystic mass in the head of the pancreas that appears to communicate with the
pancreatic ductal system. On endoscopy, mucin can be seen oozing from the ampulla of Vater.
Endoscopic retrograde cholangiopancreatography (ERCP) can be used to confirm that the cysts
communicate with the pancreatic ducts.
MCNs are the main entity to consider in the differential diagnosis of IPMNs (Table 55-5). Two
morphologic features distinguish IPMNs from MCNs: IPMNs communicate with ducts, mucinous cysts do
not; IPMNs also lack an ovarian stroma that is present in mucinous cysts. In addition, mucinous cysts
are usually seen in the tail of the pancreas and occur in middle-aged women, whereas IPMNs are found
in the head of the pancreas and occur in older individuals of either sex.
1403
booksmedicos.org
As noted, IPMNs represent a continuum of disease from benign to malignant. In a large series of
resected IPMNs from the Johns Hopkins Hospital,10 the prognosis for the benign forms of the disease
appears to be significantly better than for invasive IPMNs with 1-, 2-, and 5-year actuarial survivals of
97%, 94%, and 77%, respectively. Although invasive IPMNs are associated with disease progression and
death, the prognosis remains markedly better than for invasive ductal carcinoma of the pancreas with
survivals of 72%, 58%, and 43% at 1, 2, and 5 years, respectively. It is unclear if this fact is due to
earlier presentation or differences in tumor biology.
DIAGNOSIS
Table 55-5 Comparison between Mucinous Cystic Neoplasm (MCN) and
Intraductal Papillary Mucinous Neoplasm (IPMN)
2 International consensus guidelines for the management of IPMNs have been developed.11 CT or
MRI with MRCP is recommended for imaging IPMNs. IPMNs are classified as having either “high-risk
stigmata” or “worrisome features.” High-risk stigmata include obstructive jaundice in the setting of a
cyst in the head of the pancreas, a main duct >10 mm, or a cyst with a solid enhancing component in
the wall. Worrisome features include cyst >3 cm, thickened enhanced cyst walls, nonenhanced mural
nodules, main duct size between 5 and 9 mm, abrupt change in the MPD caliber with distal pancreatic
atrophy, and lymphadenopathy. All cysts with “worrisome features” and cysts of >3 cm without
“worrisome features” should undergo endoscopic ultrasonography (EUS), and all cysts with “high-risk
stigmata” should be resected. If no “worrisome features” are present, no further initial work-up is
recommended, although surveillance is still required (Algorithm 55-1).
The goal of surgical therapy for IPMNs should be a complete surgical resection yielding negative
margins for all invasive and noninvasive disease. Unlike those patients with completely resected
noninvasive MCNs (who are routinely cured), patients with completely resected noninvasive IPMNs
should undergo careful follow-up and surveillance for the development of recurrent disease.
Furthermore, patients with resected invasive IPMNs should also undergo careful follow-up and
surveillance as they, too, remain at risk for the development of recurrent disease.
Solid-Pseudopapillary Tumor
Solid-pseudopapillary tumors (SPTs), also termed solid and cystic tumors, papillary cystic tumors,
Hamoudi tumors, and Frantz tumor occur primarily in women in their third to fourth decades of life.
Grossly, the masses range from 5 to 15 cm in diameter. Radiologically, they present as a well-
demarcated heterogeneous mass with solid and cystic components, with a peripheral capsule which
rarely shows calcification. EUS-guided fine needle aspiration (FNA) or core biopsy is often diagnostic,
showing uniform cells forming microadenoid structures, branching, and papillary clusters with delicate
fibrovascular cores. Most SPTs exhibit a benign behavior, and even the less than 20% that have vascular
or perineural invasion, lymph node involvement or liver metastases can have a very indolent course.
The overall 5-year survival is close to 97% in patients undergoing surgical resection.
1404
booksmedicos.org
Algorithm 55-1. International consensus guidelines for the management of IPMNs. From Tanaka M, Fernandez-del Castillo C,
Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology
2012;12:183–197.
CLINICOPATHOLOGIC STAGING
Accurate pathologic staging of pancreatic cancer is important for providing prognostic information to
patients and for comparing the results of various therapeutic trials. The American Joint Committee on
Cancer (AJCC) staging for pancreatic cancer is shown in Table 55-6. This system, based on the TNM
classification, takes into account the extent of the primary tumor (T), the presence or absence of
regional lymph node involvement (N), and the presence or absence of distant metastatic disease (M).
DIAGNOSIS
Clinical Presentation
Many of the difficulties associated with the management of pancreatic cancer result from our inability
to make the diagnosis at an early stage. The early symptoms of pancreatic cancer include anorexia,
weight loss, abdominal discomfort, and nausea. Unfortunately, the nonspecific nature of these
symptoms often leads to a delay in the diagnosis. Specific symptoms usually develop only after invasion
or obstruction of nearby structures has occurred. Most pancreatic cancers arise in the head of the
pancreas, and obstruction of the intrapancreatic portion of the common bile duct leads to progressive
jaundice, acholic stools, darkening of the urine, and pruritus. Pain is a common symptom of pancreatic
cancer. The pain usually starts as vague upper abdominal or back pain that is often ignored by the
patient or attributed to some other cause. It is usually worse in the supine position and is often relieved
by leaning forward. Pain may be caused by invasion of the tumor into the splanchnic plexus and
retroperitoneum, and by obstruction of the pancreatic duct. Other digestive symptoms are also common
in pancreatic cancer (Table 55-7).
Occasionally, pancreatic cancer may be discovered in an unusual manner. The onset of diabetes may
be the first clinical feature in 10% to 15% of patients. An episode of acute pancreatitis may also be the
initial presentation of pancreatic cancer if the tumor partially obstructs the pancreatic duct. It is
important to consider a pancreatic cancer in patients presenting with acute pancreatitis, especially those
1405
booksmedicos.org
without an obvious cause for their pancreatitis (alcohol or gallstones).
The most common physical finding at the initial presentation is jaundice (Table 55-8). Hepatomegaly
and a palpable gallbladder may be present in some patients. In cases of advanced disease, cachexia,
muscle wasting, or a nodular liver, consistent with metastatic disease, may be evident. Other physical
findings in patients with disseminated cancer include left supraclavicular adenopathy (Virchow node),
periumbilical adenopathy (Sister Mary Joseph node), and pelvic drop metastases (Blumer shelf). Ascites
can be present in 15% of patients.
STAGING
Table 55-6 American Joint Committee on Cancer Staging of Pancreatic Cancer,
7th Edition
DIAGNOSIS
Table 55-7 Symptoms of Pancreatic Cancer
1406
booksmedicos.org
Laboratory Studies
In patients with cancer of the head of the pancreas, laboratory studies usually reveal a significant
increase in serum total bilirubin, alkaline phosphatase, and γ-glutamyl transferase indicating bile duct
obstruction. The transaminases can also be elevated but usually not to the same extent as the alkaline
phosphatase. In patients with localized cancer of the body and tail of the pancreas, laboratory values are
frequently normal early in the course. Patients with pancreatic cancer may also demonstrate a
normochromic anemia and hypoalbuminemia secondary to the nutritional consequences of the disease.
In patients with jaundice, the prothrombin time can be abnormally prolonged. This usually is an
indication of biliary obstruction, which prevents bile from entering the gastrointestinal tract and leads
to malabsorption of fat-soluble vitamins and decreased hepatic production of vitamin K–dependent
clotting factors. The prothrombin time can usually be normalized by the administration of parenteral
vitamin K. Serum amylase and lipase levels are usually normal in patients with pancreatic cancer.
A wide variety of serum tumor markers have been proposed for use in the diagnosis and follow-up of
patients with pancreatic cancer. The most extensively studied of these is CA 19–9, a Lewis blood group-
related mucin glycoprotein. Approximately 5% of the population lacks the Lewis gene and therefore
cannot produce CA 19–9. When a normal upper limit of 37 U/mL is used, the accuracy of the CA 19–9
level in identifying patients with pancreatic adenocarcinoma is only about 80%. When a higher cutoff
value of more than 90 U/mL is used, the accuracy improves to 85%, and increasing the cutoff value to
200 U/mL increases the accuracy to 95%.12 The combined use of CA 19–9 and ultrasonography, CT, or
ERCP can improve the accuracy of the individual tests, so that the combined accuracy approaches 100%
for the diagnosis of pancreatic cancer. Levels of CA 19–9 have also been correlated with prognosis and
tumor recurrence. In general, higher CA 19–9 values before surgery indicate an increased size of the
primary tumor and increased rate of unresectability. In addition, the CA 19–9 level has been used to
monitor the results of neoadjuvant and adjuvant chemoradiation therapy in patients. Increasing CA 19–9
levels usually indicate recurrence or progression of disease, whereas stable or declining levels indicate a
stable tumor burden, absence of recurrence on imaging studies, and an improved prognosis.
DIAGNOSIS
Table 55-8 Signs of Pancreatic Cancer
1407
booksmedicos.org
Radiologic Investigations
Radiologic imaging plays a crucial role in the diagnosis, staging, and follow-up of patients with
pancreatic cancer. In addition to identifying the primary tumor, the goals of imaging include the
assessment of local and regional invasion, evaluation of lymph nodes and vascular structures,
identification of distant metastatic disease, and the determination of tumor resectability.
Ultrasonography, computed tomography (CT), and magnetic resonance imaging (MRI) are all useful
noninvasive tests in the patient suspected of having a pancreatic cancer.
Transabdominal ultrasonography (US) will reveal a pancreatic mass in 60% to 70% of patients with
cancer. Pancreatic cancer typically appears as a hypoechoic mass on US. Ultrasonography may also
demonstrate dilated intrahepatic and extrahepatic bile ducts, liver metastases, pancreatic masses,
ascites, and enlarged peripancreatic lymph nodes. Because helical CT is just as sensitive as
ultrasonography and provides more complete information about surrounding structures and the local
and distant extent of the disease, transabdominal ultrasonography has been largely replaced by CT.
Figure 55-3. Computed tomogram of the abdomen of a patient with adenocarcinoma of the pancreas. A: The obstructed and
dilated common bile duct (light arrow) and pancreatic duct (dark arrow) can be seen. In the adjacent cross section B, a large mass is
present in the head of the pancreas (arrow).
3 Computed tomography (CT) scanning is currently the preferred noninvasive imaging test for the
diagnosis of pancreatic cancer. Pancreas protocol CT should be performed with rapid injection of
intravenous iodinated contrast. Slices should be reconstructed at less than or equal to 3 mm with
overlap. At least two postcontrast acquisitions, in the late arterial (or parenchymal) and venous phases
are useful to assess the arteries (celiac, common hepatic, peripancreatic, and superior mesenteric
arteries) and veins (portal, splenic, and superior mesenteric veins). The parenchymal phase best shows
the tumor as an ill-defined hypodense mass in the pancreatic parenchyma (Fig. 55-3), while the venous
phase is best for detecting liver metastases. Neutral enteral contrast such as water should be given, since
this allows for better identification of the duodenal wall and results in artifact-free reformations. In
many centers, no oral contrast is used. Coronal and sagittal reformations in both arterial and venous
phases increase the sensitivity for determining local invasion. In addition to determining the primary
tumor size, CT is used to evaluate invasion into local structures or metastatic disease.
1408
booksmedicos.org
In general, MRI offers no significant advantages over CT because of a low signal-to-noise ratio,
motion artifacts, lack of bowel opacification, and low spatial resolution. MRI can be considered an
alternative preoperative staging examination in patients with allergies to iodinated contrast agents and
in patients with renal insufficiency. On MRI, a typical pancreatic adenocarcinoma appears hypointense
on T1-weighted, unenhanced images, and has a variable appearance on T2-weighted sequences. The T2
signal of the tumor is often dependent on the amount of desmoplastic response associated with the
tumor. On dynamic imaging following a gadolinium contrast injection, an adenocarcinoma enhances
relatively less than the background pancreatic parenchyma in the early phase and then reveals
progressive enhancement in the subsequent phases. Magnetic resonance imaging with MRCP is currently
indicated for noninvasive diagnostic imaging to evaluate the biliary and pancreatic ducts and may be
the optimal method to survey patients with IPMN and the pancreatic remnant after surgery.
Traditionally, the next step in the evaluation of the jaundiced patient has been cholangiography,
either by the endoscopic or by the percutaneous route. If the endoscopic approach is used, the
duodenum and ampulla can be visualized and biopsy specimens obtained if necessary. In addition, ERCP
allows for direct imaging of the pancreatic duct. The sensitivity of ERCP for the diagnosis of pancreatic
cancer approaches 90%. The finding of a long, irregular stricture in an otherwise normal pancreatic duct
is highly suggestive of a pancreatic cancer (Fig. 55-4). Often, the pancreatic duct will be obstructed with
no distal filling. Although ERCP is reliable in confirming the presence of a clinically suspected
pancreatic cancer, it should not be used routinely. Diagnostic ERCP should be reserved for patients with
presumed pancreatic cancer and obstructive jaundice in whom no mass is demonstrated on CT,
symptomatic but nonjaundiced patients without an obvious pancreatic mass, and patients with chronic
pancreatitis who develop jaundice.
EUS is a minimally invasive technique in which a high-frequency ultrasonographic probe is placed
into the stomach and duodenum endoscopically and the pancreas is imaged. Tumors appear as
hypoechoic areas in the pancreatic substance (Fig. 55-5). The strengths of EUS techniques for pancreatic
cancer are the clarification of small lesions (<2 cm) when CT findings are questionable or negative,
detection of malignant lymphadenopathy, detection of vascular involvement, and the ability to perform
EUS-guided FNA for definitive diagnosis and staging. EUS is not effective in assessing metastatic disease
to the liver. In patients for whom a tissue diagnosis is required (poor operative candidates or
undergoing neoadjuvant therapy), EUS-guided FNA has been used to acquire tissue samples for cytologic
analysis. This approach may avoid the risks of tumor seeding from percutaneous biopsy. The accuracy of
EUS without FNA averages 85% for determining T-stage and 70% for determining N-stage diseases. The
combination of EUS and FNA has a sensitivity of 93% and a specificity of 100% for T stage and an
accuracy of 88% for N stage.13 At the time of diagnosis, only 10% of patients have tumors confined to
the pancreas, 40% have locally advanced disease, and more than 50% have distant spread.
Figure 55-4. Endoscopic retrograde cholangiopancreatography in a patient with adenocarcinoma of the pancreas demonstrates a
stricture of both the distal common bile duct and the pancreatic duct (arrow).
1409
booksmedicos.org
Figure 55-5. Endoscopic ultrasonogram of a 2.2-cm mass in the head of the pancreas. The transducer tip is located in the
duodenum. The dilated common bile duct and gallbladder (GB) can be seen at the top of the image. The pancreatic duct (PD) is
also dilated. The mass involves the portal vein (PV).
Percutaneous FNA of pancreatic masses is helpful in selected patients. The technique is safe and
generally reliable but is of limited use in patients in whom surgical exploration for attempted resection
or palliation is planned. The reasons for not using FNA or percutaneous biopsy in potentially resectable
lesions are twofold. First, even after repeated sampling, a negative result does not exclude malignancy;
in fact, it is the smaller and likely more curable tumors that are likely to be missed by the needle. The
second concern is the potential for seeding of the tumor, either along the needle tract or with
intraperitoneal spread. Percutaneous biopsy is primarily indicated in patients with unresectable cancers
based on preoperative staging to direct palliative chemoradiation therapy or in patients with cancer in
the head of the pancreas in whom neoadjuvant protocols are being considered. Currently, however, EUS
is the preferred technique when possible in either situation.
PREOPERATIVE STAGING
The goal of preoperative staging of pancreatic cancer is to determine the feasibility of surgery and the
optimal treatment for each individual patient. Specific anatomy-based CT criteria can stratify patients
into four distinct groups (Table 55-9): (1) Resectable, (2) Borderline, (3) Locally advanced, or (4)
Metastatic. The extent of further staging to be performed depends on the individual patient and the
surgeon’s preference. Historically, patients with resectable CT criteria were offered operation as the
first modality of therapy followed by adjuvant chemotherapy or chemoradiotherapy. Recent advances in
the efficacy of systemic chemotherapy agents have further supported the hypothetical benefits of
preoperative neoadjuvant chemotherapy even for resectable tumors. Patients with borderline or locally
advanced pancreatic cancer based on CT criteria should receive preoperative chemotherapy or
chemoradiotherapy. Ideally, patients in these high-risk categories of disease should be offered
enrollment in clinical trials investigating novel treatment agents. Algorithm 55-2 outlines an algorithm
for approaching patients with pancreatic cancer after complete staging and determination of
resectability based on local vascular involvement according to CT findings.
STAGING LAPAROSCOPY
The use of diagnostic laparoscopy in pancreatic cancer remains controversial. Proponents believe that
laparoscopy can identify a substantial number of unresectable patients with advanced disease and,
therefore, should be uniformly applied to all patients with potentially resectable tumors.14 On the other
hand, opponents believe that the inherent cost of such a practice far outweighs the benefit to the small
number of patients in whom diagnostic laparoscopy is useful. The liver and peritoneum are the most
common sites of distant spread of pancreatic carcinoma. Once distant metastases have developed,
survival is so limited that a conservative approach is usually indicated. Liver metastases larger than 1
cm in diameter can usually be detected by CT, but approximately 30% of these metastases are smaller
1410
booksmedicos.org
and therefore may not be routinely detected. Moreover, peritoneal and omental metastases are usually
only 1 to 2 mm in size and frequently can be detected only by direct visualization. With the recent
improvements in CT imaging, the rate of unsuspected positive peritoneal findings approaches 10% to
15% for all patients. The percentage however varies with tumor location. Patients presenting with
obstructive jaundice secondary to tumors in the head of the pancreas typically have only a 15% to 20%
incidence of unexpected intraperitoneal metastasis after routine staging studies. In contrast, unexpected
peritoneal metastasis is found in up to 50% of patients with cancer of the body and tail of the
pancreas.15
Selective use of staging laparoscopy should be considered for patients at high risk of occult metastatic
disease (Table 55-10). The information gained from preoperative staging provides the basis for planning
therapy for each individual patient. If the results of preoperative staging with CT/MRI and laparoscopy
show localized disease, resectability rates may approach 90% for tumors in the head of the pancreas.
Table 55-9 Preoperative Staging based on CT Findings
Algorithm 55-2. Management strategy based on CT criteria for resectability of pancreatic cancer.
RESECTION OF PANCREATIC CARCINOMA

Carcinoma of the Head, Neck, or Uncinate Process
In 1912, Kaush16 reported the first successful resection of the duodenum and a portion of the pancreas
for an ampullary cancer. In 1935, Whipple et al.17 described a technique for radical excision of a
periampullary carcinoma. The operation was originally performed in two stages. A
cholecystogastrostomy to decompress the obstructed biliary tree and a gastrojejunostomy to relieve
gastric outlet obstruction comprised the first stage. The second stage was performed several weeks later
when the jaundice had resolved and the nutritional status had improved. During the second stage, an en
bloc resection of the second portion of the duodenum and head of the pancreas was performed without
reestablishing pancreatic–enteric continuity. Although earlier contributions had been made, the report
1411
booksmedicos.org
by Whipple et al. began the modern-day approach to the treatment of pancreatic carcinoma.
DIAGNOSIS
Table 55-10 Signs of High Risk of Occult Metastatic Disease
The operative management of pancreatic cancer consists of two phases: first, assessing tumor
resectability and then, if the tumor is resectable, completing a PD and restoring gastrointestinal
continuity. After the abdomen has been opened through an upper midline or bilateral subcostal incision,
a careful search for tumor outside the limits of a pancreaticoduodenal resection should be carried out.
The liver, omentum, and peritoneal surfaces are inspected and palpated, and suspect lesions are sampled
and specimens submitted for frozen-section analysis. Next, regional lymph nodes are evaluated for
tumor involvement. The presence of tumor in the periaortic lymph nodes of the celiac axis indicates that
the tumor is beyond the limits of normal resection. However, the presence of tumor-bearing lymph
nodes that normally would be incorporated within the resection specimen does not constitute a
contraindication to resection.
Once distant metastases have been excluded, the primary tumor is assessed in regard to resectability.
Local factors that preclude pancreaticoduodenal resection include retroperitoneal extension of the tumor
to involve the inferior vena cava or aorta or direct involvement or encasement of the superior
mesenteric artery, hepatic artery, and celiac axis. Involvement of the superior mesenteric vein (SMV),
or portal vein can be managed with venous resection and reconstruction in select cases. The technical
aspects of determining local resectability begin with a Kocher maneuver and mobilization of the
duodenum and head of the pancreas from the underlying inferior vena cava and aorta. Once the
duodenum and head of the pancreas are mobilized sufficiently, the surgeon’s hand can be placed under
the duodenum and head of the pancreas to palpate the relationship of the tumor mass to the superior
mesenteric artery. Inability of the surgeon to identify a plane of normal tissue between the mass and the
arterial pulsation indicates direct tumor involvement of the superior mesenteric artery, and the
possibility of complete tumor resection is eliminated.
The final step to determine resectability involves dissection of the superior mesenteric and portal
veins to rule out tumor invasion. Identification of the portal vein can be simplified greatly if the
common hepatic duct is divided and reflected early in the dissection. Once the hepatic duct has been
divided, the posteriorly located portal vein can be identified easily. After the anterior surface of the
portal vein is dissected posterior to the neck of the pancreas, the next step is to identify the SMV and
dissect its anterior surface. This is done most easily by extending the Kocher maneuver past the second
portion of the duodenum to include the third and fourth portions of the duodenum. During this
extensive kocherization, the first structure that one encounters anterior to the third portion of the
duodenum is the SMV. Alternatively the SMV may also be identified by tracing either the middle colic
vein or the right gastroepiploic vein back to the SMV after entering the lesser sac thru the gastrocolic
ligament. The anterior surface of the SMV then can be cleaned rapidly and dissected under direct vision
by retracting the neck of the pancreas anteriorly. The dissection is continued until it connects to the
portal vein dissection from above.
Most experienced pancreatic surgeons, at this point, proceed with a PD without obtaining a tissue
diagnosis. The clinical presentation, results of preoperative CT and cholangiography, and operative
findings of a palpable mass in the head of the pancreas surpass the ability of an intraoperative biopsy to
define the diagnosis of malignancy.
Having excluded regional and distant metastases and demonstrated no tumor involvement in major
vascular structures, the surgeon can proceed with PD with a high degree of certainty that the tumor is
1412
booksmedicos.org
resectable. In the pylorus-preserving modification of PD, the duodenum is first mobilized and divided
approximately 2 cm distal to the pylorus. If a classic Whipple procedure is to be performed, the stomach
is divided to include approximately 40% to 50% of the stomach with the resected specimen. The
gastroduodenal artery is exposed, ligated, and divided near its origin at the common hepatic artery. It is
always important to confirm, before ligation, that the structure to be ligated is indeed the
gastroduodenal artery and not a replaced right hepatic artery. Next, the neck of the pancreas is divided,
with care taken to avoid injury to the underlying superior mesenteric and portal veins. The portal and
superior mesenteric veins are then dissected from the uncinate process and head of the pancreas. At this
point, the fourth portion of the duodenum and the proximal jejunum are mobilized, with the proximal
jejunum divided approximately 10 cm distal to the ligament of Treitz. The proximal jejunum and fourth
portion of the duodenum are passed under the superior mesenteric vessels to the right, and the uncinate
process is dissected from the superior mesenteric artery clearing all of the tissue along the right border
of the artery. The course of the superior mesenteric artery should be clearly identified to avoid injury to
this structure. At this point, the specimen consisting of the gallbladder and common bile duct; the head,
neck, and uncinate process of the pancreas; the entire duodenum; and the proximal jejunum (and the
distal stomach for a traditional Whipple procedure) is freed completely and removed from the operative
field (Fig. 55-6). Margins should be inked to facilitate pathologic analysis of the specimen.
Figure 55-6. Pancreaticoduodenectomy. A: The tissue to be resected in a standard pancreaticoduodenectomy. B: Reconstruction

after a standard pancreaticoduodenectomy. C: Reconstruction after the pylorus-sparing variation.
Table 55-11 Randomized Prospective Trials of Standard Versus Extended

Lymphadenectomy for Pancreatic Cancer
1413
booksmedicos.org
There are a number of techniques for restoring gastrointestinal continuity after a pancreaticoduodenal
resection. Our preferred technique is to bring the end of the divided jejunum through the transverse
mesocolon in a retrocolic fashion and perform an end-to-side pancreaticojejunostomy. The anastomosis
is begun by placing a series of interrupted 3-0 silk sutures between the side of the jejunum and the
posterior capsule of the end of the pancreas. A small enterotomy is then made in the jejunum to match
the size of the pancreatic duct and an inner layer of interrupted 5-0 absorbable monofilament sutures
are used to create a duct-to-mucosa anastomosis. Some surgeons prefer to stent this anastomosis with
either a short indwelling pancreatic stent or an externalized pancreatic stent. The anastomosis is
completed with an outer layer of 3-0 silk sutures placed between the anterior pancreatic capsule and the
jejunum. An alternative to this duct-to-mucosa technique is to create an enterotomy approximately the
same size as the pancreatic neck and to complete a running anastomosis circumferentially around the
entire gland. This technique then allows invagination of the neck 1 to 2 cm into the lumen of the bowel
by the outer anterior layer of the anastomosis. The biliary–enteric anastomosis is performed 10 cm
distal to the pancreaticojejunostomy. An end-to-side hepaticojejunostomy is performed with a single
interrupted layer of 4-0 absorbable synthetic suture material. No T tube or stent is generally necessary.
Approximately 20 cm distal to the biliary–enteric anastomosis, an end-to-side duodenojejunostomy is
performed in an antecolic manner with an inner continuous layer of 3-0 absorbable synthetic suture
material and an outer interrupted layer of 3-0 silk. The final reconstruction is shown in Figure 55-6C.
Extent of Resection
Several technical aspects of PD remain controversial. These controversies include: (1) whether or not a
radical lymph node dissection is necessary, (2) should a pylorus preserving or classic PD be performed,
and (3) is there a role for laparoscopic pancreatic resections.
Several nonrandomized retrospective studies have advocated adding a radical (extended)
retroperitoneal lymph node dissection to PD in an attempt to improve survival. However, results from
four randomized prospective trials (Table 55-11)18–22 have shown extended lymph node dissections not
to be beneficial. The prospective trial performed by Pedrazzoli et al.18 suggested a survival advantage
to extended retroperitoneal lymph node dissection in patients with positive lymph nodes. Eighty-one
patients with pancreatic adenocarcinoma were randomized to either standard or radical
lymphadenectomy over 3 years at six different institutions. While the two groups were similar with
respect to preoperative parameters, operative morbidity, and overall survival, a subgroup analysis of
the 48 patients with positive lymph nodes showed a statistically significant survival advantage for
patients undergoing the extended lymph node dissection. However, the largest prospective randomized
trial from the Johns Hopkins Hospital failed to demonstrate a survival advantage for a radical resection
as compared with a classic PD.19 Two hundred and ninety-four patients undergoing resection for
periampullary adenocarcinoma were randomized between a standard resection (pylorus preserving PD
with en bloc resection of the anterior and posterior pancreaticoduodenal lymph nodes, lower
hepatoduodenal lymph nodes, and nodes along the right lateral aspect of the superior artery and vein)
and a radical resection (standard resection plus distal gastrectomy and retroperitoneal lymph node
dissection extending from the right renal hilum to the left lateral border of the aorta and from the
portal vein to the inferior mesenteric artery). The groups did not differ with respect to age, gender, site
of primary tumor, lymph node status, or margin status. There were no significant differences in 1-, 3-,
or 5-year and median survival when comparing the standard and radical groups (Fig. 55-7). However,
the radical group had a higher overall morbidity (43% vs. 29%) with significantly higher rates of
delayed gastric emptying and pancreatic fistula in addition to a longer postoperative hospital stay.
In 1978, Traverso and Longmire23 popularized the pylorus-preserving modification of the Whipple
procedure. Preserving antral and pyloric function, the pylorus-preserving Whipple procedure reduces
1414
booksmedicos.org
the incidence of troublesome postgastrectomy symptoms. A number of studies have documented that
gastrointestinal function is better preserved in the pylorus-sparing modification than in the traditional
operation. In addition, compared with the classic Whipple operation, the pylorus-preserving procedure
is less time-consuming and technically easier to perform. Concerns exist in the use of the pylorus-
preserving Whipple procedure for the management of periampullary tumors because of the possibility
of compromising the already small proximal surgical margin of resection. This question has been
addressed by a number of authors, and no difference appears to be found in survival among those
patients treated with the pylorus-sparing Whipple procedure and those managed by the traditional
Whipple resection.24–26 Therefore, many pancreatic surgeons favor pylorus-preserving PD because it
shortens the operative time, retains the entire stomach as a reservoir, and has a similar survival rate as
compared with the classic PD.
Figure 55-7. Actuarial survival for standard versus radical pancreaticoduodenectomy. From Yeo CJ, Cameron JL, Lillemoe KD, et
al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for
periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg
2002;236:355–366; discussion 366–368, with permission.
In recent years, significant advances have been made in the application of minimally invasive
techniques to the management of both benign and malignant pancreatic disorders. Initially, laparoscopic
pancreatic surgery was limited to diagnostic staging in patients with pancreatic cancer prior to
resection. More recently, minimally invasive techniques have been used to manage benign and
malignant lesions of the pancreas. While laparoscopic distal pancreatic resections are being performed
with increasing frequency,27 the role of minimally invasive PD remains controversial. Laparoscopic or
robotic PD is a technically demanding procedure due to the retroperitoneal location of the pancreas, its
intimate association with surrounding gastrointestinal and major vascular structures, and the need for
three separate anastomoses to complete the reconstruction. In addition, it is unclear whether an
adequate cancer operation can be performed with respect to lymph node harvest and margin status in
patients with malignancy. Currently, laparoscopic PD is only performed in a handful of specialized
centers (Table 55-12). The procedures are performed as either robotic, pure laparoscopic, hand assisted,
or as laparoscopic-assisted procedures with the resection being performed laparoscopically and the
reconstruction being completed via a “mini” laparotomy or through a hand port.
Carcinoma of the Body and Tail

The surgical management of adenocarcinoma of the body and tail of the pancreas is much more limited
than that of the head of the pancreas because of the extent of the disease usually present at the time of
symptomatic presentation. Most patients are unable to undergo resection, based on findings of major
vascular involvement on CT or peritoneal or liver metastases on laparoscopy. If an attempt at open
exploration for possible cure is undertaken, the exploration should be started with a search for evidence
of either metastatic disease to the liver or peritoneal implants. If this is not the case, the lesser sac is
opened, and the SMV is identified as it passes under the neck of the pancreas. If this vessel is normal,
and if the splenic vein does not appear to be obstructed preoperatively, a distal pancreatectomy with
splenectomy is performed. The spleen is mobilized, as is the distal pancreas, and an en bloc resection of
the structure, including the mass, is obtained. The resection should be extended as proximally as
possible, with the transected pancreas simply oversewn. The tumor bed should be marked with the
1415
booksmedicos.org
placement of clips for postoperative radiation therapy. If, as in most cases, the tumor cannot be
resected, a tissue biopsy should be performed, in addition to a chemical splanchnicectomy with alcohol
for pain management. In some cases, a prophylactic gastrojejunostomy may be indicated because of the
potential for obstruction by tumor at the ligament of Treitz.
Postoperative Results
4 During the 1960s and 1970s, many centers reported operative mortality following PD in the range of
20% to 40%, with postoperative morbidity rates as high as 40% to 60%. During the last three decades, a
dramatic decline in operative morbidity and mortality following PD has been reported at a number of
centers, with operative mortality rates in the range of 2% to 3%.33–35 The reasons behind this decline
appear to be the following: (a) fewer, more experienced surgeons are performing the operation on a
more frequent basis, (b) preoperative and postoperative care has improved, (c) anesthetic management
has improved, and (d) large numbers of patients are being treated at high-volume centers.36
Although the operative mortality rates for pancreatic cancer have been reduced significantly, the
complication rates approach 40% (Table 55-13). Pancreatic fistula remains the most frequent serious
complication following PD, with an incidence ranging from 5% to 15%. In the past, the development of
pancreatic fistula after PD was associated with mortality rates of 10% to 40%. Although the incidence of
pancreatic fistula following PD remains stable, the overall associated mortality rate has diminished
owing to improved management. Important supportive measures include careful maintenance of fluid
and electrolyte balance, parenteral nutrition, and controlling the pancreatic leak with percutaneous or
intraoperative drainage.
Table 55-12 Results for Minimally Invasive Pancreatoduodenectomy
COMPLICATIONS
Table 55-13 Complications After Pancreaticoduodenectomy
Long-Term Survival
5 Historically, 5-year survival rates for patients undergoing resection for adenocarcinoma of the head of
1416
booksmedicos.org
the pancreas were reported to be in the range of 5%. However, recent studies have suggested an
improved survival for patients following PD. In 2006, Winter et al.37 reported on 1,175 patients who
underwent operative resection for pancreatic adenocarcinoma. The actuarial 5-year survival for these
patients was 18%, with a median survival of 18 months (Fig. 55.8). In this study, factors found to be
important predictors of survival included tumor diameter (<3 cm), negative resection margin status,
well/moderate tumor differentiation, and postoperative chemoradiation treatment. Patients who
underwent resection with negative margins had a median survival of 20 months and a 5-year survival of
21%, whereas those with positive margins fared significantly worse, with a median survival of 14
months and a 5-year survival of 12%. The outcome was particularly favorable in the subgroup of
patients with small tumors (<3 cm) who underwent margin-negative, node-negative resections; the
median survival was 44 months and the 5-year survival was 43%.
ADJUVANT AND NEOADJUVANT THERAPY

6 At present, the general consensus of most surgeons treating patients with pancreatic carcinoma is that
any future improvement in survival for this disease will involve improvements in systemic therapy.
Despite advances in surgery and perioperative care that have resulted in markedly reduced
postoperative mortality after pancreatoduodenectomy, the median survival for pancreatic cancer
patients has changed minimally over the past two decades. Even with optimal surgical management, 5-
year survival averages 15% to 20% for resectable disease and 3% for all stages combined.
Approximately 85% of patients with resected pancreatic cancer will ultimately recur and die of their
disease. These outcomes suggest that in most cases pancreatic cancer is a systemic disease at the time of
diagnosis, making surgical resection alone inadequate therapy. The results of the most important
randomized prospective trials of adjuvant therapy for pancreatic cancer are summarized in Table 55.14.
In 1985, the Gastrointestinal Tumor Study Group reported encouraging results from a prospective,
randomized trial to evaluate the efficacy of adjuvant radiation and chemotherapy following curative
resection for adenocarcinoma of the head of the pancreas.38 Forty-three patients were randomized to
either adjuvant therapy with radiation and 5-fluorouracil (5-FU) or no adjuvant therapy. The median
survival for the 21 patients who received adjuvant therapy was 20 months, and three (14%) survived 5
years or longer. For the 22 patients who received no adjuvant therapy, the median survival was 11
months, and only 1 patient (4.5%) survived 5 years.
The randomized trial conducted by the European Organization for Research and Treatment of Cancer
(EORTC),39 sought to recapitulate the results of the GITSG study in 114 patients with pancreatic head
lesions (observation, n = 54 and adjuvant treatment, n = 60). However, chemotherapy (5-FU) given
during radiation was given as a continuous infusion (rather than via bolus) during each radiation
sequence, depending on toxicity, for up to 5 days. No chemotherapy was given postchemoradiation.
Fifty-six percent of patients received the intended chemotherapy dose during radiation. Patients in the
chemoradiation arm had a median survival of 17.1 months versus 12.6 months in the observation arm (p
= 0.099); 2- and 5-year overall survivals were 37% and 20%, respectively, for the experimental arm
and 23% and 10%, respectively, for the control arm.
The ESPAC-1 trial published in 2004 analyzed 289 patients recruited from 53 hospitals in a 2 × 2
factorial design.40 The four study groups included (1) surgery only (n = 69); (2) chemotherapy only (n
= 73) consisting of 5-FU, 425 mg/m2, and leucovorin, 20 mg/m2, given daily for 5 days every 4 weeks
for six cycles of treatment; (3) radiation therapy and 5-FU given (n = 75) according to the original
GITSG method; and (4) both treatments (n = 73, chemoradiation followed by chemotherapy). The
major study conclusions were that the 5-year overall survival comparisons between patients who
received chemotherapy versus those that did not (21% vs. 8%, p = 0.009) and those that received
radiation therapy versus those that did not (10% vs. 20%, p = 0.05). The authors concluded that
adjuvant chemotherapy had a beneficial effect in resected pancreatic cancer, whereas chemoradiation
had a deleterious effect. A quality-of-life questionnaire showed no difference between those that
received chemotherapy and those that did not, and those that received chemoradiation and those that
did not. Thus, the survival benefit of adjuvant chemoradiation for pancreatic cancer patients remains
unclear, and the optimal regimen has yet to be determined.
The RTOG 9704 trial, presented in abstract form in 2006,41 contained 442 eligible patients who
received adjuvant chemoradiation (5,040 cGy) given as continuous fractions with radiosensitizing doses
of 5-FU. The comparisons were with the addition of either three cycles of 5-FU (one prechemoradiation,
two postchemoradiation for 12 weeks) versus four cycles of gemcitabine (one prechemoradiation, three
1417
booksmedicos.org
postchemoradiation). Although the study showed no overall difference in aggregate survival, when
pancreatic head lesions only were considered (eliminating study results from resected lesions in the
pancreatic body or tail), both median survival (16.7 vs. 18.8 months) and overall survival at 3 years
(21% vs. 31%) favored the gemcitabine arm (p = 0.047). The study concluded that the addition of
adjuvant gemcitabine to postoperative 5-FU chemoradiation was superior to the addition of 5-FU.
Figure 55-8. Survival of patients with pancreaticoduodenectomy based on tumor size (A), lymph node status (B), margin status
(C), histologic grade (D), and historical context (E). From Winter JM. Cameron JL. Campbell KA, et al. 1423
pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 2006; 10:1199–210, with
permission.
TREATMENT
Table 55-14 Randomized Prospective Trials of Adjuvant Therapy for Pancreatic
Cancer
1418
booksmedicos.org
The CONKO-1 trial,42 conducted in Germany and Austria, represented a randomization of 368 patients
following R0 or R1 resection to either observation or an experimental arm of gemcitabine. After a
median follow-up time of 53 months, the median disease-free survival was 13.9 months in the
gemcitabine arm versus 6.9 months in the observation arm (p <0.001). There was no difference in
overall survival for the gemcitabine arm versus the control group – median survival was 22 versus 20
months. Although survival was not different, the authors concluded that postoperative gemcitabine
significantly delayed the development of recurrent disease after complete resection of pancreatic cancer
compared with observation alone and, thus, was supported as adjuvant therapy in resectable pancreatic
cancer.
At present, many centers are utilizing preoperative neoadjuvant chemoradiation for the treatment of
pancreatic cancer (Table 55-15). Neoadjuvant therapy offers several potential benefits including: (1)
delivery of treatment to well-oxygenated tissue which enhances efficacy of chemoradiation, (2)
downstaging can enhance ability to achieve a negative-margin resection and thereby reduce local
recurrence, and (3) avoidance of surgery in patients with rapidly progressive disease. Neoadjuvant
therapy can be completed without increasing the subsequent morbidity and mortality of surgical
resection. The group from the M.D. Anderson Cancer Center reported on the multimodality treatment of
142 consecutive patients with localized adenocarcinoma of the pancreatic head.43 A subset of 41 patients
treated by preoperative chemoradiation and pancreatoduodenectomy were compared with 19 patients
receiving pancreatoduodenectomy and postoperative adjuvant chemoradiation. Surgery was not delayed
for any patient who received preoperative chemoradiation because of chemoradiation toxicity, but 24%
of the eligible patients did not receive their intended postoperative chemoradiation because of delayed
recovery following PD. The patients treated with rapid fractionation were reported to have a
significantly shorter duration of treatment (median, 62.5 days) than patients who received
postoperative chemoradiation (median, 98.5 days). In early follow-up, no patient who received
preoperative chemoradiation experienced a local recurrence, and peritoneal recurrence developed in
only 10% of these patients. Local or regional recurrence developed in 21% of patients who received
postoperative chemoradiation. The overall survival curves were similar for both cohorts.
Wolff et al.46 examined 86 patients treated with weekly gemcitabine at a dose of 400 mg/m2 and 30
Gy of radiation. Sixty-one patients ultimately underwent resection (71%). The median survival in the
resected patients was 36 months which is significantly longer than those seen in regimens using 5-FU or
paclitaxel as the radiation sensitizer. Analysis of the specimens revealed two pathologic complete
responses and more than 50% nonviable tumor cells in 36 (59%). A gemcitabine-based regimen was also
used in a multi-institutional study of 20 patients reported by Talamonti et al.47 This group used full-dose
gemcitabine and limited field radiation to 36 Gy (2.4 Gy/fraction). The authors described 14 patients as
resectable and six as borderline resectable. Ultimately, all patients were explored and 17 resected
(85%), again representing a very high rate of resectability. A single pathologic complete response was
observed and, in 24% of tumors, greater than 90% of the tumor cells were felt to be nonviable. Also
notable was the low incidence (6%) of margin positivity in this trial. The median survival in the
resected patients was 26 months. Based on the results of these initial trials, gemcitabine-based
neoadjuvant regimens remain of considerable interest.
TREATMENT
Table 55-15 Selected Neoadjuvant Trials for Potentially Resectable Pancreatic
Cancer
1419
booksmedicos.org
PALLIATION
7 Unfortunately, it has been the experience nationwide that only a minority of patients with carcinoma
of the pancreas can undergo resection for possible cure at the time diagnosis is made. Therefore, the
optimal palliation of symptoms to maximize quality of life is of primary importance in most patients
with pancreatic cancer. Both operative and nonoperative options are available for the palliation of
pancreatic cancer.
Jaundice
Obstructive jaundice is present in most patients who have pancreatic cancer. If left untreated, it can
result in progressive liver dysfunction, hepatic failure, and early death. In addition, the pruritus
associated with obstructive jaundice can be debilitating and usually does not respond to medication.
When patients undergo exploration for possible cure and are found to have unresectable disease, a
biliary bypass should be performed.
Traditionally, surgeons have performed either choledochojejunostomy or cholecystojejunostomy for
the relief of malignant biliary obstruction. Both procedures are effective in relieving jaundice, but it
appears that the rate of recurrent jaundice after cholecystojejunostomy is approximately 10%.
Therefore, our preference for the palliation of obstructive jaundice is a hepaticojejunostomy or
choledochojejunostomy reconstructed with a Roux-en-Y limb of jejunum. The surgical palliation of
jaundice can be accomplished safely, with a mortality rate of less than 3% and an overall morbidity rate
of 30% to 40%.50 In recent years, nonoperative palliation has become available as an option for
managing patients who are deemed unresectable by preop staging. Plastic or metal stents can be placed
across the biliary obstruction by either an endoscopic or a percutaneous technique. For pancreatic
cancer, the endoscopic approach is usually preferred. The overall morbidity rate for endoscopic stenting
ranges up to 35%, but the rate of major procedure-related morbidity is less than 10%. Early
complications include cholangitis, pancreatitis, and bile duct or duodenal perforation. The major late
complications of stent placement are cholecystitis, duodenal perforation, and stent migration. Stent
occlusion can result in episodes of cholangitis and recurrent jaundice. For most patients, an exchange of
stents is required every 3 to 6 months. The newer metal stents appear to remain patent for longer
periods.
Nonoperative palliation appears to be associated with lower complication rates, lower procedure-
related mortality rates, and shorter initial periods of hospitalization in comparison with surgical
palliation. However, the rate of recurrent jaundice is higher. No advantage with respect to long-term
survival has been noted for either approach. Therefore, nonoperative palliation should be offered to
patients with advanced disease or poor performance status. Surgical palliation should be considered for
patients with an anticipated life expectancy of at least 6 months.
Duodenal Obstruction
At the time that pancreatic cancer is diagnosed, approximately one-third of patients have symptoms of
nausea or vomiting. Although true mechanical obstruction of the duodenum seen by radiologic or
endoscopic examination is much less frequent, duodenal obstruction develops in almost 20% of patients
before they die as the disease progresses.51 Duodenal obstruction can be caused in the C-loop by cancers
of the head or at the ligament of Trietz by cancers of the body and tail. In patients with evidence of
duodenal obstruction or impending obstruction, a gastrojejunostomy is indicated for palliation. This is
typically performed as a retrocolic, isoperistaltic loop gastrojejunostomy with a loop of jejunum 20 to
30 cm distal to the ligament of Trietz.
In patients with unresectable pancreatic cancer who do not have symptoms of gastric outlet
obstruction, whether or not to perform a prophylactic gastric bypass at the time of biliary bypass is a
1420
booksmedicos.org
matter of debate. Surgeons who do not perform a prophylactic bypass feel that it needlessly increases
the postoperative length of stay and can be associated with delayed gastric emptying and increased
morbidity and mortality. However, data from a prospective, randomized trial of prophylactic
gastrojejunostomy in patients with unresectable cancer do not support this view.52 In this study, 44
patients were randomized to a gastrojejunostomy, and 43 did not undergo gastric bypass. No mortality
occurred in either group. No difference was observed in either the complication rate or the
postoperative length of stay (Table 55-16). However, late duodenal obstruction developed in 19% of the
patients who did not undergo bypass. A recent multicenter prospective randomized controlled trial has
confirmed these results.53 Therefore, we believe that a prophylactic gastrojejunostomy should be
performed in patients undergoing surgical palliation for unresectable pancreatic carcinoma.
Pain
Tumor-associated pain can be incapacitating in patients with unresectable pancreatic cancer. The
postulated causes of tumor-associated pain are many and include tumor infiltration into the celiac
plexus, increased parenchymal pressure caused by pancreatic duct obstruction, pancreatic inflammation,
gallbladder distention resulting from biliary obstruction, and gastroduodenal obstruction. The
management of pain in patients dying of carcinoma of the pancreas is one of the most important aspects
of their care. The appropriate use of oral agents can be successful in most patients. Patients with
significant pain should receive their medication on a regular schedule and not on an “as-needed” basis.
The use of long-acting morphine derivative compounds appears to be best suited for such treatment.
Percutaneous neurolytic block of the celiac axis, performed under either fluoroscopic or CT guidance, is
also successful in the majority of patients at eliminating pain. Patients with unresectable cancer at the
time of surgical exploration should receive a chemical splanchnicectomy, with 20 mL of 50% alcohol
injected on either side of the aorta at the level of the celiac axis.54
MANAGEMENT
Table 55-16 Prospective Randomized Trial of Prophylactic Gastrojejunostomy in
Patients with Unresectable Periampullary Cancer
SUMMARY
8 The decision to perform nonoperative versus surgical palliation for pancreatic cancer is influenced by
a number of factors, including the patient’s symptoms, overall health status, predicted procedure-related
morbidity and mortality, and projected survival. Surgical palliation can be completed with acceptable
perioperative morbidity and mortality and postoperative length of stay. The avoidance of late
complications of recurrent jaundice, duodenal obstruction, and disabling pain would strengthen the
argument in favor of surgical palliation in those patients expected to survive 6 months or more.
Nonoperative methods of palliation should be considered for patients in whom preoperative staging
suggests distant metastatic disease or a locally unresectable tumor, patients who are not candidates for
operative intervention, and those not expected to survive more than 3 months.
Radiation and Chemotherapy for Unresectable Pancreatic Carcinoma

Specific antitumor therapies in patients with advanced pancreatic carcinoma have been studied for
years, with limited success. Trials evaluating the use of chemotherapy and radiation therapy both alone
and in combination have shown a marginal improvement in survival, often with relatively high toxicity
rates and some negative impact on quality of life. Recently gemcitabine, a deoxycytidine analog capable
of inhibiting DNA replication and repair, has become increasingly popular. When gemcitabine was
compared with bolus 5-FU in a randomized phase III trial, it was shown to confer a significant survival
benefit in advanced pancreatic cancer, increasing median survival from 4.4 to 5.7 months and increasing
1-year survival from 2% to 18%, respectively.55 A key end-point in this study was “clinical benefit
1421
booksmedicos.org
response,” based on reducing pain, improving performance status, and inducing weight gain, which was
attained in 24% of patients receiving gemcitabine compared with 5% for those receiving 5-FU. In
patients with metastatic pancreatic cancer that had progressed with 5-FU and then been treated with
gemcitabine, the median survival (in 63 of 74 patients enrolled) was 3.9 months.56 Seventeen patients
(27%) attained a clinical benefit response with a median duration of 14 weeks. Gemcitabine is generally
well tolerated with a low incidence of significant toxicity and therefore seems to be a reasonable choice
for palliative therapy.
Long before gemcitabine was established as an option for adjuvant therapy, it was approved in the
metastatic setting based on clinical benefit in patients who had symptomatic advanced disease.55 Over
the last two decades, several combinations of gemcitabine based chemotherapy have failed to improve
outcome in patients with metastatic disease. Recently, both FOLFIRINOX (5-FU, leucovorin, irinotecan,
and oxaliplatin) and nab-paclitaxel/gemcitabine were proven superior to gemcitabine alone in patients
with metastatic pancreatic cancer leading to improvement in response rate (RR), progression-free
survival (PFS) and OS.57,58 Objective response rates have improved by nearly fivefold with these newer
systemic regimens.
In addition to gemcitabine, other agents are currently being studied for a role in the palliation of
patients with pancreatic adenocarcinoma. Examples of such agents are paclitaxel (Taxol), matrix
metalloproteinase inhibitors (e.g., marimastat and perillyl alcohol), and inhibitors of angiogenesis, such
as TNP-470. The results of such studies are eagerly awaited.
References
1. American Cancer Society. Cancer Facts & Figures 2015. Atlanta: American Cancer Society; 2015.
2. Sohn TA, Yeo CJ, Cameron JL, et al. Resected adenocarcinoma of the pancreas 616 patients: results,
outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567–579.
3. Yeo CJ, Cameron JL. Pancreatic cancer. Curr Probl Surg 1999;36:61–152.
4. Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a
population based study. Gastroenterology 2005;129:504–511.
5. Takai E, Yachida S. Genomic alteration in pancreatic cancer and their relevance to therapy. World J
Gastrointest Oncol 2015;7:250–258.
6. Brune KA, Kliein AP. Familial pancreatic cancer. In: Lowy Am, Leach SD, Philip PA, eds. Pancreatic
Cancer. New York, NY: Springer Science + Buisness; 2008:65–79.
7. Brosens LA, Hackeng WM, Offerhaus GJ, et al. Pancreatic adenocarcinoma pathology: changing
“landscape.” J Gastrointest Oncol 2015;6:358–374.
8. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell carcinoma of the pancreas in the United
States: prognostic factors and comparison to ductal adenocarcinoma. J Gastrointest Surg
2008;12:2078–2086.
9. Farrell JJ. Prevalence, diagnosis and management of pancreatic cystic neoplasms: current status and
future directions. Gut and Liver 2015;9:571–589.
10. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas an
updated experience. Ann Surg. 2004;239:788–797; discussion 797–799.
11. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the
management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–197.
12. Ritts RE, Pitt HA. CA 19–9 in pancreatic cancer. Surg Oncol Clin North Am 1998;7:93–101.
13. Dye CE, Waxman I. Endoscopic ultrasound. Gastroenterol Clin North Am 2002; 31:863–879.
14. Conlon KC, Dougherty E, Klimstra DS, et al. The value of minimal access surgery in the staging of
patients with potentially resectable peripancreatic malignancy. Ann Surg 1996;223:134–140.
15. Barreiro CJ, Lillemoe KD, Koniaris LG, et al. Diagnostic laparoscopy for periampullary and
pancreatic cancer: what is the true benefit? J Gastrointest Surg 2002;6:75–81.
16. Kausch W. Das Carcinom der papilla duodeni and seine radikale entfeinung. Beitrage zur Klinische
Chirurgie 1912;78:439.
17. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg
1935;102:763–779.
18. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended lymphadenectomy associated
1422
booksmedicos.org
with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the
pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. Ann Surg
1998;228:508–517.
19. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal
gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma,
part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg
2002;236:355–366; discussion 366–368.
20. Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial comparing standard
pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in
resectable pancreatic head adenocarcinoma. Surgery 2005;138:618–630.
21. Nimura Y, Nagino M, Takao S, et al. Standard versus extended lymphadenectomy in radical
pancreatoduodenectomy for ductal adenocarcinoma of the head of the pancreas: long-term results
of a Japanese multicenter randomized controlled trial. J Hepatobiliary Pancreat Sci 2012;19:230–241.
22. Jang JY, Kang MJ, Heo JS, et al. A prospective randomized controlled study comparing outcomes
of standard resection and extended resection, including dissection of the nerve plexus and various
lymph nodes, in patients with pancreatic head cancer. Ann Surg 2014;259:656–664.
23. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg
Gynecol Obstet 1978;146:959–962.
24. Kozuschek W, Reith HB, Waleczek H, et al. A comparison of long term results of the standard
Whipple procedure and the pylorus preserving pancreatoduodenectomy. J Am Coll Surg 1994;
178:443–453.
25. Takada T, Yasuda H, Amano H, et al. Results of a pylorus-preserving pancreatoduodenectomy for
pancreatic cancer: a comparison with results of the Whipple procedure. Hepatogastroenterology
1997;44:1536–1540.
26. Tran KT, Smeenk HG, van Eijck CH, et al. Pylorus-preserving pancreaticoduodenectomy versus
standard Whipple procedure a prospective randomized multicenter analysis of 170 patients with
pancreatic and periampullary tumors. Ann Surg 2004;240:738–745.
27. Kooby D, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of
laparoscopic and open approaches. Ann Surg 2008;248:438–446.
28. Palanivelu C, Jani K, Senthilnathan P, et al. Laparoscopic pancreaticoduodenectomy: technique and
outcomes. J Am Coll Surg 2007;205:222–230.
29. Kendrick ML, Cusati D. Total laparoscopic pancreaticoduodenectomy: feasibility and outcome in an
early experience. Arch Surg 2010;145:19–23.
30. Asbun HJ, Stauffer JA. Laparoscopic vs open pancreaticoduodenectomy: overall outcomes and
severity of complications using the accordion severity grading system. J Am Coll Surg
2012;215:810–819.
31. Chalikonda S, Aguilar-Saavedra JR, Walsh RM. Laparoscopic robotic-assisted
pancreaticoduodenectomy: a case-matched comparison with open resection. Surg Endosc
2012;26:2397–2402.
32. Zureikat AH, Moser AJ, Boone BA, et al. 250 Robotic pancreatic resections: safety and feasibility.
Ann Sur 2013;258:554–562.
33. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the head of the
pancreas: 201 patients. Ann Surg 1995;221:721–733.
34. Richter A, Neidergethmann M, Sturm JW, et al. Long-term results of partial
pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience.
World J Surg 2003;27:324–329.
35. Schmidt CM, Powell ES, Yiannoutsos CT, et al. Pancreaticoduodenectomy: a 20-year experience in
516 patients. Arch Surg 2004;139:718–725; discussion 725–727.
36. Sosa JA, Bowman HM, Gordon TA, et al. Importance of hospital volume in the overall management
of pancreatic cancer. Ann Surg 1998;228:320–330.
37. Winter JM. Cameron JL. Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic
cancer: a single-institution experience. J Gastrointest Surg 2006;10:1199–1210.
38. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and
chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006–2010.
1423
booksmedicos.org
39. Kinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative
resection of cancer of the pancreas and periampullar region. Ann Surg 1999;230:776–782; discussion
782–784.
40. Neoptolemos JP, Stocken DD, Freiss H, et al. A randomized trial of chemoradiotherapy and
chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200–1210.
41. Regine WF, Winter KW, Abrams R, et al. RTOG 9704 a phase III study of adjuvant pre and post
chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. J Clin
Oncol 2006;24:18S.
42. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in
patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.
JAMA 2007;297:267–277.
43. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in
patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol
1997;15:928–937.
44. Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and
chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern
Cooperative Oncology Group Study. J Clin Oncol 1998;16:317–323.
45. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation
radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-
free outcome. J Clin Oncol 2002;20:2537–2544.
46. Wolff RA, Evans DB, Crane CH. Initial results of preoperative gemcitabine-based chemoradiation
for resectable pancreatic Adenocarcinoma (abstract). Proc Am Soc Clin Oncol 2002;21:130a.
47. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative
full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic
carcinoma. Ann Surg Oncol 2006;13:150–158.
48. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for
patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26(21):3496–
3502.
49. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation
effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single
institution experience. Oncology 2009;76(6):413–419.
50. Sohn TA, Lillemoe KD, Cameron JL, et al. Surgical palliation of unresectable periampullary
carcinoma in the 1990s. J Am Coll Surg 1999;188:658–666; discussion 666–659.
51. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of the pancreas. Surgery
1982; 91:123–133.
52. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for
unresectable periampullary cancer? Ann Surg 1999;230:322–328; discussion 328–330.
53. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophylactic gastrojejunostomy for
unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on
assessment of quality of life. Ann Surg 2003;238:894–902; discussion 902–905.
54. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with
unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 1993;217:447–455;
55. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with
gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J
Clin Oncol 1997;15(6):2403–2413.
56. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU
refractory pancreas cancer. Ann Oncol 1996;7:347–353.
57. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic
cancer. NEJM 2011;364(19):1817–1825.
58. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel
plus gemcitabine. NEJM 2013;369(18):1691–1703.
1424
booksmedicos.org
Chapter 56
Neoplasms of the Endocrine Pancreas

Harish Lavu, Jonathan R. Brody, and Charles J. Yeo
Key Points
1 Pancreatic endocrine neoplasms (PENs) originate from multipotential stem cells in pancreatic
ductules. Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged,
in favor of the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.
2 PENs have traditionally been classified according to the size and the mitotic rate of the tumor into
one of three categories: pancreatic endocrine microadenomas, well-differentiated PENs, and poorly
differentiated or high-grade endocrine carcinomas.
3 The most recent World Health Organization classification uses the combination of a proliferative
index (Ki-67) and mitotic rate to grade PENs while incorporating traditional TNM staging taking into
account tumor size, peripancreatic invasion, and metastatic spread to lymph nodes/distant locations,
which result in the classification of carcinoma.
4 The best initial imaging technique for a PEN is a high-quality multidetector computed tomography
(CT) scan.
5 Endoscopic ultrasonography is particularly useful in localizing tumors in patients with gastrinoma
and insulinoma.
6 Insulinomas may present with either neuroglycopenic symptoms (confusion, seizure, obtundation,
and coma) or hypoglycemic-induced symptoms (palpitations, diaphoresis, and tachycardia).
7 Ninety percent of insulinomas are solitary, 90% are sporadic, and 90% are benign with their location
evenly distributed throughout the pancreas.
8 Seventy-five percent of gastrinomas are sporadic (25% are associated with multiple endocrine
neoplasia type 1 syndrome), and all should be considered to be of malignant potential.
9 Most gastrinomas are located in the gastrinoma triangle and may be intrapancreatic, within the wall
of the duodenum, or in a peripancreatic lymph node, and in most cases local resection (enucleation)
may be adequate therapy.
10 Glucagonomas usually present with a characteristic severe dermatitis (termed necrolytic migratory
erythema) and are typically large and bulky and often with metastatic disease.
1 Pancreatic endocrine neoplasms (PENs) are rare tumors that account for 3% of pancreatic neoplasms
and 7% of all neuroendocrine tumors.1 Their incidence has increased nearly fivefold over the past 30
years, corresponding to the dramatic rise in the use of cross-sectional imaging in modern medicine. This
has led to an increase in the rate of incidental diagnoses in asymptomatic patients.2 First described by
Nicholls in 1902 as a tumor arising from pancreatic islet cells, these “islet cell adenomas” were long
thought to arise from the islets of Langerhans.3 Recent investigations have revealed that PENs more
likely originate from multipotential stem cells in pancreatic ductules.4,5 This non–islet cell origin has
been further demonstrated in tumors arising in patients with multiple endocrine neoplasia type1.6
Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged, in favor of
the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.7,8
2 Traditionally, PENs were classified according to their size and the mitotic rate of the tumor. This
system placed PENs into one of three categories: pancreatic endocrine microadenomas, well-
differentiated PENs, and poorly differentiated or high-grade endocrine carcinomas. PENs are also
differentiated by the presence (i.e., functional tumors) or absence (i.e., nonfunctional tumors) of a
syndrome due to hormone production, with nonfunctional PENs (91%) being much more common than
functional tumors (9%).9,10 The production of certain hormones by the functional tumors and their
resulting symptoms lead to well-described clinical syndromes, which are detailed later in this chapter.
PENs less than 0.5 cm in diameter are classified as pancreatic endocrine microadenomas.
1425
booksmedicos.org
Oncologically, they are considered to be benign lesions. Their prevalence is estimated to be as high as
10% of the population in autopsy series.11,12 Most pancreatic endocrine microadenomas are noted as
incidental findings in pancreata resected for other indications and, by definition, produce no neoplastic
syndromes (i.e., are nonfunctional). Functional PENs less than 0.5 cm are classified with well-
differentiated PENs.
PENs measuring greater than 0.5 cm in diameter and having a low mitotic rate of less than 10 mitoses
per 10 high-power fields are referred to as well-differentiated PENs. This group comprises the large
majority of clinically relevant PENs. They are uncommon, with an estimated incidence of approximately
1 out of 100,000 people.13,14 Although rare in children, cases have been described at all ages, and the
peak incidence occurs between the ages of 40 and 60 years.7 Overall distribution is equal between men
and women with some differences in ratio among different functional types.
3 The classification of PENs has in the past been controversial, with no single dominant staging
system in existence.15 Multiple varying staging schemes (including those by the European
Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC))16,17
have been put forward, attempting to establish prognostic characteristics such as size, mitotic count,
presence of necrosis, extrapancreatic invasion, vascular and perineural invasion, nuclear polymorphisms,
and nodal involvement.18–21 The most recent World Health Organization (WHO) classification attempts
to standardize PEN grading by using a proliferation-based system together with classical histopathologic
diagnostic criteria. This new classification takes into account the increasing importance of the
proliferative index Ki-67 as a prognostic marker for PENs. In this schema, PENs are graded into one of
three categories based upon their Ki-67 proliferation index and mitotic rate. These include two
categories of well-differentiated endocrine tumors and a third category of poorly differentiated
endocrine carcinomas. In this system, the well-differentiated tumors include those which are grade 1
(Ki-67 <3%, <2 mitoses per 10 hpf) and grade 2 (Ki-67 3% to 20%, 2 to 20 mitoses per 10 hpf).
Whereas, grade 3 (Ki-67 >20%, >20 mitoses per 10 hpf) tumors are considered poorly differentiated
carcinomas.22,23 By convention, the tumor is assigned the higher grade if the Ki-67 index and mitotic
rate differ. Any local invasion beyond the pancreas or metastatic spread to lymph nodes or distant
locations results in the classification of carcinoma (Table 56-1).
Table 56-1 WHO 2010 Classification of Well-Differentiated Pancreatic Endocrine

Tumors
Well-differentiated PENs can also be classified as functional or nonfunctional based on the presence or
absence of an associated clinically recognizable syndrome (Table 56-2). These syndromes are the result
of the secretion of biologically active hormones by the tumors and are confirmed by measurable
elevations of the hormones in the blood. The most common functional PENs include insulinomas,
gastrinomas, vasoactive intestinal polypeptide-omas (VIPomas), glucagonomas, and somatostatinomas.
The incidence of these lesions ranges from 1 per 1 million for insulinomas to 1 per 40 million for
somatostatinomas.24 Even less common PENs secreting calcitonin,25,26 parathyroid hormone–related
protein,27 growth hormone–releasing factor, and adrenocorticotropic hormone28 have been reported.
Nonfunctional PENs are classified as such due to their lack of an associated clinical syndrome. Some of
the tumors in this group do secrete elevated amounts of hormones, including chromogranin A, which
can be detected in either the serum or in surgical specimens using immunohistochemistry.29 These
secreted hormones either produce no clinical syndromes, as is seen with tumors that secrete pancreatic
polypeptide,30 or secrete hormones in subclinical amounts or inactive forms. Traditionally, functional
PENs were reported to comprise the majority of PENs. As methods of detecting these lesions and
patterns of presentation have evolved, due primarily to the widespread use of high-quality cross-
1426
booksmedicos.org
sectional imaging, nonfunctional PENs now comprise the vast majority of surgically resected cases.18,31
The least common group of PENs is the poorly differentiated or high-grade endocrine carcinomas.
These are aggressive tumors characterized by their high mitotic count and proliferation index (>20
mitotic figures per 10 high-powered fields, Ki-67 >20%).23,32 These tumors primarily occur in adults
and have a male predominance. Some have been reported to be functional, producing varied clinical
syndromes (commonly gastrinoma, VIPoma, glucagonoma, and, less frequently, insulinoma). Prognosis
is often poor, with the clinical course varying from a rapid decline to a more indolent, prolonged
survival.
Table 56-2 Classification of Functional Pancreatic Endocrine Tumors
MOLECULAR GENETICS
The majority of PENs are sporadic. Some of them, however, occur as part of inherited familial
syndromes such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel–Lindau (VHL) syndrome,
neurofibromatosis (NF-1), and tuberous sclerosis (TSC) (see section below on genetic syndromes) (Table
56-3). Recent advances in high throughput DNA sequencing techniques have provided new insights into
the genesis of PENs and possible reasons why certain tumors behave more aggressively than others as
well as why tumors may respond more favorable to specific therapies (i.e., a more personalized
approach to therapy of PENs).
Whole-Exome Sequencing of PENs

Specifically, in a 2011 landmark paper, Jiao et al. sequenced ∼18,000 coding genes of 10 clinically
well-characterized PENs.33 Technically, this work dovetailed eloquently and aligned with the group’s
previous work of sequencing and analyzing multiple pancreatic ductal adenocarcinoma genomes.34
Importantly, the investigators microdissected the samples in an effort to achieve a high purity and
quality of DNA from neoplastic tissue. In the PENs cancer genomes compared to pancreatic ductal
adenocarcinoma genomes a number of differences were discovered including >50% fewer mutations in
PENs compared to pancreatic adenocarcinoma genomes; and commonly mutated genes such KRAS were
not mutated in PENs (Table 56-4).35 These genetic data support the notion that the chromosomal
instability (CIN) and tumorigenesis process between these two pathologically distant pancreatic
neoplasms are initiated by unique molecular and/or environmental events. The study went on to
validate the common findings in the 10 PENs (labeled a discovery set) with an additional 58 PENs.
Validating previous work and also underscoring the importance of the disruption in the chromatin-
remodeling pathway in PENS, a majority of PENs harbored a tumor-specific inactivating mutation in
MEN-1. Additional genes functionally important in a chromatin-remodeling complex, DAXX (death-
domain–associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked), were
frequently mutated in PENs as well. Correlating the clinical outcomes of these tumors, the study
demonstrated that patients in this cohort with MEN-1, DAXX, and ATRX mutated tumors had unique
outcomes compared to the other PENs. More recent work published in 2014, correlated DAXX and ATRX
mutations, activation of alternative lengthening of telomeres, and global chromosomal alterations with
pathologic features and outcome data.36 Interestingly, this study identified that PENs harboring DAXX
1427
booksmedicos.org
and ATRX mutations were more likely to have CIN and patients with this subtype of PENs had a
reduction in survival.
Table 56-3 Familial Genetic Syndromes Associated with Pancreatic Endocrine

Neoplasms (PENs)
This landmark sequencing work underscored the potential clinical importance of mutations in the
mTOR pathway in a subset of PEN patients. As a reminder, the drug rapamycin targets mTOR, and thus,
this finding should provide the framework in which we may stratify PEN patients for TOR inhibitor–
based therapies (e.g., everolimus).33 As this work demonstrated that mTOR dysregulation may be an
important predictive marker, others have shown that in a large panel of neuroendocrine tumors (195 of
which only 19 where pancreatic) mTOR overexpression and/or its downstream-activated targets were
associated with worse clinical outcomes (i.e., adverse prognostic markers).37 This work provides
another instance where a poor prognostic marker (for even development of disease) may serve
counterintuitively as a positive predictive marker (for everolimus); an established biomarker, BRCA2,
acts in a similar fashion.
Table 56-4 Portal Vein Sampling
Genetic Links and Syndromes Related to PENs

Significant progress has been made in the genetic understanding of the MEN-1 syndrome in relation to
PENs.38 Chromosomal linkage studies have localized the genetic defect to the 11q13 locus, and studies
of DNA markers have localized the MEN-1 gene between PYGM and D11S97. The gene contains 10
exons that code for a 610-amino-acid protein called menin, whose function is unknown, although it is
classically labeled as a tumor suppressor gene. Some studies provide a possible explanation for loss of
this gene in neuroendocrine tumors.39 The menin protein is expressed in diverse tissues and is highly
conserved evolutionarily. Menin is predominately a nuclear protein, which binds to JunD and may
repress JunD-mediated transcription. Studies in patients with MEN-1 have shown allelic deletions at
chromosome 11q13 in nearly 100% of parathyroid tumors, 85% of nongastrinoma islet cell tumors, and
up to 40% of gastrinomas. In patients with sporadic tumors (without MEN-1), 11q13 deletions are seen
in about 25%, 20%, and almost 50% of parathyroid tumors, nongastrinoma PENs, and gastrinomas,
respectively. Recently it has been shown that a comprehensive genetic testing program for patients at
risk for MEN-1 can identify patients harboring a MEN-1 mutation almost 10 years before the
development of clinical signs or symptoms of disease.40 Since MEN-1 loss has been detected in both the
sporadic and the familial forms of PENs, the menin pathway is most likely involved in the overall
pathogenesis of this disease, whether familial or sporadic in nature.39
Less frequently than MEN-1, PENs may be associated with VHL syndrome. VHL syndrome is another
autosomal dominant inheritance disease that includes many clinical disorders41 including retinal
hemangioblastomas, cerebellar and medullary hemangioblastomas, and PENs. PENs are found in a small
percentage of patients with VHL syndrome. A mutation in the VHL gene, a tumor suppressor located on
chromosome 3p25–26, which regulates hypoxia-induced cell proliferation, is responsible. Although
1428
booksmedicos.org
germline mutations with loss of heterozygosity (LOH) are associated with this disease, it has been
proposed that other tumor suppressors most likely cooperate with VHL in order to form PENs. VHL-
mutated PENs have been shown to have specific defects in angiogenesis and hypoxia-inducible factor
pathways.42
NF-1 (von Recklinghausen disease) is an autosomal dominant disorder that produces a well-described
clinical syndrome characterized by café-au-lait spots and neurofibromas. These patients may develop
pancreatic somatostatinomas, often near the ampulla of Vater. The NF-1 gene is a tumor suppressor
gene located on 17q11.2 that encodes for neurofibromin, a regulator of the mammalian target of
rapamycin (mTOR) pathway. Loss of NF-1 results in mTOR activation and tumor development.43,44
Complementary Progression Modeling

Based on the data from the Marinoni study that attempted to molecularly subtype PENs,36 a stepwise
progression model of PENs were put forth: (1) initiation occurs (unknown mechanism); (2) DAXX/ATRX
mutations induce transformation; (3) alternative lengthening of telomere (ALT)45 activation and CIN;
(4) clonal heterogeneity and a selection of clones; and (5) metastases.36 Complementary to this work,
Zhang described a “double hit model” of PEN progression35 wherein a first mutational hit (e.g., MEN1
or p53) can induce cell cycle progression, even under harsh tumor microenvironment conditions (low
glucose). Then, the second hit (ATRX and mTOR) can cause cell growth and enhance cell invasion and
metastatic potential,35 even in the absence of cell–cell adhesion. These models highlight our recent and
enhanced knowledge of the molecular etiology of PEN. However, future work will need to define the
main initiating event that sets the stage for PEN transformation. Since KRAS activation appears to be
unnecessary, other nonclassical genetic events (e.g., epigenetics and posttranscriptional gene regulation)
should be surveyed as critical key events in this tumorigenesis process.
Molecular Targeting of PENs

In summary, PENs are becoming easier to characterize molecularly (and clinically) due to large scale
sequencing efforts and a better understanding behind the molecular biologic aspects of these pancreatic
tumors. Ongoing efforts to search for candidate genes and novel pathways that set the stage for CIN and
initiation of tumorigenesis in these tumors will aid in unraveling the molecular etiology of this disease
and perhaps even better druggable targets (see Table 56-4 for molecular pathways to target in PENs vs.
pancreatic ductal adenocarcinoma). Still, the molecular characterization of these tumors have helped to
pave the way for clinical trials targeting tyrosine kinases (e.g., sunitinib) and the mTOR pathways (e.g.,
everolimus). In fact, recent work explored targeting multiple points throughout the dysregulated
pathway (PI3K/AKT/mTOR) in PENs by combining PI3K inhibitors with mTOR inhibitors and
demonstrated that this combination may break initial and acquired drug resistance in PENs.46 Future
molecular interrogation of PENs combined with these types of preclinical targeting approaches should
continue to move the field closer to a personalized approach to treating PENs with better targeted
therapies.
PRESENTATION AND EVALUATION

There are three primary ways by which patients with PENs come to clinical attention: the incidental
discovery of a mass in the pancreas during cross-sectional imaging, symptoms secondary to the mass
effect of a lesion in the pancreas (i.e., obstructive jaundice or pain), and, as a consequence of the
symptoms of a syndrome associated with a functional PEN. As mentioned previously, incidentally
detected nonfunctional PENs currently comprise the majority of clinically relevant tumors. They are
typically hypervascular on imaging studies such as computed tomography (CT) or magnetic resonance
imaging (MRI). In the absence of any clinical syndrome, these lesions can be managed as any other
incidental pancreatic lesion. Typically, the size of a PEN at discovery guides decision making between
three standard options: serial observation, endoscopic ultrasound-guided biopsy, or definitive surgical
resection. Size greater than 2 cm is a standard stratification measure, with lesions larger than this
usually managed in a more aggressive fashion. If a nonfunctional PEN is suspected, baseline serum
levels of chromogranin A and pancreatic polypeptide can be useful diagnostic markers prior to surgical
resection. Chromogranin A is a 49-kDa protein contained within the neurosecretory vesicles of PENs,
whose levels should be measured prior to surgical resection and are expected to significantly decline in
the postoperative period with removal of the tumor burden. The chromogranin A levels can be tracked
over time to document tumor recurrence, often before the lesions become visible on cross-sectional
1429
booksmedicos.org
imaging studies.47 Pancreatic polypeptide is secreted by the PP cells of the islets of Langerhans and can
also be used to track patients with PENs, though its sensitivity (63%) is lower than that of
chromogranin A.48 Neuron-specific enolase is another tumor marker that is elevated in approximately
50% of PENs, most commonly in patients with pulmonary metastases.49
PENs presenting due to mass effect on surrounding structures resulting in jaundice, pain, or gastric
outlet obstruction are uncommon. These lesions should be addressed as any other symptomatic
pancreatic lesion with definitive surgical resection if clinically appropriate.
Patients presenting with symptoms from a functional PEN can be a diagnostic challenge. Three
general principles apply to the diagnosis and treatment of patients with suspected functional neoplasms
of the endocrine pancreas. One must first recognize the abnormal physiology or characteristic
syndrome. Patients are often misdiagnosed or have their symptoms disregarded for years before an
accurate diagnosis is reached. Characteristic clinical syndromes are well described for insulinoma,
gastrinoma, VIPoma, and glucagonoma. The somatostatinoma syndrome is nonspecific, much more
difficult to recognize, and exceedingly rare. Second is the detection of hormone elevations in the serum
by radioimmunoassay. Such assays are readily available for measuring insulin, gastrin, vasoactive
intestinal peptide (VIP), and glucagon. Assays for somatostatin, pancreatic polypeptide (PP),
prostaglandins, and other hormonal markers are less commonly available but can be obtained from
certain laboratories. The third step involves localizing and staging the tumor in preparation for possible
operative intervention (Algorithm 56-1).
LOCALIZATION AND STAGING

Computed Tomography
4 The initial imaging technique used to localize a PEN and stage the disease is high-quality
multidetector three-dimensional CT.50 The accuracy of CT in detecting primary PENs ranges from 64%
to 82% and depends largely on the size of the tumor.51,52 PENs are typically hyperdense (bright) on
arterial phases of imaging. Lesions that are obvious during the early arterial phase can become isodense
on later phases of imaging. Therefore, a multiphase approach is typically recommended.53,54 CT is
useful in assessing size and location of the primary tumor, proximity to visceral vessels, peripancreatic
lymph node involvement, and the presence or absence of liver metastases (Fig. 56-1).
Magnetic Resonance Imaging

MRI is increasingly used in the detection of PENs, particularly small lesions. They are especially well
visualized on T1- and T2-weighted images with fat suppression. MRI has the advantage of increased soft
tissue contrast without the administration of intravenous contrast when compared to CT.42 PENs
characteristically have high signal intensity on T2-weighted images.55 On dynamic contrast-enhanced
T1-weighted images, the tumors show the same typical enhancement pattern as on CT scan. The
sensitivity of MRI has been reported to be between 74% and 100%.51,52
1430
booksmedicos.org
Algorithm 56-1. Diagnosis and management of pancreatic endocrine neoplasms.
Somatostatin Receptor Scintigraphy (Octreoscan)

Somatostatin receptor scintigraphy (SRS) also plays an important role in imaging patients with
pancreatic endocrine tumors.56–62 In this technique, the octapeptide analog of somatostatin (Octreotide)
labeled with indium-111 is administered intravenously to patients in whom a PEN is suspected. Because
neuroendocrine tumors often express large numbers of somatostatin receptors on their cell surfaces (Fig.
56-2), the tracer preferentially identifies tumors. The overall sensitivity of SRS has been reported to
range from 74% to near 100% depending on the functional type of PEN.63 There is a significant false-
negative rate, indicating that negative SRS findings in patients with PENs should be viewed with
caution. Nonfunctional tumors and insulinomas seem to be localized less frequently by SRS, while SRS
performs well for gastrinoma, VIPoma, and glucagonoma. In addition, SRS appears to play a role in the
evaluation of patients with metastatic pancreatic endocrine tumors, especially in identifying
extrahepatic tumor spread. In a study by Frilling et al.,62 54% of patients with liver metastases had
extrahepatic tumor spread detected by SRS that was not detected by alternate imaging techniques.
Figure 56-1. Computed tomography with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The
neoplasm (arrow) is seen as a contrast-enhancing structure, 3 cm in diameter, in the tail of the pancreas posterior to the stomach
(S). (From Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, MO: Mosby;
1993:272, with permission.)
1431
booksmedicos.org
Figure 56-2. Octreotide scan (anterior view) in a patient with a large endocrine tumor in the tail of the pancreas (large dark mass,
upper right) and several hepatic metastases (upper left quadrant). A small amount of the tracer is seen in the bladder (lower
midline).
Endoscopic Ultrasound
5 Endoscopic ultrasonography (EUS) has also shown utility in localizing PENs.64–68 Rosch et al.67 were
able to localize 32 of 39 tumors (82%) correctly with EUS after CT had failed to locate the tumor (Fig.
56-3). In their experience, EUS was more sensitive than the combination of CT and visceral
angiography. A more recent study by Proye et al.69 evaluated preoperative EUS and SRS in 41 patients
with insulinoma and gastrinoma. The sensitivity and positive predictive value of EUS were 77% and
94%, respectively, for pancreatic tumors; 40% and 100%, respectively, for duodenal gastrinomas; and
58% and 78%, respectively, for metastatic lymph nodes. These results indicate that EUS is best at
detecting lesions in the head of the pancreas. It is less successful at evaluating the distal pancreas and
the duodenal wall. Additionally, the procedure is operator dependent.70 These results have been
duplicated by others and have led some to suggest that EUS should serve as the initial localization
procedure in patients with insulinoma and gastrinoma. Of note, the drawback to EUS is that it does not
evaluate accurately for hepatic metastatic disease; rather, it is more sensitive than CT for imaging the
duodenal wall, pancreatic parenchyma, and peripancreatic lymph nodes.
Intraoperative Ultrasound
Historically, the primary methods of localizing PENs intraoperatively have been visualization and
palpation. With the advent of laparoscopic exploration for PENs, intraoperative ultrasound has been
substituted for palpation. Results have been promising, with sensitivities reported between 75% and
90%.71,72
Figure 56-3. Endoscopic ultrasonographic image from a patient with an insulinoma (arrows) in the body of the pancreas. SV,
splenic vein. (From Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic
ultrasonography. N Engl J Med 1992;326:1721–1726, with permission.)
1432
booksmedicos.org
Figure 56-4. Schematic depiction of data from percutaneous transhepatic portal venous sampling (PTPVS) in a patient with an
insulinoma. Insulin levels are given in microunits per milliliter. These data localize the neoplasm to the head of the pancreas.
(Adapted from Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma by intraoperative ultrasonography. Surgery
1985;97:381–384.)
Venous Sampling
Percutaneous transhepatic portal venous sampling (PTPVS) and arterial stimulation with venous
sampling (ASVS) are two techniques that are used exclusively for the diagnosis and localization of PENs.
In a small number of cases, CT, MRI, SRS, and EUS are unsuccessful at localizing a PEN. When
insulinoma or gastrinoma are suspected, PTPVS may help in localizing the occult neoplasm.73–77 The
technique involves placing a catheter percutaneously through the liver into the portal vein and then
sequentially sampling for hormone levels in the splenic vein, superior mesenteric vein, and portal vein,
thereby regionalizing the location of hormone production (Fig. 56-4). The overall accuracy of this test
ranges from 70% to greater than 95% depending on the number of samples obtained, the persistence of
autonomous hormone production by the tumor, and the careful handling and assaying of all samples.
ASVS involves the selective visceral arterial injection of secretin or calcium with concurrent hepatic
venous sampling for either gastrin or insulin.78,79 Gastrinoma cells are known to respond to secretin by
releasing gastrin,80,81 and insulinoma cells are known to respond to calcium by releasing insulin. The
provocative secretogogue is serially injected through an arterial catheter into at least three sites – the
splenic, gastroduodenal, and inferior pancreaticoduodenal arteries. Samples are drawn from a hepatic
vein catheter before and immediately after each injection. The arterial supply to the occult tumor can
then be deduced based on which selective secretogogue injection is followed by a large increase in
hepatic vein hormone concentration (Fig. 56-5). This technique, particularly when combined with
intraoperative ultrasonography, results in a sensitivity of greater than 90%, essentially obviating the
need for blind resection in unlocalized insulinomas.71,82 Additionally, ASVS can differentiate the 5% of
patients with nesidioblastosis from those with insulinoma.83
SURGICAL EXPLORATION
At the time of surgical exploration for PEN, a complete evaluation of the pancreas and peripancreatic
regions is performed. The body and tail of the pancreas are exposed by dividing the gastrocolic ligament
and entering the lesser sac. This portion of the pancreas can be partially elevated out of the
retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second
portion of the duodenum has been elevated out of the retroperitoneum by means of the Kocher
maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully
assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumor are evaluated in all
cases, with particular attention paid to the duodenum, splenic hilum, small intestine and its mesentery,
peripancreatic lymph nodes, and reproductive tract in women. The goals of surgical therapy for PENs
include controlling the symptoms of hormone excess, safely resecting maximal tumor mass, and
preserving maximal pancreatic parenchyma. Management strategies, including preoperative,
intraoperative, and postoperative considerations, vary for the different types of endocrine neoplasms of
the pancreas.
1433
booksmedicos.org
Figure 56-5. Graphic depiction of the results of arterial stimulation with venous sampling (ASVS) in a patient with gastrinoma.
The rise in hepatic vein gastrin concentration (gastrin gradient) is plotted on the y-axis, and basal values are plotted on the x-axis:
1, 100% rise; 2, 200% rise; and so forth. A rise in the hepatic vein gastrin concentration observed after the injection of secretin into
the superior mesenteric artery (SMA) and gastroduodenal artery (GDA) localizes the neoplasm to the head of the pancreas or
duodenum. SPL, splenic artery. (Adapted from Thom AK, Norton JA, Doppman JL, et al. Prospective study of the use of intra-
arterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery 1992;112:1002–1028; discussion
1008–1009.)
INSULINOMA
Insulinoma is the most common functional neoplasm of the endocrine pancreas (Table 56-5). The
insulinoma syndrome is associated with the following features, known as Whipple triad84:
1. Symptoms of hypoglycemia during fasting
2. Documentation of hypoglycemia, with a serum glucose level typically below 50 mg/dL
3. Relief of hypoglycemic symptoms following administration of exogenous glucose
6 Autonomous insulin secretion in insulinomas leads to spontaneous hypoglycemia, with symptoms
that can be classified into two groups (Table 56-5). Neuroglycopenic symptoms include confusion,
seizure, obtundation, personality change, and coma. Hypoglycemia-induced symptoms, related to a
surge in catecholamine levels, include palpitations, trembling, diaphoresis, and tachycardia. In most
cases, patients consume carbohydrate-rich meals and snacks to relieve or prevent these symptoms.
Table 56-5 Insulinoma
Whipple triad is not specific for insulinoma. The differential diagnosis of adult hypoglycemia is
extensive and includes the following: reactive hypoglycemia, functional hypoglycemia associated with
gastrectomy or gastroenterostomy, nonpancreatic tumors, pleural mesothelioma, sarcoma, adrenal
carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism, chronic adrenal insufficiency,
extensive hepatic insufficiency, and surreptitious self-administration of insulin or ingestion of oral
hypoglycemic agents.
A common error made in evaluating a patient with suspected insulinoma is to begin with an oral
glucose tolerance test. Instead, insulinoma is most reliably diagnosed by means of a monitored fast (via
1434
booksmedicos.org
the withholding of exogenous glucose). During a monitored fast, blood is sampled for glucose and
insulin determinations every 4 to 6 hours and when symptoms appear. Hypoglycemic symptoms
typically occur when glucose levels are below 50 mg/dL, with concurrent serum insulin levels often
exceeding 25 microunits/mL. Additional support for the diagnosis of insulinoma comes from the
calculation of the insulin-to-glucose ratio at different times during the monitored fast. Normal persons
have insulin-to-glucose ratios below 0.3, whereas patients with insulinoma typically demonstrate
insulin-to-glucose ratios above 0.4 after a prolonged fast. Other measurable β-cell products synthesized
in excess in patients with insulinoma include C peptide and proinsulin. Elevated levels of both are
typically found in the peripheral blood of patients with insulinoma.
The possibility of the surreptitious administration of insulin or oral hypoglycemic agents should be
considered in all patients with suspected insulinoma. Levels of C peptide and proinsulin are not elevated
in patients who self-administer insulin. Additionally, patients self-administering either bovine or porcine
insulin may demonstrate anti-insulin antibodies in circulating blood. The ingestion of oral hypoglycemic
agents, such as sulfonylureas, can be assessed by means of standard toxicologic screening.
7 Insulinomas are evenly distributed throughout the pancreas, with one-third found in the head and
uncinate process, one-third in the body, and one-third in the tail of the gland.85 Less than 3% are located
outside the pancreas, with these lesions located in the peripancreatic area.86 Ninety percent are found to
be benign solitary adenomas amenable to surgical cure. Ninety percent of insulinomas are sporadic,
with approximately 10% being associated with the MEN-1 syndrome. In patients with MEN-1, the
possibility of multiple insulinomas must be considered, and recurrence rates are higher. In
approximately 10% of patients, insulinoma is metastatic to the peripancreatic lymph nodes or liver,
making the diagnosis of malignant insulinoma.
Figure 56-6. The technique for enucleating a benign pancreatic endocrine neoplasm with scissors (A) or electrocautery (B). C:
After enucleation, the site of excision is drained.
After the diagnosis of insulinoma has been confirmed biochemically, the appropriate localization and
staging studies described earlier are performed (typically CT and EUS). Once the lesion has been
localized,87 patients undergo surgical exploration, where the pancreas is assessed not only by operative
palpation but also by intraoperative ultrasonography. This allows for confirmation of preoperative
localization and evaluates for the presence or absence of multiple primary tumors. Small, benign tumors
that are not close to the main pancreatic duct can be removed by enucleation88 (Fig. 56-6), regardless of
their location in the gland. Larger tumors in the neck or proximal body may be resected via central
pancreatectomy.89–91 In the body and tail of the pancreas, insulinomas more than 2 cm in diameter and
those close to the pancreatic duct are most commonly removed via distal pancreatectomy. Large lesions
in the head or uncinate process of the gland may not be amenable to local resection and may
occasionally require pancreaticoduodenectomy for complete excision.92,93 Increasingly, experienced
surgeons are utilizing a laparoscopic approach to these tumors. Both laparoscopic pancreatectomy and
1435
booksmedicos.org
enucleation are now performed on a routine basis with excellent results.94–98
In rare instances, preoperative localization studies and intraoperative ultrasound fail to identify the
tumor. Intraoperative biopsy of the pancreatic tail may help make the diagnosis of nesidioblastosis as
the cause of hyperinsulism. Some authors have recommended a “blind” distal pancreatic resection to the
level of the superior mesenteric vein (60% to 70% pancreatectomy), in the hope of excising an
unidentified insulinoma in the body and tail. Others have suggested blind pancreaticoduodenectomy,
because the thickness of the gland in this region makes it more likely to harbor an occult neoplasm. The
favored approach at the current time is to defer any blind resection, close the patient without
pancreatectomy, and perform postoperative selective arterial calcium stimulation with hepatic venous
insulin sampling to allow for specific tumor localization and directed surgical excision at a second
operation.99
Approximately 10% of insulinomas are malignant, presenting with lymph node or liver metastases. In
the presence of hepatic metastases, resection of the primary tumor and accessible metastases should be
considered if it can be performed safely.100–102 Such tumor debulking can be helpful in reducing
hypoglycemic symptoms and improving long-term survival. In patients with unresectable disease,
medications such as diazoxide and octreotide can be used to reduce insulin secretion from the tumor,
minimizing hypoglycemia. One promising new treatment is everolimus, an oral rapamycin analog that
inhibits mammalian target of rapamycin (mTOR). In a pilot study of patients with refractory
hypoglycemia due to metastatic insulinoma, everolimus resulted in improved glycemic control.103
Dietary manipulations, including judicious spacing of carbohydrate-rich meals and the consumption of
nighttime snacks, can also reduce the number of hypoglycemic episodes. Multiple chemotherapeutic
regimens have been used including streptozocin, dacarbazine, doxorubicin, and 5-fluorouracil.104–106
Combination chemotherapy has yielded the highest response rates but has not been shown to be
curative.
GASTRINOMA (ZOLLINGER–ELLISON SYNDROME)

8 In 1955, Zollinger and Ellison described two patients with severe peptic ulcer disease and pancreatic
endocrine tumors and postulated that an ulcerogenic agent originated from the pancreatic tumor.107–109
It has been estimated that approximately 1 in 1,000 patients with primary duodenal ulcer disease and 2
in 100 patients with recurrent ulcer after ulcer surgery harbor gastrinomas.110 Seventy-five percent of
gastrinomas occur sporadically, and 25% are associated with the MEN-1 syndrome. Historically, the
majority of gastrinomas were found to be malignant, with metastatic disease present at the time of
initial workup. With increased awareness and screening for hypergastrinemia, the diagnosis of
gastrinoma is made earlier and a higher percentage of patients present with benign and potentially
curable neoplasms.111
Table 56-6 Gastrinoma
The clinical symptoms of patients with gastrinoma are a direct result of increased levels of circulating
gastrin (Table 56-6). Abdominal pain and peptic ulceration of the upper gastrointestinal (UGI) tract are
seen in up to 90% of patients. Diarrhea is seen in 50% of patients, with 10% having diarrhea as their
only symptom. Esophageal symptoms or endoscopic abnormalities resulting from gastroesophageal
reflux are seen in up to half of patients. The diagnosis of gastrinoma should be suspected in several
clinical settings, including the initial diagnosis of peptic ulcer disease, recurrent ulcer after medical or
surgical therapy, postbulbar ulcer, family history of ulcer disease, ulcer with diarrhea, prolonged
undiagnosed diarrhea, MEN-1 kindred, nongastrinoma pancreatic endocrine tumors (high association of
secondary hormone elevations), and prominent gastric rugal folds on UGI examination. Serum gastrin
1436
booksmedicos.org
levels should be obtained in all of these settings.
In most patients with gastrinoma, the fasting serum gastrin level is greater than 200 pg/mL. Gastrin
levels greater than 1,000 pg/mL in the setting of documented hyperacidity and ulcer disease are
virtually pathognomonic for gastrinoma. Because hypergastrinemia can occur in other pathophysiologic
states (Table 56-7), fasting hypergastrinemia alone is not sufficient for the diagnosis of gastrinoma.
Gastric acid analysis (or at least gastric pH testing) is critical in differentiating between ulcerogenic
(high levels of acid) and nonulcerogenic (low levels of acid) causes of hypergastrinemia. To obtain an
accurate gastric acid analysis, patients must not be taking antisecretory medications including histamine
(H2)-receptor antagonists or proton pump inhibitors (PPIs). The diagnosis of gastrinoma is supported by
a basal acid output above 15 mEq/hr in nonoperated patients, a basal acid output exceeding 5 mEq/hr
in patients with previous vagotomy or ulcer operations, or a ratio of basal acid output to maximal acid
output exceeding 0.6.
Table 56-7 Disease States Associated With Hypergastrinemia
Figure 56-7. Results of intravenous secretin stimulation tests in patients with atrophic gastritis (triangles), gastric outlet obstruction
(squares), and gastrinoma (circles). A positive test result, consistent with the presence of gastrinoma, is indicated by an increase
over basal serum gastrin levels of at least 200 pg/mL. (Adapted from Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: current
concepts in diagnosis and management. N Engl J Med 1987;317:1200–1209.)
After documenting that hypergastrinemia and excessive acid secretion exist, provocative testing with
secretin should be performed to differentiate between gastrinoma, antral G-cell hyperplasia or
hyperfunction, and the other causes of ulcerogenic hypergastrinemia. This is achieved with a secretin
stimulation test (Fig. 56-7). A baseline gastrin level is drawn. The patient is then stimulated with 2
units/kg of secretin as an intravenous bolus and subsequent gastrin samples are collected at 5-minute
intervals for 30 minutes. An increase in the gastrin level by more than 200 pg/mL above the basal level
supports the diagnosis of gastrinoma.
After the biochemical diagnosis of gastrinoma has been made, the gastric acid hypersecretion should
be pharmacologically controlled. The PPIs are now considered the drugs of choice for doing so.112,113
The dose is adjusted to achieve a nonacidic pH during the hour immediately before the next dose of the
drug. Typically, PPI doses needed for acid control exceed usual dosing levels. After the initiation of
antisecretory therapy, all patients should undergo imaging studies to localize the primary tumor and to
assess for metastatic disease.
If localization studies reveal unresectable hepatic metastases, the patient should undergo
percutaneous or laparoscopic-directed liver biopsy to obtain a definitive histologic diagnosis. These
patients should be maintained on long-term PPI therapy. Virtually all patients can be rendered
achlorhydric with an appropriate dose of PPIs. Patients noncompliant with antisecretory therapy who
experience complications related to their ulcer diathesis may require removal of the end organ (total
1437
booksmedicos.org
gastrectomy) if tumor resection is not possible. However, total gastrectomy, once the operation of
choice for gastrinoma, is now only rarely used.
9 If unresectable disease is not identified by staging studies, patients should be offered surgical
exploration with curative intent. On exploration, the entire abdomen should be assessed for areas of
extrapancreatic and extraduodenal gastrinomas. Most gastrinomas are found in the gastrinoma
triangle85,114 (Fig. 56-8), the area to the right of the superior mesenteric vessels, in the head of the
pancreas or in the duodenal wall. Both intraoperative ultrasound and intraoperative upper endoscopy
may be helpful in tumor localization. Transillumination of the duodenum may help identify small
duodenal gastrinomas.115,116 Well-encapsulated tumors less than 2 cm in size and distant from the
pancreatic duct can be enucleated. Those situated deep in the parenchyma may require partial resection
by pancreaticoduodenectomy or distal pancreatectomy. If no pancreatic tumor is identified, a
longitudinal duodenotomy should be performed at the level of the second portion of the duodenum in
search of duodenal microgastrinomas.117,118 Small gastrinomas in the duodenal wall can be locally
resected with primary closure of the duodenal defect. The routine use of duodenotomy increases the
short- and long-term cure rates in patients with sporadic gastrinoma, because such a duodenotomy
allows detection of more duodenal gastrinomas.119 Duodenotomy did not impact the occurrence of
hepatic metastases or disease-related mortality. In a small percentage of patients, gastrinoma is found
only in peripancreatic lymph nodes, with these lymph nodes harboring the apparent primary tumor.
Resection of these apparent lymph node primary gastrinomas has been associated with long-term
eugastrinemia and biochemical cure in up to half of cases.120 A review from the National Institutes of
Health identified likely primary lymph node gastrinomas in 26 of 176 gastrinoma patients (14.7%),
with 69% being eugastrinemic at a mean of 10 years after resection.121
Figure 56-8. Most gastrinomas are found within the gastrinoma triangle.
Occasionally, preoperative localization studies may identify the tumor in the gastrinoma triangle, but
at the time of exploration, the tumor is not demonstrable. Several surgical options are available at this
point. First, a parietal cell vagotomy has been proposed as a way to reduce antisecretory drug dose
requirements in patients on high-dose antisecretory drug therapy but without prior life-threatening
complications.122 However, this approach leaves behind potentially resectable gastrinoma and has lost
favor as an option. A second option is total gastrectomy; however, the availability of PPIs has
drastically reduced the need to perform this operation for gastrinoma. It may have a limited role in
patients whose tumors cannot be localized, if they cannot or will not take their PPIs. Like parietal cell
vagotomy, this leaves tumor behind. A third, controversial option in patients with localization to the
gastrinoma triangle is blind pancreaticoduodenectomy. Some argue this should include distal
gastrectomy, as duodenal gastrinomas may arise close to the pylorus and be left behind during a
pylorus-preserving resection.
Patients with sporadic gastrinomas tend to fare better following resection than those with MEN-1. In
a series of 151 patients reported by Norton et al.,123 123 had sporadic gastrinoma and 28 had MEN-1–
associated gastrinoma. Of those with sporadic gastrinoma, 34% were free of disease 10 years following
resection. None of the MEN-1 patients were free of disease at 10 years. A more recent review of 195
patients from the same institution demonstrated clear superiority of surgical intervention over other
treatment strategies.124 The rate of disease-related death was increased 23-fold in the group of patients
1438
booksmedicos.org
treated without surgery. These data provide compelling evidence that patients with sporadic gastrinoma
benefit from surgical exploration and complete tumor resection.
The management of gastrinoma in MEN-1 is not as clear. The surgical treatment of hypercalcemia
caused by parathyroid hyperplasia should precede any surgery for hypergastrinemia in patients with
MEN-1. In these patients, gastrin-secreting tumors are often multicentric and associated with lymph
node metastases. Although some groups have favored exploration only when MEN-1 gastrinoma tumors
exceed 3 cm, it seems that earlier intervention may be warranted.125,126 Unfortunately, more data from
an appropriate clinical trial are needed to better define the timing of surgery for MEN-1 gastrinoma.
In the 1950s and 1960s, most gastrinomas were diagnosed late in the course of the disease, when the
tumor burden was already significant. At that time, effective medical therapy did not exist, nor did
sophisticated radiographic localization and staging techniques. Patients often suffered multiple ulcer
complications, required total gastrectomy to control the ulcer diathesis, and typically succumbed to
continued tumor growth following gastrectomy. Recent reviews of patients with surgically treated
gastrinoma provide room for optimism.127–130 Currently, up to 35% of patients who undergo resection
with curative intent have been rendered eugastrinemic at follow-up. Cure rates approach 60% to 70%
when the extent of disease allows a complete resection.
Most patients with incurable metastatic disease eventually die of tumor growth and dissemination.
Multiple modalities have been used to treat such patients. Chemotherapy including streptozocin, 5-
fluorouracil, and doxorubicin provides response rates of less than 50%.131 Hormonal therapy with
octreotide may relieve symptoms, reduce hypergastrinemia, and diminish hyperchlorhydria.132,133 In
patients with hepatic metastases, aggressive resection for debulking,134–137 hepatic transplantation,138
hepatic artery embolization, and interferon therapy have all been used, with variable results.
VIPOMA (VERNER–MORRISON SYNDROME)

Synonyms for VIPoma include WDHA syndrome (watery diarrhea, hypokalemia, and either a

Greenfields Surgery Scientific Principles 6th Edition

Uploaded by

Copyright:

Available Formats

Greenfields Surgery Scientific Principles 6th Edition

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Greenfields Surgery Scientific Principles 6th Edition

Uploaded by

Copyright:

Available Formats

ERRNVPHGLFRVRUJ Greenfield’s

SURGERY Scientific Principles & Practice

Michael W. Mulholland, MD, PhD

Gilbert R. Upchurch, Jr., MD

Timothy M. Pawlik, MD, MPH, PhD

Illustrations by Holly R. Fischer, MFA

Copyright © 2017 Wolters Kluwer

Library of Congress Cataloging-in-Publication Data

Names: Mulholland, Michael W., editor.

Shehab Ahmad Redha AlAnsari, MD

Bradley D. Beasley, DPM, CWS

Elizabeth R. Benjamin, MD, PhD

Jonathan R. Brody, PhD

Carlos V.R. Brown, MD

Andrew M. Cameron, MD, PhD

Darrell A. Campbell, Jr., MD

Jayer Chung, MD, MSc

Kevin C. Chung, MD, MS

Bryan A. Cotton, MD, MPH

Kimberly A. Davis, MD, MBA

Jonathan D’Cunha, MD, PhD

M. George DeBusk, MD, MSc, FACS, FCCP

Demetrios Demetriades, MD, PhD

Robert L. Ferris, MD, PhD

Robert J. Fitzgibbons, Jr., MD

Julio Garcia-Aguilar, MD, PhD

Batya R. Goldwaser, DMD, MD

Niraj J. Gusani, MD, MS

Thomas S. Huber, MD, PhD

Craig M. Jarrett, MD, MBA

Leonard B. Kaban, MD, DMD

Jussuf T. Kaifi, MD, PhD

George Kasotakis, MD, MPH

Eric T. Kimchi, MD, MBA

Marijan Koprivanac, MD, MS

Jeffrey H. Kozlow, MD, MS

Devi Mukkai Krishnamurty, MD

William M. Kuzon, Jr., MD, PhD

David W. Larson, MD, MBA

Geoffrey T. Manley, MD, PhD

David J. Maron, MD, MBA

Peter T. Masiakos, MS, MD

Amit K. Mathur, MD, MS

Dianna Milewicz, MD, PhD

Charles C. Miller III, PhD

Michael W. Mulholland, MD, PhD

Satish N. Nadig, MD, PhD

Hari Nathan, MD, PhD

Erika Adams Newman, MD

John A. Olson, Jr., MD, PhD

Francis D. Pagani, MD, PhD

Richard N. Pierson III, MD

Thomas H. Quinn, MS, PhD

Reza Rahbar, DMD, MD

Steven E. Raper, MD, JD

John E. Rectenwald, MD, MS

Peter Rhee, MD, MPH

Taylor S. Riall, MD, PhD

William P. Robinson III, MD

Matthew R. Rosengart, MD, MPH

ERRNVPHGLFRVRUJ Greenfield’s